Combination therapy with multispecific antibody conjugates targeting her3 and trop2

Abstract

The present disclosure relates to use of multispecific antibody conjugates for combination therapy, and in particular, to use of multispecific antibody conjugates targeting HER3 and TROP2 in the combination therapy for non-small cell lung cancer.

Description

Combination therapy with multispecific antibody-drug conjugates targeting HER3 and TROP2

[0001] Cross-references to related applications

[0002] This application is based on and claims priority to Chinese Patent Application No. CN202510231025.0, filed on February 28, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the biomedical field, specifically to multispecific antibodies targeting HER3 and TROP2, their conjugates, and their use in combination therapy for cancer. Background Technology

[0004] Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent, accounting for approximately 85% of all lung cancer cases. According to the World Health Organization (WHO), approximately 2.2 million new lung cancer cases and 1.8 million deaths occurred globally in 2020. The high mortality rate of NSCLC is closely related to its insidious early symptoms and the fact that most patients are diagnosed at an advanced stage (stage III / IV). Traditional NSCLC treatment primarily involves surgical resection, radiotherapy, and chemotherapy, but the prognosis for advanced-stage patients is poor. With advancements in molecular biology, treatment has shifted towards precision medicine, centered on targeted therapies (such as EGFR-TKIs and ALK inhibitors) and immunotherapies (such as PD-1 / PD-L1 inhibitors). Despite significant progress in NSCLC treatment, the 5-year survival rate remains below 20%. Drug resistance (such as acquired resistance to EGFR-TKIs), tumor microenvironment heterogeneity, and the lack of effective biomarkers limit further improvements in efficacy. New drugs and therapies for NSCLC are still needed clinically.

[0005] As early as the beginning of the 20th century, Paul Ehrlich first proposed the concept of "magic bullets," hypothesizing that certain compounds could directly enter target tumor cells. Theoretically, these compounds could effectively kill cancer cells while remaining harmless to normal cells. One possible approach is to find markers that can distinguish tumor cells from normal cells, such as the HER2 molecule on the surface of breast cancer cells and the CD20 molecule on the surface of B-cell lymphoma cells. Since the advent of hybridoma technology in 1975, an increasing number of monoclonal antibodies targeting these tumor antigens have been developed. Although monoclonal antibody drugs have relatively good targeting properties, their killing effect on tumor cells is far less than that of chemotherapy. Therefore, a new concept, antibody-drug conjugates (ADCs), has emerged, aiming to improve the therapeutic window for tumors by bridging antibodies and cytotoxic substances with a linker.

[0006] Trophoblast cell surface antigen 2 (TROP2) is a single-transmembrane surface glycoprotein belonging to the GA733 gene family. It is primarily expressed in epithelial cells and regulates intracellular calcium levels. Evidence suggests that TROP2 can influence intracellular signaling pathways, playing a role in cell growth, proliferation, and transformation. During embryonic development, TROP2 protein plays a crucial role in placental formation, embryo implantation, stem cell proliferation, and organ development. Evidence indicates that TROP2 expression is upregulated in many tumor cells, and this upregulation can promote tumor growth, proliferation, and invasion. TROP2 is widely expressed in solid tumors; one study showed that 100% of squamous cell carcinomas (n=72) and 93.9% of adenocarcinomas (n=181) overexpress TROP2, as its expression is involved in signaling pathways related to tumor proliferation, migration, invasion, and metastasis. Therefore, high expression of Trop-2 is an adverse prognostic factor affecting overall survival in various solid tumors, including breast cancer. At the same time, given that the expression rate of Trop-2 can reach 78% in breast cancer, and as high as 78.5% in HR+ / HER2- breast cancer, and even as high as 95% in TNBC, Trop-2 has naturally become the "hottest target" for breast cancer after HER2.

[0007] Human epidermal growth factor receptor 3 (HER3), also known as ErbB3, is a cell surface receptor tyrosine kinase and a member of the ErbB family, which includes EGFR (ErbB1), HER2 / neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Discovered in 1989, no drugs targeting HER3 have been approved in the more than 30 years since. HER3 overexpression is common in various cancers. Unlike other molecules in the HER family, HER3 lacks intracellular kinase activity, but it can phosphorylate tyrosine kinases by forming heterodimers with other receptors, such as HER2. The ligand-induced dimerization of the receptor facilitates intracellular signal transduction via PI3K / AKT and MAPK / ERK signaling, playing a crucial role in cell survival and proliferation, ultimately leading to tumor progression. Recent studies suggest that HER3 overexpression may be associated with poor prognosis in many solid tumors, including breast cancer, gastric cancer, ovarian cancer, and melanoma. Summary of the Invention

[0008] In a first aspect, this disclosure relates to a method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a platinum-based chemotherapy drug, and optionally a PD-1 inhibitor, to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0009] Secondly, this disclosure relates to a pharmaceutical combination comprising the aforementioned protein-drug conjugate and a platinum-based chemotherapy drug, and optionally a PD-1 inhibitor.

[0010] Thirdly, this disclosure also relates to the use of the protein-drug conjugate in combination with platinum-based chemotherapy drugs, and optionally PD-1 inhibitors in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0011] Fourthly, this disclosure relates to a pillbox containing the pharmaceutical combination described in the second aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0012] Fifthly, this disclosure relates to a combination of medicines for the treatment and / or prevention of non-small cell lung cancer (NSCLC) or a kit for the fourth aspect.

[0013] Sixthly, this disclosure relates to the use of the pharmaceutical combination of the second aspect or the medicament of the fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0014] Seventhly, this disclosure relates to the use of the pharmaceutical combination of the second aspect or the medicament of the fourth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0015] Eighthly, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with platinum-based chemotherapy drugs and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0016] The protein-drug conjugate is used in the preparation of a drug for use in combination with platinum-based chemotherapy drugs and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0017] The use of the protein-drug conjugate, which is used in combination with platinum-based chemotherapy drugs and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0018] Ninthly, this disclosure relates to platinum-based chemotherapy drugs used in combination with the aforementioned protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0019] The use of platinum-based chemotherapy drugs in the preparation of medicaments for use in combination with the protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0020] Use of platinum-based chemotherapy drugs, wherein the platinum-based chemotherapy drugs are used in combination with the protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0021] In a tenth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with platinum-based chemotherapy agents and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0022] Eleventhly, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0023] In a twelfth aspect, this disclosure relates to a pharmaceutical combination comprising the protein-drug conjugate and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).

[0024] In a thirteenth aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0025] In a fourteenth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the twelfth aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0026] In the fifteenth aspect, this disclosure relates to a pharmaceutical combination of the twelfth aspect or a medicine box of the fourteenth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0027] In the sixteenth aspect, this disclosure relates to the use of the pharmaceutical combination of the twelfth aspect or the medicament of the fourteenth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0028] In a seventeenth aspect, this disclosure relates to the use of the pharmaceutical combination of the twelfth aspect or the medicament of the fourteenth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0029] Eighteenthly, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0030] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0031] The use of the protein-drug conjugate, which is used in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0032] In a nineteenth aspect, this disclosure relates to an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for use in combination with the aforementioned protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0033] Use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the preparation of medicaments for use in combination with said protein-drug conjugates for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0034] Use of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC) in combination with the protein-drug conjugate.

[0035] In a twentieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0036] In a twentieth aspect, this disclosure relates to a method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering to a subject in need a protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF, and optionally a platinum-based chemotherapy drug, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0037] In a twentieth aspect, this disclosure relates to a pharmaceutical combination comprising the protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF, and optionally a digoxin-based chemotherapy drug.

[0038] In a twentieth aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with a bispecific antibody targeting PD-1 / VEGF, and optionally a platinum-based chemotherapy drug in the preparation of a drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0039] In a twentieth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the twentieth aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0040] In the twentieth aspect, this disclosure relates to a pharmaceutical combination of the twentieth aspect or a medicine box of the twentieth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0041] In a twentieth aspect, this disclosure relates to the use of the pharmaceutical combination of the twentieth aspect or the medicament of the twentieth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0042] In a twentieth aspect, this disclosure relates to the use of the pharmaceutical combination of the twentieth aspect or the medicament of the twentieth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0043] In a twentieth aspect, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0044] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0045] The use of the protein-drug conjugate, which is used in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0046] In a twentieth aspect, this disclosure relates to a bispecific antibody against PD-1 / VEGF, used in combination with the aforementioned protein-drug conjugate and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0047] The use of a PD-1 / VEGF bispecific antibody in the preparation of a drug for use in combination with the protein-drug conjugate, and optionally with platinum-based chemotherapy drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0048] Use of the PD-1 / VEGF bispecific antibody, wherein the PD-1 / VEGF bispecific antibody is used in combination with the protein-drug conjugate, and optionally with a platinum-based chemotherapy drug, for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0049] In a thirtieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0050] In a thirtieth aspect, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and docetaxel to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0051] In a thirty-second aspect, this disclosure relates to a pharmaceutical combination comprising the said protein-drug conjugate and docetaxel.

[0052] In a thirty-third aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with docetaxel in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0053] In a thirty-fourth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the thirty-second aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0054] In the thirty-fifth aspect, this disclosure relates to a pharmaceutical combination of the thirty-second aspect or a medicine box of the thirty-fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0055] In the thirty-sixth aspect, this disclosure relates to the use of the pharmaceutical combination of the thirty-second aspect or the medicament of the thirty-fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0056] In a thirty-seventh aspect, this disclosure relates to the use of the pharmaceutical combination of aspect thirty-two or the medicament of aspect fourteen in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0057] In a thirty-eighth aspect, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0058] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0059] The use of the protein-drug conjugate, which is used in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0060] Thirty-ninthly, this disclosure relates to docetaxel, used in combination with the said protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0061] The use of docetaxel in the preparation of a medicament for use in combination with the protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0062] The use of docetaxel, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with the protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0063] In a fortieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0064] In a forty-first aspect, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering to a subject in need a protein-drug conjugate and a PD-1 inhibitor and optionally a diplatin-based chemotherapy drug, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0065] In a forty-second aspect, this disclosure relates to a pharmaceutical combination comprising the aforementioned protein-drug conjugate and a PD-1 inhibitor, and optionally a diplatin-based chemotherapy drug.

[0066] In aspect forty-three, this disclosure also relates to the use of the protein-drug conjugate in combination with a PD-1 inhibitor and optionally a diplatin-based chemotherapy drug in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0067] In a forty-fourth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in aspect forty-two, optionally, the pillbox further containing pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0068] In aspect forty-five, this disclosure relates to a pharmaceutical combination of aspect forty-two or a medicine box of aspect forty-four for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0069] In aspect forty-six, this disclosure relates to the use of the pharmaceutical combination of aspect forty-two or the medicament of aspect forty-four for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0070] In a forty-seventh aspect, this disclosure relates to the use of the pharmaceutical combination of aspect forty-two or the medicament of aspect forty-four in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0071] In aspect forty-eight, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0072] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0073] The use of the protein-drug conjugate, which is used in combination with PD-1 inhibitors and optionally platinum-based chemotherapy drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0074] In aspect forty-nine, this disclosure relates to a PD-1 inhibitor for use in combination with the aforementioned protein-drug conjugate and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0075] Use of PD-1 inhibitors in the preparation of medicaments for use in combination with the protein-drug conjugates, and optionally with platinum-based chemotherapy agents for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0076] Use of the PD-1 inhibitor, wherein the PD-1 inhibitor is used in combination with the protein-drug conjugate and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0077] In a fiftieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0078] As described above in various aspects, such as the first through fiftieth aspects of this disclosure, they are described in more detail below. Various variations of the aspects described in this disclosure, including those not directly described, are also included within the scope of this disclosure, provided they do not depart from its intent. Attached Figure Description

[0079] Figure 1 shows the overall reaction formula for preparing antibody A-ADC from antibody A.

[0080] Figure 2 shows the MS comparison results of the conjugated product antibody A-ADC and the naked antibody A.

[0081] Figure 3 shows the tumor volume change curves in the HCC827 CDX model under different doses of antibody A-ADC.

[0082] Figure 4 shows the tumor volume change curves in the NCI-N87 CDX model under different doses of antibody A-ADC.

[0083] Figure 5 shows the tumor volume change curves in a human lung cancer PDX model resistant to osimertinib under different doses of antibody A-ADC.

[0084] Figure 6 shows the tumor volume change curves in the HCC827 CDX model under the action of antibody A-ADC and different doses of positive control drugs. The arrows marked on the horizontal axis (time axis) indicate the specific time points of the four drug administrations. Detailed Implementation

[0085] Terminology Definition

[0086] Unless otherwise indicated or defined, all terms used herein have their ordinary meaning as will be understood by those skilled in the art. References include, for example, standard manuals such as Sambrook et al., “Molecular Cloning: A Laboratory Manual” (2nd edition), Volumes 1–3, Cold Spring Harbor Laboratory Press (1989); Lewin, “Genes IV”, Oxford University Press, New York (1990); and Roitt et al., “Immunology” (2nd edition), Gower Medical Publishing, London, New York (1989), and general prior art cited herein; furthermore, unless otherwise stated, all methods, procedures, techniques, and operations not specifically detailed herein can and have been performed in a manner known per se as will be understood by those skilled in the art. Also refer to, for example, standard manuals, the aforementioned general prior art, and other references cited therein.

[0087] Unless otherwise stated, the singular form also represents the plural form, and vice versa.

[0088] The term "about," when used in conjunction with a numerical value, means to encompass a range of values ​​having a lower limit that is 5%, 4%, 3%, 2%, or 1% smaller than the specified numerical value and an upper limit that is 5%, 4%, 3%, 2%, or 1% larger than the specified numerical value. When the term "about" is used in conjunction with a numerical range, it is intended to encompass a range of values ​​whose lower limit is 5%, 4%, 3%, 2%, or 1% smaller than the lower limit of the range associated with "about," and whose upper limit is 5%, 4%, 3%, 2%, or 1% larger than the upper limit of the range associated with "about." When the term "about" is used in conjunction with multiple numerical values ​​or ranges, it indicates that each of the stated numerical values ​​or ranges is individually associated with the term "about."

[0089] As used herein, the term "and / or" means any one of the options or two or more or all of the options. For example, the expression "A and / or B" includes the following cases: A alone; B alone; and A+B. The expression "A and / or B and / or C" includes the following cases: A alone; B alone; C alone; A+B combined; A+C combined; B+C combined; and A+B+C combined.

[0090] The term "complete antibody" or "full-length antibody" or "all antibody" may be used interchangeably herein, generally referring to an immunoglobulin molecule composed of two pairs of identical polypeptide chains (each pair having one "light" (L) chain and one "heavy" (H) chain). Antibody light chains can be classified as κ and λ light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within both the light and heavy chains, variable and constant regions can be linked by a "J" region of approximately 12 or more amino acids, and the heavy chain may also contain a "D" region of approximately 3 or more amino acids. The heavy chain can consist of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region can consist of three domains (CH1, CH2, and CH3). The light chain can consist of... The antibody consists of a variable region (VL) and a constant region (CL). The constant region can consist of a single domain (CL). The constant region mediates the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can be further subdivided into highly degenerated regions (called complementarity-determining regions (CDRs)) interspersed with more conserved regions called framework regions (FRs). For example, the VH and VL can each contain or consist of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus, in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy chain / light chain pair form the antibody binding site.

[0091] The term "antibody fragment" or "antigen-binding fragment" refers to a molecule distinct from a full-length antibody that comprises a portion of the full-length antibody and retains the ability to specifically bind an antigen (i.e., bind the same antigen to a full-length antibody from which the portion or fragment is derived). Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; biantibodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent antibodies or fragments thereof; and camelid antibodies (heavy chain antibodies). The term also covers fragments of bispecific or multispecific antibodies, and / or bispecific or multispecific antibodies formed from antibody fragments.

[0092] The complementarity-determining region (CDR) or CDR is a region within the antibody variable domain that is highly variable in sequence and forms a structurally defined loop ("hypervariant loop") and / or contains antigen contact residues ("antigen contact sites"). The CDR is primarily responsible for binding to antigen epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus. CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while those located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any or a combination of many known antibody CDR assignment systems, including, for example: Chothia (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)) based on antibody three-dimensional structure and CDR loop topology; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDapartment of Health and Human Services, National Institutes of Health (1987)) based on antibody sequence variability; AbM (University of Bath); Contact (University College London); International ImMunoGeneTics. The database (IMGT) (www.imgt.cines.fr / ) and the North CDR definition based on affinity propagation clustering of a large number of crystal structures (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)). Unless otherwise specified, this disclosure adopts the Kabat scheme definition.

[0093] The term "antibody" is not limited to any particular method of producing antibodies. For example, it includes, in particular, recombinant antibodies, monoclonal antibodies, and polyclonal antibodies. Antibodies can be different isotypes of antibodies, such as IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[0094] As used herein, the terms “antigen-binding protein,” “binding protein,” or “binding molecule” include a molecule containing at least one antigen-binding site, wherein said site specifically binds to a target molecule. An antigen-binding protein may be an antibody, such as a full-length antibody, or an antigen-binding fragment of an antibody, or a chimeric antigen receptor (CAR), or any other polypeptide with a higher-than-normal affinity, such as a scaffold protein, a cyclic peptide, a soluble receptor, a receptor-antibody (Rab) protein, or fragments of these polypeptides. The target molecule may be any molecule, but in particular herein it may be HER3, TROP2, and especially conformational epitopes of HER3 and TROP2.

[0095] As used herein, the term "multispecific antigen-binding protein" is used in the broadest sense to refer to a binding protein capable of binding (preferably specifically binding) two or more antigens. Without being bound by theory, in general, a multispecific antigen-binding protein comprises a plurality of relatively independent structures, each providing binding specificity against said plurality of antigens. For example, said plurality of structures independently contain one or more binding sites against their respective target antigens; for example, at least one of said plurality of structures is an antibody or antibody fragment. In some aspects, at least one binding specificity is provided by an antibody. In some aspects, at least one binding specificity is provided by a full-length antibody. In some aspects, at least one binding specificity is provided by a VHH domain. In some aspects, a multispecific binding protein is a bispecific antibody.

[0096] In this disclosure, the term "bispecific antibody" generally refers to an antibody capable of binding to two antigens or antigenic epitopes, respectively. In some embodiments of this disclosure, the bispecific antibody may include light and heavy chains of an antibody capable of specifically binding to a first antigen or antigenic epitope, and light and heavy chains of an antibody capable of specifically binding to a second antigen or antigenic epitope. In some embodiments of this disclosure, the bispecific antibody may include a VHH domain capable of specifically binding to a first antigen or antigenic epitope, and light and heavy chains of an antibody capable of specifically binding to a second antigen or antigenic epitope.

[0097] The term "epitope" or "antigenic epitope" generally refers to a site on an antigen that is specifically bound by an immunoglobulin or antibody. "Epitope" is also known in the art as an "antigenic determinant." An epitope or antigenic determinant typically consists of chemically active surface groups of a molecule, such as amino acids or carbohydrate or sugar side chains, and usually has specific three-dimensional structural features and specific charge characteristics. For example, an epitope typically comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or discontinuous amino acids in a unique spatial conformation, which can be "linear" or "conformal." See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GEMorris, Ed. (1996). In a linear epitope, all points of interaction between the protein and the interacting molecule (e.g., an antibody) are linear along the primary amino acid sequence of the protein. In a conformational epitope, points of interaction are separated by protein amino acid residues.

[0098] The term "specificity" refers to the number of different types of antigens or epitopes that a particular antigen-binding molecule or antigen-binding protein can bind. Specificity can be determined based on the affinity and / or cohesion of the antigen-binding protein. Affinity, expressed as the dissociation equilibrium constant (KD) between the antigen and the antigen-binding protein, is a measure of the strength of binding between the epitope and the antigen-binding site on the antigen-binding protein: the smaller the KD value, the stronger the binding between the epitope and the antigen-binding protein (or, affinity can also be expressed as the association constant (KA), which is 1 / KD). As those skilled in the art will understand, affinity can be determined in known ways depending on the specific antigen of interest. Affinity is a measure of the strength of binding between an antigen-binding protein (e.g., an immunoglobulin, antibody, a single variable domain of an immunoglobulin, or a polypeptide containing such a domain) and the associated antigen. Affinity relates to both the affinity between the antigen and the antigen-binding site on the antigen-binding protein and the number of associated binding sites present on the antigen-binding protein.

[0099] As used in this disclosure, the term "domain" (of a polypeptide or protein) refers to a folded protein structure that is able to maintain its tertiary structure independently of the rest of the protein. Generally, a domain is responsible for a single functional property of a protein and in many cases can be added to, removed from, or transferred to other proteins without loss of the function of the rest of the protein and / or the domain itself.

[0100] As used herein, the term "immunoglobulin domain" refers to a globular region of an antibody chain (e.g., a chain of a conventional four-chain antibody or a chain of a heavy-chain antibody), or to a polypeptide that is substantially composed of such globular regions. An immunoglobulin domain is characterized by its ability to maintain the immunoglobulin folding characteristics of the antibody molecule.

[0101] As used herein, the term "immunoglobulin variable domain" refers to an immunoglobulin domain substantially composed of four "frame regions" referred to in the art and hereinafter as "frame region 1" or "FR1", "frame region 2" or "FR2", "frame region 3" or "FR3", and "frame region 4" or "FR4", respectively, and three "complementarity-determining regions" or "CDRs" spaced apart from the frame regions, referred to in the art and hereinafter as "complementarity-determining region 1" or "CDR1", "complementarity-determining region 2" or "CDR2", and "complementarity-determining region 3" or "CDR3", respectively. Therefore, the general structure or sequence of an immunoglobulin variable domain can be represented as: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The immunoglobulin variable domain confers the specificity of an antibody to an antigen by possessing an antigen-binding site. The variable domains of the heavy and light chains of natural antibodies typically have similar structures.

[0102] The "VHH domain," also known as a single-domain antibody, VHH, VHH domain, VHH antibody fragment, and VHH antibody, is a variable domain of an antigen-binding immunoglobulin called a "heavy chain antibody" (Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R.: "Naturally occurring antibodies devoid of light"). "chains"; Nature 363, 446-448 ((1993)). The term "VHH domain" is used to distinguish the variable domain from the heavy chain variable domain (referred to herein as the "VH domain") present in conventional 4-chain antibodies. The VHH domain specifically binds to epitopes without the need for other antigen-binding domains (unlike the VH or VL domains in conventional 4-chain antibodies, in which case the epitope is recognized by both the VL and VH domains). The VHH domain is a small, stable, and efficient antigen-recognition unit formed by a single immunoglobulin domain. VHHs are derived, for example, from camels. Examples include alpaca, or its humanized or sequence-optimized forms (e.g., affinity-matured forms to increase binding affinity). In some embodiments, the VHH is a monovalent, monospecific polypeptide molecule consisting of or substantially consisting of a single heavy chain variable region (e.g., the heavy chain variable region of a heavy chain antibody). Preferably, in one embodiment, this disclosure provides an immunoglobulin single variable domain comprising a humanized VHH. Preferably, in one embodiment, this disclosure provides an antibody comprising a humanized VHH. Preferably, in one embodiment, this disclosure provides a multispecific antigen-binding protein (e.g., a multispecific antibody) comprising a humanized VHH.

[0103] In the context of this disclosure, the terms “VHH domain”, single-domain antibody, “VHH”, “VHH domain”, “VHH antibody fragment”, and “VHH antibody” are used interchangeably.

[0104] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of its constant region. This term includes native sequence Fc regions and variant Fc regions. A native immunoglobulin "Fc domain" contains two or three constant domains: a CH2 domain, a CH3 domain, and optionally a CH4 domain. For example, in native antibodies, the immunoglobulin Fc domain contains the second and third constant domains (CH2 and CH3 domains) of two heavy chains derived from IgG, IgA, and IgD antibodies; or it contains the second, third, and fourth constant domains (CH2, CH3, and CH4 domains) of two heavy chains derived from IgM and IgE antibodies. Unless otherwise stated herein, the amino acid residues in the Fc region or heavy chain constant region are numbered according to the EU numbering system (also known as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. In this document, the term "Fc region" does not include the heavy chain variable region VH and light chain variable region VL of immunoglobulins, nor the heavy chain constant region CH1 and light chain constant region CL, but in some cases may include the hinge region at the N-terminus of the heavy chain constant region. In some embodiments, the Fc region of this disclosure is derived from IgG1, IgG2, IgG3, or IgG4. In some embodiments, the Fc region of this disclosure comprises the amino acid sequence shown in SEQ ID NO: 2 or 3, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with said amino acid sequence.

[0105] The term "protein-drug conjugate" generally refers to a binding protein (e.g., an antibody or its antigen-binding fragment) linked to one or more chemical drugs, such as antibody-drug conjugates (ADCs). The chemical drug can be any therapeutic agent and / or cytotoxic agent. The antibody-drug conjugate can have any number of drugs conjugated to the antibody, ranging from 1 to 16 or 1 to 20, for example, it can include 2, 4, 6, or 8 drug-loaded species. In this disclosure, the drug can include mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemotherapeutic agents, hormones, anti-hormonal agents, corticosteroids, photosensitizing agents, oligonucleotides, radioactive isotopes, topoisomerase inhibitors, tyrosine kinase inhibitors, and / or radiosensitizers, etc.

[0106] In this disclosure, the term "drug / antibody ratio" or "DAR" generally refers to the number of drugs linked to an antibody (or protein) of an ADC. The DAR of an ADC can range from 1 to 8, or even higher loads (e.g., 10), and the range of DAR can depend on the number of binding sites on the antibody. In this disclosure, the DAR can be the number of drugs loaded onto a single antibody. The DAR can also be the average or mean DAR of a group of ADCs.

[0107] The term "linker" refers to a structural segment that connects a drug (e.g., a small molecule drug) to an antibody. It should be understood that a linker has functional groups that can form bonds with functional groups of the antibody or its antigen-binding fragment before it is linked to the antibody or its antigen-binding fragment.

[0108] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms.

[0109] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0110] The term "cycloalkylene" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms.

[0111] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.

[0112] The term “heterocyclic alkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms.

[0113] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definitions of alkyl or cycloalkyl are as described above.

[0114] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, with phenyl being more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, and heterocyclic alkylthio.

[0115] The term "arylene" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system, and is derived from residues derived by removing two hydrogen atoms from two different carbon atoms of the parent aromatic ring.

[0116] The term "heteroaryl" refers to a 5- to 14-membered heteroaryl system containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as furanyl, thiophene, pyridyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, and heterocyclic alkylthio.

[0117] The term “hybrid aryl” refers to a 5- to 14-membered heteroaromatic polycyclic aromatic ring containing 1 to 4 heteroatoms, and is derived from residues derived by removing two hydrogen atoms from two different carbon atoms of the parent aromatic ring.

[0118] The term "optional" or "optionally" means that the event or condition described below either occurs or does not occur, and the description includes instances where the event or condition occurs as well as instances where the event or condition does not occur. For example, when a group or structure is "optionally substituted," the group or structure may or may not be substituted.

[0119] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the conjugates of this disclosure, and that such salt is not biologically or otherwise undesirable. The conjugates of this disclosure may exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. In this disclosure, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by the conjugate of this disclosure with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the couplings in this disclosure with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by the couplings with N-containing organic bases.

[0120] Where there is no contradiction in the context, "pharmaceutical acceptable" and "medicinal" are used interchangeably in this article.

[0121] As used herein, the term “and / or” refers to any one of the options or two or more of the options.

[0122] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover combinations of the stated elements, integers, or steps.

[0123] The term "administration" generally refers to a method of giving a dose of a compound or pharmaceutical composition to a subject (e.g., a patient). Administerment can be made by any suitable means, including parenteral, intrapulmonary, and intranasal administration, as well as intralesional administration (if necessary for local treatment). Parenteral infusion includes, for example, intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0124] In this disclosure, the term "about" generally refers to a variation within a range of 0.5% to 10% above or below a specified value, such as a variation within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below a specified value. Unless otherwise specified, all values ​​mentioned in this disclosure are considered to be modified by "about". In case of doubt, or where the range of error for a particular value or parameter is not generally understood in the art, "about" means ±5% of that value or parameter.

[0125] The term "effective amount" refers to such an amount or dose of the antibody, fragment, composition, or combination thereof as disclosed, which, when administered to a patient in a single or multiple doses, produces the intended effect in a patient requiring treatment or prevention. Depending on the intended effect, it may include "therapeutic effective amount" and "prophylactic effective amount".

[0126] "Therapeutic effective dose" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired therapeutic outcome. A therapeutic effective dose is also a dose in which any toxic or harmful effects of the antibody, antibody fragment, composition, or combination are less than the beneficial therapeutic effect. "Prophylactic effective dose" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired preventative outcome. Typically, because prophylactic doses are administered in subjects before or at an earlier stage of the disease, the prophylactic effective dose will be less than the therapeutic effective dose.

[0127] "Individual" or "subject" includes mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0128] The term "non-small cell lung cancer" refers to a histological subtype of lung cancer that is distinct from small cell lung cancer (SCLC), accounting for approximately 80%-85% of all lung cancer cases. According to the World Health Organization (WHO) Classification of Thoracic Tumors (5th edition, 2021), NSCLC includes, but is not limited to, the following pathological subtypes: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, as well as adenosquamous carcinoma and sarcomatoid carcinoma.

[0129] The term "carboplatin" refers to a platinum-based antitumor drug with the chemical name cis-diammino-1,1-cyclobutanedicarboxylic acid platinum(II). Carboplatin is its International Nonproprietary Name (INN) and its CAS Registry Number is 41575-94-4. The term "carboplatin" as used in this disclosure also covers all pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and pharmacopoeia-compliant equivalents of carboplatin.

[0130] The term "Furmonertinib," formerly known as Alflutinib / Furmonertinib, with the research code AST2818, refers to a highly selective, irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), belonging to the small molecule targeted anti-tumor drugs. Furmonertinib is its International Nonproprietary Name (INN). The term "Furmonertinib" as used in this disclosure encompasses the free base of fermetinib (CAS Registry No. 1869057-83-9), pharmaceutically acceptable salts (such as fermetinib mesylate, CAS Registry No. 2130958-55-1), polymorphs, solvates, and formulations (such as tablets, extended-release formulations), for example, fermetinib mesylate tablets, marketed under the brand name Evosa.

[0131] The term "Ivonescimab" refers to a humanized bispecific antibody targeting the binding of human vascular endothelial growth factor-A (VEGF-A) and programmed death protein-1 (PD-1) to the IgG1 subtype. Ivonescimab is its International Nonproprietary Name (INN). The amino acid sequence of evoscimab is described in WHO Drug Information, Vol. 35, No. 2, 2021, Proposed INN: List 125, and its CAS registry number is 2428381-53-5. When "evoscimab" is mentioned in this document, it includes the original drug under the generic name, whose development stage code is AK112, and its trade name is Idafoam; it also includes biosimilars. Evonescimab can simultaneously bind to VEGF-A and PD-1, competitively blocking the interaction between VEGF-A, PD-1, and their ligands, thereby exerting antitumor activity.

[0132] The term "tislelizumab" refers to a humanized IgG4 monoclonal antibody targeting programmed death receptor-1 (PD-1). Tislelizumab is its International Nonproprietary Name (INN). The amino acid sequence of tislelizumab is described in WHO Drug Information, Vol. 31, No. 2, 2017, Proposed INN: List 117, and its CAS registry number is 1858168-59-8. When "tislelizumab" is mentioned in this article, it includes the original drug under this generic name, whose development phase code is BGB-A317, and its trade name is Bai Ze An; it also includes biosimilars.

[0133] The term "pembrolizumab" refers to a humanized PD-1 monoclonal antibody used in cancer immunotherapy. Pembrolizumab is its International Nonproprietary Name (INN). Its amino acid sequence is described in WHO Drug Information, Vol. 28, No. 3, 2014 Recommended INN: List 72, and its CAS registry number is 1374853-91-4. When "pembrolizumab" is mentioned in this article, it includes the original drug under the generic name, whose development phase code is MK-3475, and its trade name is Keytruda; it also includes biosimilars.

[0134] The term "standard treatment" refers to a treatment regimen based on high-level clinical evidence (such as the results of randomized controlled phase III clinical trials), recommended by authoritative international or regional clinical practice guidelines (such as NCCN, ESMO, CSCO, etc.), and widely adopted and accepted in clinical practice. For NSCLC patients with driver gene-positive NSCLC, targeted therapy with corresponding tyrosine kinase inhibitors (TKIs) is currently the first-line standard treatment. Although TKI targeted therapy significantly improves patients' prognosis and quality of life, most patients develop resistance during treatment. For example, about half of patients who develop resistance after receiving first- or second-generation EGFR-TKI treatment will have the T790M mutation, and this group is sensitive to third-generation EGFR inhibitors; however, after using third-generation EGFR-TKI treatment, most patients will still face the challenge of resistance again. For patients who fail EGFR-TKI treatment, sintilimab + bevacizumab biosimilar + platinum-based chemotherapy, or evosimab combined with platinum-based chemotherapy are currently the standard treatment regimens.

[0135] For driver gene-negative locally advanced or metastatic NSCLC that has not received prior systemic therapy, current standard of care is based on PD(L)-1 inhibitors: For PD-L1-negative patients (TPS < 1%), PD(L)-1 inhibitors combined with platinum-based chemotherapy are the standard of care approved by the NMPA and FDA; PD(L)-1 inhibitors + CTLA-4 inhibitors ± platinum-based chemotherapy are the standard of care approved by the FDA. For PD-L1-positive patients (TPS ≥ 1%), in addition to the above therapies, PD(L)-1 inhibitor monotherapy is also the current standard of care. For driver gene-negative NSCLC patients who have failed first-line platinum-based chemotherapy and immunotherapy, second-line standard of care is docetaxel monotherapy.

[0136] “EGFR wild-type non-small cell lung cancer” refers to NSCLC that is confirmed by tumor histology gene testing to be EGFR wild-type and negative for ALK fusion gene, and has no known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy.

[0137] "EGFR-sensitive mutation non-small cell lung cancer" refers to NSCLC with EGFR-sensitive mutations confirmed by tumor histology, cytology (including malignant serous cavity effusion and cerebrospinal fluid), or hematological genetic testing, including exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0138] Invention Details

[0139] Combination of protein-drug conjugates with platinum-based chemotherapy drugs

[0140] In a first aspect, this disclosure relates to a method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a platinum-based chemotherapy drug, and optionally a PD-1 inhibitor, to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0141] In some embodiments, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a platinum-based chemotherapy drug to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0142] In some embodiments, the multispecific antigen-binding protein includes a TROP2-binding protein, such as an antibody that binds to TROP2 or an antigen-binding fragment thereof.

[0143] In some embodiments, the antibody or antigen-binding fragment of the TROP2-binding antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: H1CDR1, which comprises or consists of the amino acid sequence shown in SEQ ID NO: 1; H1CDR2, which comprises or consists of the amino acid sequence shown in SEQ ID NO: 2; and H1CDR3, which comprises or consists of the amino acid sequence shown in SEQ ID NO: 3.

[0144] The light chain variable region comprises: LCDR1, which contains or consists of the amino acid sequence shown in SEQ ID NO: 4; LCDR2, which contains or consists of the amino acid sequence shown in SEQ ID NO: 5; and LCDR3, which contains or consists of the amino acid sequence shown in SEQ ID NO: 6.

[0145] In some embodiments, the heavy chain variable region of the TROP2-binding antibody or its antigen-binding fragment comprises (1) SEQ ID NO: 7; (2) has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 7; or (3) comprises one or more amino acid substitutions compared to SEQ ID NO: 7, preferably conserved amino acid substitutions, for example, the amino acid sequence shown in the sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions, or is composed of therewith. In some embodiments, the heavy chain variable region of the TROP2-binding antibody or its antigen-binding fragment comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 7.

[0146] In some embodiments, the light chain variable region of the TROP2-binding antibody or its antigen-binding fragment comprises (1) SEQ ID NO: 8; (2) has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 8; or (3) comprises one or more amino acid substitutions compared to SEQ ID NO: 8, preferably conserved amino acid substitutions, for example, the amino acid sequence shown in the sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions, or is composed of therefrom. In some embodiments, the light chain variable region of the TROP2-binding antibody or its antigen-binding fragment comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 8.

[0147] In some embodiments, the TROP2-binding antibody or its antigen-binding fragment comprises a heavy chain. In some embodiments, the TROP2-binding antibody or its antigen-binding fragment comprises a light chain. In some embodiments, the TROP2-binding antibody or its antigen-binding fragment comprises both a heavy chain and a light chain. In some embodiments, the TROP2-binding antibody or its antigen-binding fragment comprises two heavy chains and two light chains. In some embodiments, the TROP2-binding antibody or its antigen-binding fragment comprises two identical heavy chains and two identical light chains.

[0148] In some embodiments, the heavy chain of the antibody binding to TROP2 or its antigen-binding fragment further comprises a constant region of human IgG1 or a variant thereof, for example, the constant region or a variant thereof comprising (1) SEQ ID NO: 9; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 9; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 9, preferably conserved amino acid substitutions, for example, the amino acid sequence shown by the amino acid sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions.

[0149] In some embodiments, the light chain of the antibody binding to TROP2 or its antigen-binding fragment further comprises a constant region of human Igκ or a variant thereof, for example, the constant region or a variant thereof comprising (1) SEQ ID NO: 10; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 10; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 10, preferably conserved amino acid substitutions, for example, the amino acid sequence shown by the amino acid sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions.

[0150] In some specific embodiments, the heavy chain of the TROP2-binding antibody or its antigen-binding fragment comprises (1) SEQ ID NO: 11; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 11; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 11, preferably conserved amino acid substitutions, for example, the amino acid sequence shown by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions. In some specific embodiments, the heavy chain of the TROP2-binding antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO: 11.

[0151] In some specific embodiments, the light chain of the TROP2-binding antibody or its antigen-binding fragment comprises (1) SEQ ID NO: 12; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 12; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 12, preferably conserved amino acid substitutions, for example, the amino acid sequence shown in the amino acid sequence with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions. In some specific embodiments, the light chain of the TROP2-binding antibody or its antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO: 12.

[0152] As an example, the TROP2-binding antibody may have the same structure as Sacituzumab (hRS7), as disclosed in WHO Drug Information Proposed INN List 115 (2016).

[0153] In some embodiments, the multispecific antigen-binding protein includes a HER3-binding protein, such as an antibody that binds to HER3 or an antigen-binding fragment thereof, such as a single-domain antibody.

[0154] In some embodiments, the multispecific antigen-binding protein comprises a single-domain antibody that binds to HER3, the single-domain antibody that binds to HER3 comprising: H2CDR1, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 13; H2CDR2, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 14; and H2CDR3, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 15.

[0155] In some embodiments, the HER3-binding single-domain antibody comprises (1) SEQ ID NO: 16; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 16; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 16, preferably conserved amino acid substitutions, for example, an amino acid sequence represented by, or composed of, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conserved amino acid substitutions.

[0156] In some embodiments, in the multispecific antigen-binding protein, the HER3-binding single-domain antibody is directly or indirectly linked to the TROP2-binding antibody or antigen-binding fragment via a linker.

[0157] In some embodiments, the linker is a polypeptide, such as a non-functional amino acid sequence of 1-20 or more amino acids without secondary or higher structures. For example, the linker is a flexible linker, such as one or more of (GGG)n, (GGGS)n, (GGGA)n, (GGGAA)n, (GGGGS)n, and (GGGGGS)n, where n is an integer selected from 1 to 30, an integer selected from 1 to 20, an integer selected from 1 to 10, an integer selected from 1 to 9, an integer selected from 1 to 8, an integer selected from 1 to 7, an integer selected from 1 to 6, an integer selected from 1 to 5, an integer selected from 1 to 4, or an integer selected from 1 to 3. In some embodiments, the linker is GGGGGS, GGGGS, GS, GAP, (GGGGS)×3, GAPGGGGGS, etc.

[0158] In some embodiments, the C-terminus of the HER3-binding single-domain antibody is linked to the N-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment. In some embodiments, the C-terminus of the HER3-binding single-domain antibody is linked to the N-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment via a connector, preferably, the connector is GGGGGS, GGGGS, GS, GAP, (GGGGS)×3, or GAPGGGGGS.

[0159] In some embodiments, the N-terminus of the HER3-binding single-domain antibody is linked to the C-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment. In some embodiments, the N-terminus of the HER3-binding single-domain antibody is linked to the C-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment via a linker, preferably, the linker is GGGGGS, GGGGS, GS, GAP, (GGGGS)×3, or GAPGGGGGS.

[0160] In some embodiments, the C-terminus of the HER3-binding single-domain antibody is linked to the N-terminus of the light chain of the TROP2-binding antibody or antigen-binding fragment. In some embodiments, the C-terminus of the HER3-binding single-domain antibody is linked to the N-terminus of the light chain of the TROP2-binding antibody or antigen-binding fragment via a connector, preferably, the connector is GGGGGS, GGGGS, GS, GAP, (GGGGS)×3, or GAPGGGGGS.

[0161] In some embodiments, the N-terminus of the HER3-binding single-domain antibody is linked to the C-terminus of the light chain of the TROP2-binding antibody or antigen-binding fragment. In some embodiments, the N-terminus of the HER3-binding single-domain antibody is linked to the C-terminus of the light chain of the TROP2-binding antibody or antigen-binding fragment via a connector, preferably, the connector is GGGGGS, GGGGS, GS, GAP, (GGGGS)×3, or GAPGGGGGS.

[0162] In some embodiments, the multispecific antigen-binding protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of the TROP2-binding antibody or antigen-binding fragment and a HER3-binding single-domain antibody, wherein the C-terminus of the HER3-binding single-domain antibody is linked to the N-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment via a linker, and the second polypeptide comprises a light chain of the TROP2-binding antibody or antigen-binding fragment, wherein the first polypeptide comprises a first heavy chain variable region and a second heavy chain variable region, and the second polypeptide comprises a light chain variable region, wherein the first heavy chain variable region is the heavy chain variable region of the heavy chain of the TROP2-binding antibody or antigen-binding fragment, the second heavy chain variable region is the HER3-binding single-domain antibody, and the light chain variable region is the light chain variable region of the heavy chain of the TROP2-binding antibody or antigen-binding fragment.

[0163] In some embodiments, the multispecific antigen-binding protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a first heavy chain variable region and a second heavy chain variable region, and the second polypeptide comprises a light chain variable region; wherein:

[0164] The first heavy chain variable region comprises: H1CDR1, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 1; H1CDR2, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 2; and H1CDR3, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 3.

[0165] The second heavy chain variable region comprises: H2CDR1, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 13; H2CDR2, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 14; and H2CDR3, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 15.

[0166] The light chain variable region comprises: LCDR1, which contains or consists of the amino acid sequence shown in SEQ ID NO: 4; LCDR2, which contains or consists of the amino acid sequence shown in SEQ ID NO: 5; and LCDR3, which contains or consists of the amino acid sequence shown in SEQ ID NO: 6.

[0167] In some embodiments, the first heavy chain variable region comprises (1) SEQ ID NO: 7; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 7; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 7, preferably conservative amino acid substitutions, for example, an amino acid sequence represented by, or composed of, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions.

[0168] In some embodiments, the second heavy chain variable region comprises (1) SEQ ID NO: 16; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 16; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 16, preferably conservative amino acid substitutions, for example, an amino acid sequence represented by, or composed of, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions.

[0169] In some embodiments, the light chain variable region comprises (1) SEQ ID NO: 8; (2) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 8; or (3) comprising one or more amino acid substitutions compared to SEQ ID NO: 8, preferably conservative amino acid substitutions, for example, an amino acid sequence represented by, or composed of, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions.

[0170] In some specific embodiments, the multispecific antigen-binding protein comprises the first polypeptide shown in SEQ ID NO: 17 and the second polypeptide shown in SEQ ID NO: 12.

[0171] In some specific embodiments, the multispecific antigen-binding protein comprises more than one first polypeptide shown in SEQ ID NO: 17 and more than one second polypeptide shown in SEQ ID NO: 12. In some embodiments, the multispecific antigen-binding protein comprises two first polypeptides and two second polypeptides. In some embodiments, the multispecific antigen-binding protein forms a homodimer through disulfide bonds in the hinge region of the first polypeptide.

[0172] In some embodiments, the protein-drug conjugate comprises a cytotoxin. In some embodiments, the cytotoxin may be selected from DNA alkylating agents, DNA destructive agents, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule inhibitors, ribosome inhibitors, and any combination thereof. In some specific embodiments, the cytotoxin may be selected from auristatin derivative, amatansine derivative, eribulin derivative, tubulin derivative, pyrrolobenzodiazepine (PDB) dimer derivative, aduomycin derivative, calicacin derivative, PNU-159682 and its derivatives, camptothecin derivative, amatoxin derivative, and any combination thereof.

[0173] In some embodiments, the protein-drug conjugate comprises a cytotoxin, which is a camptothecin derivative, such as DXd.

[0174] In some embodiments, the protein-drug conjugates of this disclosure have the structure of Formula I:

[0175] P-(L1-sp1-L2-sp2-D)n (I),

[0176] Wherein, protein P includes the multispecific antigen-binding protein described in this disclosure, D is a biologically active substance, L1 is a linker for connecting with P, sp1 is a first spacer unit, L2 is a cleavable linker, sp2 is a second spacer unit connected to D, and n = 1 to 20.

[0177] In some implementations, L1 is selected from:

[0178] (The side connected to the protein is labeled P, and the side connected to the first spacer unit is labeled sp1), where Ar represents C. 6-10 Aryl groups, optionally coated with halogens and / or C1-6 Alkyl substitution; R1 is selected from hydrogen, halogen, and C. 1-6 Alkyl group; Z is selected from straight bond, C 2-6 Ethyne group, C 2-6 imidene group, C 6-10 Aryl, 5-10 heteroaryl, amide, sulfonamide, imino and CF2.

[0179] In some implementations, L1 is selected from

[0180] In some implementations, L1 is selected from

[0181] In some implementations, the structure of the first spacer unit sp1 is shown in Equation II:

[0182] (The side connected to L1 is labeled L1, and the side connected to L2 is labeled L2), where a1 = 0 or 1, a2 = an integer from 0 to 6, b1 = 0 or 1, b2 = an integer from 0 to 20, for example, an integer from 0 to 16, b3 = an integer from 0 to 16, c = an integer from 0 to 6, and at least one of b2 and b3 is 0.

[0183] In some implementations, a1 = 1 in the structure of sp1; in other implementations, a1 = 0.

[0184] In some implementations, a2 = 0, 1, 2, 3, 4, 5, or 6.

[0185] In some implementations, b1 = 0 or 1.

[0186] In some implementations, b2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0187] In some implementations, b3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0188] In some implementations, c = 0, 1, 2, 3, 4, 5, or 6.

[0189] The above options a1, a2, b1, b2, b3 and c can be combined in any way, provided that at least one of b2 and b3 is 0.

[0190] In some specific implementations, the structure of sp1 is selected from the following group:

[0191] (1) a1 = 0, a2 = 2, 3, 4, 5 or 6, b1 = 0, b2 = 0, b3 = 0, c = 0;

[0192] (2) a1 = 0, a2 = 0, b1 = 0, b2 = 0, b3 = 0, c = 2, 3, 4, 5 or 6;

[0193] (3) a1 = 1, a2 = 2, 3, 4, 5 or 6, b1 = 1, b2 = 2, 3, 4, 5, 6, 7 or 8, b3 = 0, c = 0;

[0194] (4) a1 = 0, a2 = 2, 3, 4, 5 or 6, b1 = 1, b2 = 2, 3, 4, 5, 6, 7 or 8, b3 = 0, c = 0;

[0195] (5) a1 = 1, a2 = 0, b1 = 0, b2 = 0, b3 = 2, 3, 4, 5, 6, 7 or 8, c = 2, 3, 4, 5 or 6; and

[0196] (6) a1 = 1, a2 = 2, b1 = 1, b2 = 2, 3, 4, 5, 6, 7 or 8, b3 = 0, c = 0.

[0197] In some embodiments, the cleavable linker L2 is a dipeptide, tripeptide, or tetrapeptide residue.

[0198] In some embodiments, L2 is selected from the following dipeptide residues: -Phe-Lys-, -Val-Ala-, -Val-Lys-, -Val-Cit-, -Ala-Lys-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, -Trp-Cit-, -Gly-Gly-, -Ala-Ala-, -Gly-Val-, and -Gly-Glu-; wherein the left (amino) group of the dipeptide residue is linked to sp1, and the right (carbonyl) group is linked to sp2. Preferably, L2 is selected from -Val-Ala-, -Val-Lys-, and -Val-Cit-.

[0199] In some embodiments, L2 is selected from the following tripeptide residues: -Glu-Val-Ala-, -Glu-Val-Cit-, -αGlu-Val-Ala-, -αGlu-Val-Cit-, -Val-Lys-Gly, and -Val-Cit-Gly-; the left (amino) side of the tripeptide residue is linked to sp1, and the right (carbonyl) side is linked to sp2.

[0200] In some embodiments, L2 is selected from the following tetrapeptide residues: -Gly-Gly-Phe-Gly- (SEQ ID NO:21) and -Gly-Phe-Gly-Gly- (SEQ ID NO:22); the left (amino) side of the tetrapeptide residue is linked to sp1, and the right (carbonyl) side is linked to sp2.

[0201] In some implementations, the second spacer unit sp2 is absent, or sp2 is selected from:

[0202] (The side connected to L2 is labeled L2, and the side connected to the biologically active substance D is labeled D), where,

[0203] R2 is independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, amino, halogen, nitro, cyano d is an integer from 1 to 20, and e is an integer from 1 to 20; R3 and R4 are each independently selected from hydrogen and C. 1-6 alkyl;

[0204] The alkyl group may optionally be substituted with hydroxyl, amino, halogen, nitro, and cyano groups.

[0205] In some implementations, sp2 is

[0206] It is understood that the phrase "connected to sp2" or similar expression on the right side covers the case where the right side is directly connected to D when sp2 is not present.

[0207] In some implementations, -L1-sp1-L2-sp2- is selected from the following structures:

[0208] (The side connected to protein P is labeled P, and the side connected to biologically active substance D is labeled D); where k is an integer from 1 to 20.

[0209] In some implementations, k is an integer from 2 to 16, for example, k = 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0210] In some implementations, -L1-sp1-L2-sp2- is further selected from the following structures:

[0211] The definition of k is as described above.

[0212] In some implementations, D is a cytotoxic agent selected from: DNA alkylating agents, DNA destructive agents, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule inhibitors, ribosome inhibitors, and any combination thereof.

[0213] In some specific implementation schemes, D is selected from: auristatin derivatives, maidansine derivatives, eribulin derivatives, tubulysin derivatives, pyrrolobenzodiazepine (PDB) dimer derivatives, ducarmycin derivatives, calicacin derivatives, PNU-159682 and its derivatives, camptothecin derivatives, amatoxin derivatives, and any combination thereof.

[0214] In some embodiments, D is selected from camptothecin derivatives, which refer to compounds having the same 5-membered fused core structure as naturally derived camptothecin and having substitution modifications at positions 7, 9, 10, and 11, and having equal or stronger topoisomerase I inhibitory activity as natural camptothecin.

[0215] The optional camptothecin derivatives may be derived from the prior art as a whole, such as patent applications WO2014057687, WO2020063676, CN111689980A, WO2022068878, WO2022068878, WO2020259258, WO2020219287, WO2022121981, WO2021173773, WO2019195665, WO2021067861, WO2022170971, WO2020200880, WO2021148501, WO2023109965 and WO2022015656. The disclosures of the above patents are incorporated into this application as a whole.

[0216] In some implementations, D is selected from the following structures:

[0217] (i.e., DXd) (i.e., Exatecan) (i.e., SN-38), where the position connected to the second spacer is marked as sp2. It can be understood that this covers the case where the position is directly connected to L2 when sp2 is not present.

[0218] In some specific implementations, -L1-sp1-L2-sp2-D is selected from the following structures:

[0219] Where k is an integer from 1 to 20.

[0220] In some specific implementations, -L1-sp1-L2-sp2-D is selected from the following structures:

[0221] Where k is an integer from 1 to 20.

[0222] In some embodiments, k is an integer from 2 to 16, for example, k = 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some embodiments, k is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, k is 4, 5, or 6.

[0223] In some implementations, n = 1 to 15, for example n = 1 to 10, n = 1 to 8, n = 2 to 6, n = 2 to 5, n = 2 to 4, or n = 2.5 to 3.5, or n = 2.5 to 4.0. It can be understood that n can represent the average drug-antibody ratio (average DAR) of the molecular population of formula (I) (in this case, n can be an integer or a decimal), or n can represent the number of drug linker moieties (-L1-sp1-L2-sp2-D) coupled to a protein P in a single molecule of formula (I) (in this case, n is an integer, for example, n can be 2, 3 or 4, preferably 4).

[0224] In some embodiments, the average DAR value of the couplings of this disclosure is from about 1 to about 8. In some embodiments, the average DAR value of the couplings of this disclosure is from about 2 to about 6. In some embodiments, the average DAR value of the couplings of this disclosure is from about 2 to about 5. In some embodiments, the average DAR value of the couplings of this disclosure is from about 2 to about 4. In some embodiments, the average DAR value of the couplings of this disclosure is about 4.

[0225] In some embodiments, in Formula I, the linker unit L1 is linked to protein P via a thiol group; preferably, the thiol group is derived from the multispecific antigen-binding protein described in this disclosure; more preferably, the thiol group is obtained by reducing the disulfide bonds between heavy chains and / or between heavy chains and light chains.

[0226] In other embodiments, the linker unit L1 is connected to the protein P via an oligosaccharide; preferably, the oligosaccharide is derived from the natural sugar chain of the multispecific antigen-binding protein described in this disclosure.

[0227] In some embodiments, the oligosaccharide is derived from the N-glycan chain of the multispecific antigen-binding protein described in this disclosure.

[0228] In some embodiments, the oligosaccharide is composed of 2 to 15 monosaccharides; preferably, the oligosaccharide is composed of 2 to 10 monosaccharides.

[0229] In some embodiments, the oligosaccharide has the structure shown in formula Va or formula Vb:

[0230] P* binds to HER3 and TROP2, for example, it contains the multispecific antigen-binding protein described in this disclosure, GlcNAc is N-acetylglucosamine, Fuc is fuc is fucose, Man is mannose, f is 0 or 1, and j is 1 to 20.

[0231] Gal* is a modified galactose selected from the following structures:

[0232] The oligosaccharide is connected to P* via a core GlcNAc.

[0233] In some embodiments, the oligosaccharide has the structure shown in formula V-a' or formula V-b' (the side connected to P* is labeled P*, and the side connected to L1 is labeled L1):

[0234] Wherein, GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, and f is 0 or 1;

[0235] Gal* is a modified galactose selected from the following structures:

[0236] The P* binds to HER3 and TROP2, for example, and includes the multispecific antigen-binding protein described in this disclosure.

[0237] In some implementations, the modified galactose is linked to GlcNAc via a β-1,4-glycosidic bond.

[0238] In some embodiments, the oligosaccharide is linked to the Fc fragment of P*; preferably to the CH2 domain of the Fc fragment; more preferably to the Asn297 of the Fc fragment (according to the EU index number of Kabat).

[0239] In some specific embodiments, the protein-drug conjugates described herein have the structure shown in Formula VI:

[0240] Wherein, P* binds HER3 and TROP2, for example, it contains or is a multispecific antigen-binding protein as described in this disclosure, GlcNAc is N-acetylglucosamine, Fuc is fuc is fucose, Man is mannose, f is 0 or 1, and j is 1 to 20;

[0241] Gal* is a modified galactose selected from the following structures:

[0242] LP is selected from one of the following structures (a) to (d):

[0243] (a) and / or

[0244] (b) and / or

[0245] (c) and / or

[0246] as well as

[0247] (d) and / or

[0248] k is an integer from 1 to 20, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0249] The core GlcNAc is directly connected to P*. In some implementations, k is 2, 3, 4, 5, 6, 7, or 8. In some implementations, k is 4, 5, or 6.

[0250] In some implementations, j = 1 to 10, for example, j = 1 to 8, j = 1.2 to 6, j = 1.5 to 3, j = 1.5 to 2.5. In some implementations, j is approximately 2.

[0251] In some embodiments, the overall DAR value (average) of the coupling is from about 1 to about 8. In some embodiments, the overall DAR value (average) of the coupling is from about 2 to about 6. In some embodiments, the overall DAR value (average) of the coupling is from about 2 to about 5. In some embodiments, the overall DAR value (average) of the coupling is from about 2 to about 4. In some embodiments, the overall DAR value (average) of the coupling is about 4.

[0252] In some embodiments, the antigen-binding protein comprises a first polypeptide shown in SEQ ID NO:17 and a second polypeptide shown in SEQ ID NO:12.

[0253] In some embodiments, the oligosaccharide in the protein-drug conjugate is linked to the Fc fragment of P*; preferably to the CH2 domain of the Fc fragment; more preferably to the Asn297 (according to the Kabat EU index number) of the Fc fragment.

[0254] As previously stated, the oligosaccharide can be derived from the natural glycan chain of the multispecific antigen-binding protein described in this disclosure. Specifically, the preparation method of the oligosaccharide precursor (or referred to herein as a protein derivative) includes the following steps: reacting an antibody with an N-glycosylation mainly of G0F / G0 with UDP-GalNAz or its salt, or with other UDP-GalNAc azide derivatives, in the presence of a catalyst to obtain the aforementioned oligosaccharide precursor.

[0255] The UDP-GalNAz has the following structure:

[0256] Methods for obtaining G0F / G0 glycoform antibodies are well known in the art. For example, antibodies expressed in eukaryotic cells can be post-translational modified to convert the glycan into the G0F / G0 form by galactosidase treatment, which removes any terminal galactose residues and leaves terminal N-acetylglucosamine residues.

[0257] In other embodiments, the starting glycan of the G0F / G0 glycoform described herein can also be obtained by expression and purification using a cell line with the B4GALT1 gene knocked out. One example of knocking out the B4GALT1 gene in a cell line is through homologous recombination technology. Other examples of knocking out the B4GALT1 gene include the use of zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), as described in Nature Biotechnology, volume 33, pages 842-844 (2015). Int. J. Mol. Sci. 2015, 16(10), 23849-23866, etc.

[0258] In some embodiments, the aforementioned catalyst is a galactosyltransferase or a functional variant or fragment thereof.

[0259] In some embodiments, the catalyst is β-1,4-galactosyltransferase or a functional variant or fragment thereof.

[0260] In some embodiments, the catalyst is bovine β-1,4-galactosyltransferase, human β-1,4-galactosyltransferase, or a functional variant or fragment thereof.

[0261] In some embodiments, the catalyst is human β-(1,4)-GalT1 with the Y285L mutation or bovine β-(1,4)-GalT1 with the Y289L mutation.

[0262] In some embodiments, the catalyst is β-1,4-acetylgalactosyltransferase disclosed in patent application WO2016170186.

[0263] In some embodiments, the catalyst comprises any of the sequences shown in SEQ ID NO: 18-20.

[0264] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0265] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0266] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0267] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0268] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0269] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0270] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0271] In some implementations, prophylactic medication is given before the first administration of the protein-drug conjugate, such as diphenhydramine 50 mg orally (or an equivalent dose of an antihistamine), acetaminophen 500-1000 mg orally (or an equivalent dose of a nonsteroidal anti-inflammatory drug), and optionally dexamethasone.

[0272] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0273] In some embodiments, the platinum-based chemotherapy drug can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0274] In some implementations, the platinum-based chemotherapy drug is carboplatin.

[0275] In some embodiments, the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), is AUC = 4 to 5, for example, approximately 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0276] In some embodiments, the platinum-based chemotherapy drug is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the platinum-based chemotherapy drug. Preferably, the platinum-based chemotherapy drug is administered on the first day of each cycle.

[0277] It is understood that administration of one or more drugs may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, expressions such as once every two weeks (Q2W), once every three weeks (Q3W), and similar expressions as used herein can each cover the corresponding situation of delay or advancement by 1 day, 2 days, or 3 days. In some embodiments, administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0278] In some embodiments, the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles. In some embodiments, the platinum-based chemotherapy drug is administered 1 to 4 times, for example 2, 3, or 4 times, preferably 4 times.

[0279] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 4, once every three weeks for a total of four cycles.

[0280] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 5, once every three weeks for a total of four cycles.

[0281] In some implementations, the platinum-based chemotherapy drug is administered via intravenous infusion.

[0282] In some implementations, the administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0283] In some implementations, the method involves first administering the protein-drug conjugate, followed by the administration of the platinum-based chemotherapy drug.

[0284] In some implementations, the protein-drug conjugate and the platinum-based chemotherapy drug are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the platinum-based chemotherapy drug.

[0285] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0286] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0287] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0288] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0289] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer, preferably locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that is not suitable for radical surgery and / or radical radiotherapy (whether or not it has received concurrent / sequential chemotherapy).

[0290] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has failed standard treatment, preferably locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that has failed standard treatment.

[0291] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0292] In some implementations, the non-small cell lung cancer is NSCLC that has been confirmed by tumor histological genetic testing to be EGFR wild-type and ALK fusion gene negative, without known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy.

[0293] In some embodiments, the non-small cell lung cancer meets any one or all of the following characteristics, preferably all of them:

[0294] (i) EGFR wild-type and ALK fusion-negative NSCLC, without known ROS1 gene fusions or other known driver gene alterations approved for first-line targeted therapy; and / or

[0295] (ii) Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; or

[0296] Subjects who have received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or who have received radical therapy for locally advanced disease, are eligible if disease progression occurs ≥6 months after the end of their last treatment.

[0297] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment.

[0298] In some implementations, the subjects are ≥18 years of age and ≤75 years of age. In some implementations, the subjects have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1.

[0299] In some implementations, the subject has non-small cell lung cancer as defined herein, particularly in this section with respect to the first aspect.

[0300] In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer, preferably a patient with locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer who is not suitable for radical treatment. In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer who is not suitable for radical surgery and / or radical radiotherapy (whether or not receiving concurrent / sequential chemotherapy).

[0301] In some implementations, the subject is a non-small cell lung cancer patient who has failed standard treatment, preferably a locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer patient who has failed standard treatment.

[0302] In some implementations, the subjects are non-small cell lung cancer patients with driver gene-negative disease who have not previously received systemic therapy for locally advanced or metastatic stages.

[0303] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0304] In some implementations, the subject has previously received EGFR-TKI treatment and failed (radiographic disease progression), for example: failed treatment with a first- or second-generation EGFR-TKI and was histologically confirmed to be T790M mutation negative after treatment failure, or failed treatment with a third-generation EGFR-TKI.

[0305] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0306] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0307] In some implementations, the subject meets one or more of the following characteristics (preferably all of them):

[0308] ① NSCLC with EGFR wild-type and ALK fusion gene negative, without known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy;

[0309] ② Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; and / or

[0310] For subjects who have previously received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or who have received radical therapy for locally advanced disease, disease progression occurring ≥6 months after the end of the last treatment is considered to meet the requirements.

[0311] In some implementations, the method further includes administering a PD-1 inhibitor to the subject in need.

[0312] In some embodiments, the PD-1 inhibitor is a bispecific antibody targeting PD-1 / VEGF, such as evokinemab.

[0313] In some embodiments, the dosage of the PD-1 inhibitor (preferably a bispecific antibody targeting PD-1 / VEGF, such as edoximab) is 5 mg / kg to 30 mg / kg, or 10 mg / kg to 30 mg / kg, based on the subject's body weight, for example, approximately 5 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, or 30 mg / kg. Preferably, the dosage of the PD-1 inhibitor is 20 mg / kg based on the subject's body weight.

[0314] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0315] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0316] In some implementations, the PD-1 inhibitor is evokinemab, and the dosing regimen is 20 mg / kg based on the subject's body weight, once every three weeks.

[0317] In some implementations, the PD-1 inhibitor is an antibody that targets PD-1, such as tislelizumab or pembrolizumab.

[0318] In some embodiments, the dosage of the PD-1 inhibitor is 150 mg to 250 mg, for example, about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg; preferably, the dosage of the PD-1 inhibitor is 200 mg.

[0319] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0320] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0321] In some implementations, the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks.

[0322] In some implementations, the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks.

[0323] In some implementations, the PD-1 inhibitor is administered via intravenous infusion.

[0324] In some implementations, the PD-1 inhibitor is administered for one or more cycles or once or more until disease remission, disease progression, or intolerance occurs.

[0325] In some implementations, the PD-1 inhibitor can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0326] In some implementations, such as the method described above, the protein-drug conjugate is administered first, followed by the PD-1 inhibitor, and finally the platinum-based chemotherapy drug is administered.

[0327] In some implementations, the protein-drug conjugate, the PD-1 inhibitor, and the platinum-based chemotherapy drug are administered on the same day, with the protein-drug conjugate administered first, followed by the PD-1 inhibitor, and finally the platinum-based chemotherapy drug.

[0328] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0329] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is: 20 mg / kg of the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0330] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0331] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0332] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the pembrolizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is AUC=5, administered every three weeks for a total of 4 cycles.

[0333] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the pembrolizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is AUC=5, administered every three weeks for a total of 4 cycles.

[0334] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the pembrolizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is AUC=5, administered every three weeks for a total of 4 cycles.

[0335] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is AUC=5, administered every three weeks for a total of 4 cycles.

[0336] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is AUC=5, administered every three weeks for a total of 4 cycles.

[0337] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is an AUC=5 dose administered every three weeks for a total of 4 cycles.

[0338] The various implementation schemes described above for the first aspect also apply to the second through tenth aspects described below.

[0339] In a second aspect, this disclosure relates to a pharmaceutical combination comprising a protein-drug conjugate and a platinum-based chemotherapy drug, said protein-drug conjugate comprising a multispecific antigen-binding protein and optionally a PD-1 inhibitor, said multispecific antigen-binding protein targeting human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0340] Thirdly, this disclosure also relates to the use of the protein-drug conjugate in combination with platinum-based chemotherapy drugs, and optionally PD-1 inhibitors in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0341] Fourthly, this disclosure relates to a pillbox containing the pharmaceutical combination described in the second aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0342] Fifthly, this disclosure relates to a combination of medicines for the treatment and / or prevention of non-small cell lung cancer (NSCLC) or a kit for the fourth aspect.

[0343] Sixthly, this disclosure relates to the use of the pharmaceutical combination of the second aspect or the medicament of the fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0344] Seventhly, this disclosure relates to the use of the pharmaceutical combination of the second aspect or the medicament of the fourth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0345] Eighthly, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with platinum-based chemotherapy drugs and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0346] The protein-drug conjugate is used in the preparation of a drug for use in combination with platinum-based chemotherapy drugs and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0347] The use of the protein-drug conjugate, which is used in combination with platinum-based chemotherapy drugs and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0348] Ninthly, this disclosure relates to platinum-based chemotherapy drugs used in combination with the aforementioned protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0349] The use of platinum-based chemotherapy drugs in the preparation of medicaments for use in combination with the protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0350] Use of platinum-based chemotherapy drugs, wherein the platinum-based chemotherapy drugs are used in combination with the protein-drug conjugates and optionally PD-1 inhibitors for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0351] In a tenth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with platinum-based chemotherapy agents and optionally a PD-1 inhibitor for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0352] In the various aspects described above, the protein-drug conjugate and / or multispecific antigen-binding protein may be referred to as defined in the first aspect or as defined above.

[0353] In the various aspects described above, the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, the platinum-based chemotherapy drugs and / or the PD-1 inhibitors may also refer to the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, the platinum-based chemotherapy drugs and / or the PD-1 inhibitors in the first aspect above.

[0354] In some implementations, the drug combination is used to treat and / or prevent non-small cell lung cancer (NSCLC).

[0355] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0356] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0357] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0358] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0359] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0360] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0361] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0362] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0363] The administration of the platinum compounds can be referred to the first aspect above regarding the administration of the platinum compounds.

[0364] In some implementations, the platinum-based chemotherapy drug is carboplatin.

[0365] In some embodiments, the platinum-based chemotherapy drug can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0366] In some embodiments, the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), is AUC = 4 to 5, for example, approximately 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0367] In some embodiments, the platinum-based chemotherapy drug is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the platinum-based chemotherapy drug. Preferably, the platinum-based chemotherapy drug is administered on the first day of each cycle.

[0368] It is understood that administration of one or more drugs may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, expressions such as once every two weeks (Q2W), once every three weeks (Q3W), and similar expressions as used herein can each cover the corresponding situation of delay or advancement by 1 day, 2 days, or 3 days. In some embodiments, administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0369] In some embodiments, the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles. In some embodiments, the platinum-based chemotherapy drug is administered 1 to 4 times, for example 2, 3, or 4 times, preferably 4 times.

[0370] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 4, once every three weeks for a total of four cycles.

[0371] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 5, once every three weeks for a total of four cycles.

[0372] In some implementations, the platinum-based chemotherapy drug is administered via intravenous infusion.

[0373] In some implementations, the protein-drug conjugate may be administered first, followed by the platinum-based chemotherapy drug.

[0374] In some embodiments, the protein-drug conjugate and the platinum-based chemotherapy drug are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the platinum-based chemotherapy drug.

[0375] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0376] In some embodiments, the dosing regimen of the protein-drug conjugate in the drug combination is: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0377] In some embodiments, the dosing regimen of the protein-drug conjugate in the drug combination is: 5 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0378] In some embodiments, the dosing regimen of the protein-drug conjugate in the drug combination is: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 4, administered once every three weeks for a total of 4 cycles.

[0379] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0380] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has failed standard treatment.

[0381] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment.

[0382] In some implementations, the drug combination is applicable to subjects aged ≥18 years and ≤75 years.

[0383] In some implementations, the drug combination is intended for patients with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer.

[0384] In some implementations, the subjects are non-small cell lung cancer patients who have failed standard treatment.

[0385] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0386] In some implementations, the subject has previously received EGFR-TKI treatment and failed (radiographic disease progression), for example: failed treatment with a first- or second-generation EGFR-TKI and was histologically confirmed to be T790M mutation negative after treatment failure, or failed treatment with a third-generation EGFR-TKI.

[0387] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0388] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0389] In some embodiments, the drug combination further includes a PD-1 inhibitor. In some embodiments, the use also covers the combination administration of a PD-1 inhibitor. The definition and administration of the PD-1 inhibitor can be found in the first aspect above regarding the definition and administration of the PD-1 inhibitor.

[0390] In some embodiments, the PD-1 inhibitor is a bispecific antibody targeting PD-1 / VEGF, such as evokinemab.

[0391] In some embodiments, the dosage of the PD-1 inhibitor (preferably a bispecific antibody targeting PD-1 / VEGF, such as edoximab) is 5 mg / kg to 30 mg / kg, or 10 mg / kg to 30 mg / kg, based on the subject's body weight, for example, approximately 5 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, or 30 mg / kg. Preferably, the dosage of the PD-1 inhibitor is 20 mg / kg based on the subject's body weight.

[0392] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0393] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0394] In some implementations, the PD-1 inhibitor is evokinemab, and the dosing regimen is 20 mg / kg based on the subject's body weight, once every three weeks.

[0395] In some implementations, the PD-1 inhibitor is an antibody that targets PD-1, such as tislelizumab or pembrolizumab.

[0396] In some embodiments, the dosage of the PD-1 inhibitor is 150 mg to 250 mg, for example, about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg; preferably, the dosage of the PD-1 inhibitor is 200 mg.

[0397] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0398] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0399] In some implementations, the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks.

[0400] In some implementations, the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks.

[0401] In some implementations, the PD-1 inhibitor is administered via intravenous infusion.

[0402] In some implementations, the PD-1 inhibitor is administered for one or more cycles or once or more until disease remission, disease progression, or intolerance occurs.

[0403] In some implementations, the PD-1 inhibitor can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0404] In some embodiments, the combination involves administering the protein-drug conjugate first, followed by the PD-1 inhibitor, and finally the platinum-based chemotherapy drug.

[0405] Thirdly, this disclosure also relates to the use of protein-drug conjugates in combination with platinum-based chemotherapy drugs in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugates comprising multispecific antigen-binding proteins that target human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0406] In some embodiments, this disclosure also relates to the use of protein-drug conjugates in combination with platinum-based chemotherapy drugs and PD-1 inhibitors in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugates comprising multispecific antigen-binding proteins that target human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0407] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0408] In some implementations, the platinum-based chemotherapy drug is carboplatin.

[0409] In some embodiments, the PD-1 inhibitor is a bispecific antibody targeting PD-1 / VEGF, such as evokinemab.

[0410] In some implementations, the PD-1 inhibitor is an antibody that targets PD-1, such as tislelizumab or pembrolizumab.

[0411] The definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, platinum-based chemotherapy drugs and / or PD-1 inhibitors can also be found in the first aspect above regarding the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, platinum-based chemotherapy drugs and / or PD-1 inhibitors.

[0412] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0413] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has failed standard treatment.

[0414] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment.

[0415] Combination of protein-drug conjugates with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)

[0416] Eleventhly, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0417] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0418] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0419] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0420] In some embodiments, the protein-drug conjugate is administered once every two weeks (Q2W). Therefore, in some embodiments, a two-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0421] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0422] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0423] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0424] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0425] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q2W.

[0426] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 2 weeks.

[0427] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q2W.

[0428] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0429] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0430] In some implementations, the EGFR-TKI can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or following the dosing regimen recommended in the product instructions.

[0431] In some implementations, the EGFR-TKI is a third-generation EGFR-TKI.

[0432] In some implementations, the EGFR-TKI is vometinib.

[0433] In some embodiments, the dosage of the EGFR-TKI is 80 mg to 200 mg, for example, about 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg; preferably, the dosage of the EGFR-TKI is 80 mg or 160 mg.

[0434] In some implementations, the EGFR-TKI is administered once daily (QD).

[0435] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. In some embodiments, the administration of the EGFR-TKI may be delayed, for example, by more than 1 week, 2 weeks, or up to 3 weeks.

[0436] In some implementations, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0437] In some implementations, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0438] In some implementations, the EGFR-TKI is administered orally, for example, on an empty stomach.

[0439] In some implementations, vometinib is taken orally over a general period of time each day.

[0440] In some implementations, the EGFR-TKI is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

[0441] In some implementations, the method involves administering the EGFR-TKI first, followed by the administration of the protein-drug conjugate.

[0442] In some implementations, when the protein-drug conjugate and the EGFR-TKI are administered on the same day, for example, the EGFR-TKI is tried first, followed by the protein-drug conjugate.

[0443] The time interval between the various medications is not strictly defined and can be determined by local clinical practice or the attending physician. For example, the time interval between two medications can be from approximately 1 minute to approximately 2 hours, such as from approximately 0.5 minutes to approximately 2 hours. Preferably, vormetinib is taken orally at least 30 minutes before administering the protein-drug conjugate. More preferably, vormetinib is taken orally at least 30 minutes before administering the protein-drug conjugate and subsequently taken orally at approximately the same time period each day.

[0444] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0445] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0446] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0447] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vometinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0448] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0449] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0450] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC, preferably locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical surgery and / or radical radiotherapy (whether or not it has received concurrent / sequential chemotherapy).

[0451] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer. For example, it includes exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0452] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment. For example, the non-small cell lung cancer has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, it has failed third-generation EGFR-TKI treatment.

[0453] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has not previously received systemic anti-tumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0454] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0455] In some implementations, the non-small cell lung cancer has one or more of the following characteristics:

[0456] (i) The presence of EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations; and / or

[0457] (ii) Subjects who have not previously received systemic antitumor therapy for locally advanced or metastatic stages; or subjects who have previously received neoadjuvant or adjuvant EGFR-TKI therapy, but whose disease progression occurred ≥12 months after the last treatment.

[0458] In some implementations, the non-small cell lung cancer has one or more of the following characteristics:

[0459] (i) The presence of EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations;

[0460] (ii) Previous EGFR-TKI treatment failed;

[0461] Preferably, it meets any of the following requirements: a) failure to treat with a first- or second-generation EGFR-TKI, and histological confirmation of T790M mutation negativity after treatment failure; b) failure to treat with a third-generation EGFR-TKI regardless of T790M mutation status; and / or

[0462] (iii) Has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (e.g., the antitumor therapy is systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy); or

[0463] For patients who have previously received adjuvant / neoadjuvant chemotherapy for nonmetastatic disease with the aim of curative treatment, disease progression occurred ≥6 months after the completion of the last chemotherapy session.

[0464] In some implementations, for locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0465] In some implementations, for EGFR-sensitive mutation-positive non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0466] In some implementations, the non-small cell lung cancer is non-squamous carcinoma.

[0467] In some implementations, the subjects are ≥18 years of age and ≤75 years of age. In some implementations, the subjects have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1.

[0468] In some implementations, the subject has non-small cell lung cancer as defined herein, particularly in this section with respect to aspect eleven.

[0469] In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer, preferably a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical treatment. In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical surgery and / or radical radiotherapy (whether or not receiving concurrent / sequential chemotherapy).

[0470] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0471] In some implementations, the subject has previously received EGFR-TKI treatment and the treatment failed, for example, by failing treatment with a first- or second-generation EGFR-TKI and being histologically confirmed to be T790M mutation negative after treatment failure, or by failing treatment with a third-generation EGFR-TKI.

[0472] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0473] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy; or has previously received adjuvant / neoadjuvant chemotherapy for non-metastatic disease with the aim of cure, but disease progression occurred ≥6 months after the last chemotherapy.

[0474] In some implementations, the subjects are non-small cell lung cancer patients with EGFR-sensitive mutations who have not previously received systemic therapy for locally advanced or metastatic stages.

[0475] In some implementations, the subject has not previously received vortexinib treatment.

[0476] In some implementations, for patients with locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer who have failed EGFR-TKI treatment, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0477] In some implementations, for patients with EGFR-sensitive mutations in non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0478] In some implementations, the subjects are non-small cell lung cancer patients (non-squamous cell carcinoma).

[0479] In some implementations, the subject has one or more of the following characteristics, preferably all of them:

[0480] ① The presence of EGFR-sensitive mutations, including exon 19 deletion mutation (19del) or exon 21 L858R point mutation;

[0481] ② Those who have not previously received systemic antitumor therapy for locally advanced or metastatic stages; or those who have previously received neoadjuvant or adjuvant EGFR-TKI therapy, with disease progression occurring ≥12 months after the last treatment.

[0482] In some implementations, the subject has one or more of the following characteristics, preferably all of them:

[0483] (i) EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations;

[0484] (ii) Previous EGFR-TKI treatment failure (e.g., radiographic disease progression), preferably meeting any of the following requirements: a) failure to receive first- or second-generation EGFR-TKI treatment, with histological confirmation of T790M mutation negativity after treatment failure; b) failure to receive third-generation EGFR-TKI treatment regardless of T790M mutation status; and / or

[0485] (iii) Has not previously received systemic anti-tumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (e.g., systemic anti-tumor therapy is systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy) or has previously received adjuvant / neoadjuvant chemotherapy for non-metastatic disease with the aim of curative treatment, but disease progression occurred ≥6 months after the last chemotherapy.

[0486] The various implementation schemes described above with respect to aspect eleven also apply to aspects twelfth to twentieth as described below.

[0487] In a twelfth aspect, this disclosure relates to a pharmaceutical combination comprising a protein-drug conjugate and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0488] In a thirteenth aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0489] In a fourteenth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the twelfth aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0490] In the fifteenth aspect, this disclosure relates to a pharmaceutical combination of the twelfth aspect or a medicine box of the fourteenth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0491] In the sixteenth aspect, this disclosure relates to the use of the pharmaceutical combination of the twelfth aspect or the medicament of the fourteenth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0492] In a seventeenth aspect, this disclosure relates to the use of the pharmaceutical combination of the twelfth aspect or the medicament of the fourteenth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0493] Eighteenthly, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0494] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0495] The use of the protein-drug conjugate, which is used in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0496] In a nineteenth aspect, this disclosure relates to an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for use in combination with the aforementioned protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0497] Use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the preparation of medicaments for use in combination with said protein-drug conjugates for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0498] Use of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC) in combination with the protein-drug conjugate.

[0499] In a twentieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0500] In the various aspects described above, the protein-drug conjugate and / or multispecific antigen-binding protein may be referred to as defined in the first aspect or as defined above.

[0501] In the various aspects described above, the definition and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or EGFR-TKIs can also be found in the definition and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or EGFR-TKIs in the eleventh aspect above.

[0502] In some implementations, the drug combination is used to treat and / or prevent non-small cell lung cancer (NSCLC).

[0503] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0504] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0505] In some embodiments, the protein-drug conjugate is administered once every two weeks (Q2W). Therefore, in some embodiments, a two-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0506] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0507] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0508] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0509] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0510] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q2W.

[0511] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 2 weeks.

[0512] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q2W.

[0513] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0514] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0515] In some implementations, the EGFR-TKI can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or following the dosing regimen recommended in the product instructions.

[0516] In some implementations, the EGFR-TKI is a third-generation EGFR-TKI.

[0517] In some implementations, the EGFR-TKI is vometinib.

[0518] In some embodiments, the dosage of the EGFR-TKI is 80 mg to 200 mg, for example, about 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg; preferably, the dosage of the EGFR-TKI is 80 mg or 160 mg.

[0519] In some embodiments, the EGFR-TKI is administered once daily (QD). It is understood that some or more administrations may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. In some embodiments, the administration of the EGFR-TKI may be delayed, for example, by more than 1 week, 2 weeks, or up to 3 weeks.

[0520] In some implementations, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0521] In some implementations, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0522] In some implementations, the EGFR-TKI is administered orally, for example, on an empty stomach.

[0523] In some embodiments, the drug combination is performed by first administering the EGFR-TKI and then administering the protein-drug conjugate.

[0524] In some implementations, when the protein-drug conjugate and the EGFR-TKI are administered on the same day, for example, the EGFR-TKI is tried first, followed by the protein-drug conjugate.

[0525] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0526] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0527] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0528] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0529] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vometinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0530] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0531] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the vormetinib is: 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0532] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC, preferably locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical surgery and / or radical radiotherapy (whether or not it has received concurrent / sequential chemotherapy).

[0533] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer. For example, it includes exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0534] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment. For example, the non-small cell lung cancer has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, it has failed third-generation EGFR-TKI treatment.

[0535] In some implementations, the non-small cell lung cancer refers to systemic antitumor therapy for locally advanced or metastatic NSCLC that has not previously been received other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0536] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0537] In some implementations, for locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0538] In some implementations, for EGFR-sensitive mutation-positive non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0539] In some implementations, the non-small cell lung cancer is non-squamous carcinoma.

[0540] In some implementations, the drug combination is suitable for subjects aged ≥18 years and ≤75 years.

[0541] In some implementations, the drug combination is suitable for patients with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer.

[0542] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0543] In some implementations, the subject has previously received EGFR-TKI treatment and failed (radiographic disease progression), for example: failed treatment with a first- or second-generation EGFR-TKI and was histologically confirmed to be T790M mutation negative after treatment failure, or failed treatment with a third-generation EGFR-TKI.

[0544] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0545] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0546] In some implementations, the subjects are non-small cell lung cancer patients with EGFR-sensitive mutations who have not previously received systemic therapy for locally advanced or metastatic stages.

[0547] In some implementations, the subject has not previously received vortexinib treatment.

[0548] In some implementations, for patients with locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer who have failed EGFR-TKI treatment, the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily.

[0549] In some implementations, for patients with EGFR-sensitive mutations in non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages, the EGFR-TKI is vormetinib, administered at a dose of 80 mg once daily.

[0550] In some implementations, the subjects are non-small cell lung cancer patients (non-squamous cell carcinoma).

[0551] In a thirteenth aspect, this disclosure also relates to the use of a protein-drug conjugate in combination with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0552] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0553] In some implementations, the EGFR-TKI is a third-generation EGFR-TKI.

[0554] In some implementations, the EGFR-TKI is vometinib.

[0555] The definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or EGFR-TKIs can also be found in Section 11 above regarding the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or EGFR-TKIs.

[0556] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0557] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer. For example, it includes exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0558] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment. For example, the non-small cell lung cancer has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, it has failed third-generation EGFR-TKI treatment.

[0559] In some implementations, the non-small cell lung cancer refers to systemic antitumor therapy for locally advanced or metastatic NSCLC that has not previously been received other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0560] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0561] Combination of protein-drug conjugates with bispecific antibodies targeting PD-1 / VEGF

[0562] In a twentieth aspect, this disclosure relates to a method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering to a subject in need a protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF, and optionally a platinum-based chemotherapy drug, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0563] In some embodiments, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0564] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0565] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0566] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0567] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0568] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0569] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0570] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0571] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0572] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0573] In some implementations, the bispecific antibody targeting PD-1 / VEGF can be administered using any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or following the dosing regimen recommended in the product instructions.

[0574] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab.

[0575] In some embodiments, the dosage of the bispecific antibody targeting PD-1 / VEGF is 5 mg / kg to 30 mg / kg or 10 mg / kg to 30 mg / kg based on the subject's body weight, for example, approximately 5 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, or 30 mg / kg. Preferably, the dosage of the bispecific antibody targeting PD-1 / VEGF is 20 mg / kg based on the subject's body weight.

[0576] In some embodiments, the bispecific antibody targeting PD-1 / VEGF is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the bispecific antibody targeting PD-1 / VEGF. Preferably, the bispecific antibody targeting PD-1 / VEGF is administered on the first day of each cycle.

[0577] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the bispecific antibody targeting PD-1 / VEGF may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0578] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab, and the dosing regimen is 20 mg / kg based on the subject's body weight, once every three weeks.

[0579] In some implementations, the bispecific antibody targeting PD-1 / VEGF is administered via intravenous infusion.

[0580] In some embodiments, the method involves first administering the protein-drug conjugate, followed by administering the bispecific antibody targeting PD-1 / VEGF.

[0581] In some embodiments, the protein-drug conjugate and the bispecific antibody targeting PD-1 / VEGF are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF.

[0582] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0583] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance).

[0584] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, once or multiple times (preferably until disease remission, disease progression or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of body weight of body weight, once or multiple times every three weeks (preferably until disease remission, disease progression or intolerance).

[0585] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance).

[0586] In some embodiments, the method, in addition to administering the protein-drug conjugate and the bispecific antibody targeting PD-1 / VEGF, further includes administering a platinum-based chemotherapy drug, such as carboplatin, to the subject in need.

[0587] In some embodiments, the platinum-based chemotherapy drug can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0588] In some embodiments, the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), is AUC = 4 to 5, for example, approximately 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0589] In some embodiments, the platinum-based chemotherapy drug is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the platinum-based chemotherapy drug. Preferably, the platinum-based chemotherapy drug is administered on the first day of each cycle.

[0590] It is understood that administration of one or more drugs may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, expressions such as once every two weeks (Q2W), once every three weeks (Q3W), and similar expressions as used herein can each cover the corresponding situation of delay or advancement by 1 day, 2 days, or 3 days. In some embodiments, administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0591] In some embodiments, the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles. In some embodiments, the platinum-based chemotherapy drug is administered 1 to 4 times, for example 2, 3, or 4 times, preferably 4 times.

[0592] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 4, once every three weeks for a total of four cycles.

[0593] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 5, once every three weeks for a total of four cycles.

[0594] In some implementations, the platinum-based chemotherapy drug is administered via intravenous infusion.

[0595] In some embodiments, the method involves first administering the protein-drug conjugate, then administering the bispecific antibody targeting PD-1 / VEGF, and finally administering the platinum-based chemotherapy drug.

[0596] In some implementations, when the protein-drug conjugate, the bispecific antibody targeting PD-1 / VEGF, and the platinum-based chemotherapy drug are administered on the same day, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF, and finally the platinum-based chemotherapy drug is administered.

[0597] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0598] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0599] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0600] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0601] In some embodiments, the method further includes administering pemetrexed to a subject in need, in addition to administering the protein-drug conjugate and the bispecific antibody targeting PD-1 / VEGF.

[0602] In some implementations, the method involves starting pemetrexed administration in the next cycle after platinum-based chemotherapy drugs have been discontinued.

[0603] In some embodiments, the method replaces the platinum-based chemotherapy with pemetrexed after four cycles of administration of the protein-drug conjugate, the bispecific antibody targeting PD-1 / VEGF, and the platinum-based chemotherapy.

[0604] In some embodiments, the pemetrexed can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0605] In some embodiments, the dosage of pemetrexed, based on the subject's body surface area, is 250 mg / m². 2 ~750mg / m 2 For example, approximately 250 mg / m 2 300mg / m 2 350mg / m 2 400mg / m 2 450mg / m 2 500mg / m 2 550mg / m 2 600mg / m 2 650mg / m 2 700mg / m 2 700mg / m 2 Preferred concentration: 500 mg / m³ 2 .

[0606] In some embodiments, the pemetrexed is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the pemetrexed. Preferably, the pemetrexed is administered on the first day of each cycle.

[0607] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of pemetrexed may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0608] In some embodiments, the pemetrexed dosing regimen is as follows: the dosage, based on the subject's body surface area, is 500 mg / m². 2 Once every three weeks.

[0609] In some implementations, the pemetrexed is administered via intravenous infusion.

[0610] In some implementations, the pemetrexed is administered in one or more cycles or once or more until the disease is relieved, progresses, or becomes intolerable.

[0611] In some implementations, when the protein-drug conjugate, the bispecific antibody targeting PD-1 / VEGF, and pemetrexed are administered on the same day, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF, and finally the pemetrexed is administered.

[0612] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0613] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0614] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered once every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0615] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0616] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer, preferably locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that is not suitable for radical surgery and / or radical radiotherapy (whether or not concurrent / sequential chemotherapy).

[0617] In some embodiments, the non-small cell lung cancer is NSCLC that has failed standard treatment. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has failed standard treatment.

[0618] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer. For example, the sensitive mutation includes exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0619] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment. For example, the non-small cell lung cancer has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, it has failed third-generation EGFR-TKI treatment.

[0620] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has not previously received systemic anti-tumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (e.g., systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy).

[0621] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0622] In some implementations, the non-small cell lung cancer is EGFR wild-type NSCLC that is negative for the ALK fusion gene and has no known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy.

[0623] In some embodiments, the non-small cell lung cancer has one or more of the following characteristics, preferably all of them:

[0624] (i) EGFR wild-type and ALK fusion-negative NSCLC, with no known ROS1 gene fusions or other known driver gene alterations approved for first-line targeted therapy; and

[0625] (ii) Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; or

[0626] Patients who have previously received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or who have received radical therapy for locally advanced disease, but whose disease progression occurred ≥6 months after the end of their last treatment.

[0627] In some embodiments, the non-small cell lung cancer has one or more of the following characteristics, preferably all of them.

[0628] (i) The presence of EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations;

[0629] (ii) Previous EGFR-TKI treatment that failed

[0630] Preferably, it meets any of the following requirements: a) failure to treat with a first- or second-generation EGFR-TKI, and histological confirmation of T790M mutation negativity after treatment failure; b) failure to treat with a third-generation EGFR-TKI regardless of T790M mutation status; and / or

[0631] (iii) Has not previously received systemic anti-tumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (e.g., the systemic anti-tumor therapy is systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy); or

[0632] Patients who have previously received adjuvant / neoadjuvant chemotherapy for non-metastatic disease with the aim of curative treatment, but whose disease progression occurred ≥6 months after the last chemotherapy session.

[0633] In some implementations, locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations that has failed EGFR-TKI therapy is treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and evosimab (20 mg / kg Q3W).

[0634] In some implementations, driver gene-negative non-small cell lung cancer patients who have not previously received systemic therapy for locally advanced or metastatic stages are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and evosimab (20 mg / kg Q3W).

[0635] In some implementation schemes, for locally advanced or metastatic non-small cell lung cancer that has failed standard therapy or for driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages, antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W), evokimab (20 mg / kg Q3W), and carboplatin (AUC 5Q3W, 4 cycles) are administered.

[0636] In some implementation schemes, for driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages, after treatment with antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and carboplatin (AUC 5 Q3W, 4 cycles), antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and pemetrexed (500 mg / kg) are administered again. 2 Maintenance therapy (Q3W).

[0637] In some implementations, the subjects are ≥18 years of age and ≤75 years of age. In some implementations, the subjects have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1.

[0638] In some implementations, the subject has non-small cell lung cancer as defined herein, particularly in this section with respect to aspect 21.

[0639] In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer, preferably a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical treatment. In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical surgery and / or radical radiotherapy (whether or not receiving concurrent / sequential chemotherapy).

[0640] In some implementations, the subject is a non-small cell lung cancer patient who has failed standard treatment. In some implementations, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who has failed standard treatment.

[0641] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0642] In some implementations, the subject has previously received EGFR-TKI treatment and failed (radiographic disease progression), for example: failed treatment with a first- or second-generation EGFR-TKI and was histologically confirmed to be T790M mutation negative after treatment failure, or failed treatment with a third-generation EGFR-TKI.

[0643] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0644] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0645] In some implementations, the subjects are non-small cell carcinoma patients with driver gene-negative disease who have not previously received systemic therapy for locally advanced or metastatic stages.

[0646] In some implementations, the non-small cell lung cancer subject is a subject who has not previously received systemic antitumor therapy for locally advanced or metastatic stages, or has previously received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or has received radical treatment for locally advanced disease, but disease progression occurred ≥6 months after the end of the last treatment.

[0647] In some implementation schemes, the subject has one or more of the following characteristics, preferably all of them:

[0648] (i) EGFR wild-type and ALK fusion-negative NSCLC, with no known ROS1 gene fusions or other known driver gene alterations approved for first-line targeted therapy; and

[0649] (ii) Subjects who have not previously received systemic antitumor therapy for locally advanced or metastatic stages, or who have previously received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or who have received radical therapy for locally advanced disease, but whose disease progression occurred ≥6 months after the end of their last treatment.

[0650] In some implementations, the subject has one or more of the following characteristics, preferably all of them.

[0651] (i) EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations;

[0652] (ii) Previous EGFR-TKI treatment failed (e.g., radiographic disease progression),

[0653] Preferably, it meets any of the following requirements: a) failure to treat with a first- or second-generation EGFR-TKI, and histological confirmation of T790M mutation negativity after treatment failure; b) failure to treat with a third-generation EGFR-TKI regardless of T790M mutation status; and / or

[0654] (iii) Has not previously received systemic anti-tumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (in some implementations, the systemic anti-tumor therapy is systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy) or has previously received adjuvant / neoadjuvant chemotherapy for non-metastatic disease with the aim of curative treatment, but disease progression occurred ≥6 months after the last chemotherapy session.

[0655] In some implementations, patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI therapy are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and evosimab (20 mg / kg Q3W).

[0656] In some implementations, patients with driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and evosimab (20 mg / kg Q3W).

[0657] In some implementation schemes, patients with locally advanced or metastatic non-small cell lung cancer who have failed standard therapy or who have driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages are given antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and carboplatin (AUC 5Q3W, 4 cycles).

[0658] In some implementation schemes, for patients with driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages, after treatment with antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and carboplatin (AUC 5 Q3W, 4 cycles), antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and pemetrexed (500 mg / kg Q3W) are administered again. 2 Maintenance therapy (Q3W).

[0659] The various implementation schemes described above for aspect 21 also apply to aspects 22 to 30 described below.

[0660] In a twentieth aspect, this disclosure relates to a pharmaceutical combination comprising the protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF, and optionally a digoxin-based chemotherapy drug.

[0661] In a twentieth aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with a bispecific antibody targeting PD-1 / VEGF, and optionally a platinum-based chemotherapy drug in the preparation of a drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0662] In a twentieth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the twentieth aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0663] In the twentieth aspect, this disclosure relates to a pharmaceutical combination of the twentieth aspect or a medicine box of the twentieth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0664] In a twentieth aspect, this disclosure relates to the use of the pharmaceutical combination of the twentieth aspect or the medicament of the twentieth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0665] In a twentieth aspect, this disclosure relates to the use of the pharmaceutical combination of the twentieth aspect or the medicament of the twentieth aspect in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0666] In a twentieth aspect, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0667] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0668] The use of the protein-drug conjugate, which is used in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0669] In a twentieth aspect, this disclosure relates to a bispecific antibody against PD-1 / VEGF, used in combination with the aforementioned protein-drug conjugate and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0670] The use of a PD-1 / VEGF bispecific antibody in the preparation of a drug for use in combination with the protein-drug conjugate, and optionally with platinum-based chemotherapy drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0671] Use of the PD-1 / VEGF bispecific antibody, wherein the PD-1 / VEGF bispecific antibody is used in combination with the protein-drug conjugate, and optionally with a platinum-based chemotherapy drug, for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0672] In a thirtieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with a bispecific antibody against PD-1 / VEGF and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0673] In the various aspects described above, the protein-drug conjugate and / or multispecific antigen-binding protein may be referred to as defined in the first aspect or as defined above.

[0674] In the various aspects described above, the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, bispecific antibodies against PD-1 / VEGF, platinum-based chemotherapy drugs and / or pemetrexed can also be found in aspect 21 above regarding the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, bispecific antibodies against PD-1 / VEGF, platinum-based chemotherapy drugs and / or pemetrexed.

[0675] In some implementations, the drug combination is used to treat and / or prevent non-small cell lung cancer (NSCLC).

[0676] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, etc. 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3m g / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg; preferably 4 mg / kg to 5 mg / kg.

[0677] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0678] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0679] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0680] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0681] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0682] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0683] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0684] In some implementations, the bispecific antibody targeting PD-1 / VEGF can be administered using any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or following the dosing regimen recommended in the product instructions.

[0685] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab.

[0686] In some embodiments, the dosage of the bispecific antibody targeting PD-1 / VEGF is 5 mg / kg to 30 mg / kg or 10 mg / kg to 30 mg / kg based on the subject's body weight, for example, approximately 5 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, or 30 mg / kg. Preferably, the dosage of the bispecific antibody targeting PD-1 / VEGF is 20 mg / kg based on the subject's body weight.

[0687] In some embodiments, the bispecific antibody targeting PD-1 / VEGF is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the bispecific antibody targeting PD-1 / VEGF. Preferably, the bispecific antibody targeting PD-1 / VEGF is administered on the first day of each cycle.

[0688] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the bispecific antibody targeting PD-1 / VEGF may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0689] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab, and the dosing regimen is 20 mg / kg based on the subject's body weight, once every three weeks.

[0690] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab, and the dosing regimen is 5 mg / kg of body weight, once every three weeks.

[0691] In some implementations, the bispecific antibody targeting PD-1 / VEGF is administered via intravenous infusion.

[0692] In some embodiments, the drug combination is performed by first administering the protein-drug conjugate, followed by administering the bispecific antibody targeting PD-1 / VEGF.

[0693] In some embodiments, the protein-drug conjugate and the bispecific antibody targeting PD-1 / VEGF are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF.

[0694] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0695] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance).

[0696] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, once or multiple times (preferably until disease remission, disease progression or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of body weight of body weight, once or multiple times every three weeks (preferably until disease remission, disease progression or intolerance).

[0697] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the evosimab is: 20 mg / kg of the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance).

[0698] In some embodiments, the drug combination also includes platinum-based chemotherapy drugs, such as carboplatin.

[0699] In some embodiments, the platinum-based chemotherapy drug can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0700] In some embodiments, the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), is AUC = 4 to 5, for example, approximately 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0701] In some embodiments, the platinum-based chemotherapy drug is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the platinum-based chemotherapy drug. Preferably, the platinum-based chemotherapy drug is administered on the first day of each cycle.

[0702] It is understood that administration of one or more drugs may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, expressions such as once every two weeks (Q2W), once every three weeks (Q3W), and similar expressions as used herein can each cover the corresponding situation of delay or advancement by 1 day, 2 days, or 3 days. In some embodiments, administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0703] In some embodiments, the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles. In some embodiments, the platinum-based chemotherapy drug is administered 1 to 4 times, for example 2, 3, or 4 times, preferably 4 times.

[0704] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 4, once every three weeks for a total of four cycles.

[0705] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 5, once every three weeks for a total of four cycles.

[0706] In some implementations, the platinum-based chemotherapy drug is administered via intravenous infusion.

[0707] In some embodiments, the drug combination is administered first, followed by the administration of the protein-drug conjugate, then the administration of the bispecific antibody targeting PD-1 / VEGF, and finally the administration of the platinum-based chemotherapy drug.

[0708] In some implementations, when the protein-drug conjugate, the bispecific antibody targeting PD-1 / VEGF, and the platinum-based chemotherapy drug are administered on the same day, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF, and finally the platinum-based chemotherapy drug is administered.

[0709] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0710] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0711] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0712] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), the dosing regimen of the evosimib is: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance), and the dosing regimen of the carboplatin is: a dose AUC = 5, administered once every three weeks for a total of 4 cycles.

[0713] In some implementations, the drug combination also includes pemetrexed.

[0714] In some implementations, the pemetrexed is administered at the start of the next cycle after platinum-based chemotherapy is discontinued.

[0715] In some embodiments, the pemetrexed can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0716] In some embodiments, the dosage of pemetrexed, based on the subject's body surface area, is selected from 250 mg / m². 2 ~750mg / m 2 For example, approximately 250 mg / m 2300mg / m 2 350mg / m 2 400mg / m 2 450mg / m 2 500mg / m 2 550mg / m 2 600mg / m 2 650mg / m 2 700mg / m 2 700mg / m 2 Preferred concentration: 500 mg / m³ 2 .

[0717] In some embodiments, the pemetrexed is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the pemetrexed. Preferably, the pemetrexed is administered on the first day of each cycle.

[0718] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of pemetrexed may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0719] In some embodiments, the pemetrexed dosing regimen is as follows: the dosage, based on the subject's body surface area, is 500 mg / m². 2 Once every three weeks.

[0720] In some implementations, the pemetrexed is administered via intravenous infusion.

[0721] In some implementations, the pemetrexed is administered in one or more cycles or once or more until the disease is relieved, progresses, or becomes intolerable.

[0722] In some implementations, when the protein-drug conjugate, the bispecific antibody targeting PD-1 / VEGF, and pemetrexed are administered on the same day, the protein-drug conjugate is administered first, followed by the bispecific antibody targeting PD-1 / VEGF, and finally the pemetrexed.

[0723] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0724] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0725] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered once every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0726] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of the evosimib is as follows: 20 mg / kg of body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of the carboplatin is as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, on the first day of the next cycle after carboplatin discontinuation, pemetrexed is administered at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

[0727] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0728] In some embodiments, the non-small cell lung cancer (NSCLC) is EGFR-sensitive mutation NSCLC. For example, it includes exon 19 deletion mutations (19del) or exon 21 L858R point mutations. In some embodiments, the NSCLC is locally advanced or metastatic EGFR-sensitive mutation NSCLC that has failed EGFR-TKI treatment. For example, the NSCLC has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, has failed third-generation EGFR-TKI treatment.

[0729] In some implementations, the non-small cell lung cancer has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (including systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy).

[0730] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0731] In some embodiments, the drug combination includes treatment with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and edoximab (20 mg / kg Q3W) for locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI therapy.

[0732] In some implementations, the drug combination includes treatment with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and edoximumab (20 mg / kg Q3W) for driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0733] In some implementations, the drug combination includes treatment with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W), evokimab (20 mg / kg Q3W), and carboplatin (AUC 5Q3W, 4 cycles) for locally advanced or metastatic non-small cell lung cancer that has failed standard therapy or for driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0734] In some embodiments, the drug combination, for driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages, is followed by treatment with antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and carboplatin (AUC 5 Q3W, 4 cycles), and then further administration of antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and pemetrexed (500 mg / m²). 2 Maintenance therapy (Q3W).

[0735] In some implementations, the drug combination is applicable to subjects aged ≥18 years and ≤75 years.

[0736] In some implementations, the drug combination is intended for patients with locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0737] In some implementations, the subject has an EGFR-sensitive mutation, such as an exon 19 deletion mutation (19del) or an exon 21 L858R point mutation.

[0738] In some implementations, the subject has previously received EGFR-TKI treatment and failed (radiographic disease progression), for example: failed treatment with a first- or second-generation EGFR-TKI and was histologically confirmed to be T790M mutation negative after treatment failure, or failed treatment with a third-generation EGFR-TKI.

[0739] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations who have failed EGFR-TKI treatment.

[0740] In some implementations, the subject has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI, such as systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy.

[0741] In some embodiments, the subjects are non-small cell lung cancer patients with driver gene-negative disease who have not previously received systemic therapy for locally advanced or metastatic stages. In some embodiments, the drug combination includes, for patients with locally advanced or metastatic EGFR-sensitive mutation non-small cell lung cancer who have failed EGFR-TKI therapy, treatment with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and edoximumab (20 mg / kg Q3W).

[0742] In some implementations, the drug combination includes treatment with antibody A-ADC (4 mg / kg or 5 mg / kg Q3W) and evosimab (20 mg / kg Q3W) in patients with driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages.

[0743] In some implementations, the drug combination includes treatment with antibody A-ADC (4 mg / kg or 5 mg / kg Q3W), evokimab (20 mg / kg Q3W), and carboplatin (AUC 5Q3W, 4 cycles) for patients with locally advanced or metastatic non-small cell lung cancer who have failed standard therapy or who have driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages.

[0744] In some implementations, in the drug combination, for patients with driver gene-negative non-small cell lung cancer who have not previously received systemic therapy for locally advanced or metastatic stages, after treatment with antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and carboplatin (AUC 5 Q3W, 4 cycles), antibody A-ADC (4 mg / kg Q3W), evoxisab (20 mg / kg Q3W), and pemetrexed (500 mg / mcg) are administered again. 2 Maintenance therapy (Q3W).

[0745] In a twentieth aspect, this disclosure also relates to the use of a protein-drug conjugate in combination with a bispecific antibody targeting PD-1 / VEGF in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0746] In some embodiments, this disclosure also relates to the use of protein-drug conjugates in combination with bispecific antibodies targeting PD-1 / VEGF and platinum-based chemotherapy drugs in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugates comprising multispecific antigen-binding proteins that target human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0747] In some embodiments, this disclosure also relates to the use of protein-drug conjugates in combination with bispecific antibodies targeting PD-1 / VEGF and pemetrexed in the preparation of medicaments for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugates comprising multispecific antigen-binding proteins that target human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0748] In some embodiments, this disclosure also relates to the use of protein-drug conjugates in combination with bispecific antibodies targeting PD-1 / VEGF and platinum-based drugs, and pemetrexed in the preparation of drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugates comprising multispecific antigen-binding proteins that target human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0749] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0750] In some implementations, the bispecific antibody targeting PD-1 / VEGF is evokinemab.

[0751] In some implementations, the platinum-based chemotherapy drug is carboplatin.

[0752] The definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, bispecific antibodies targeting PD-1 / VEGF, platinum-based chemotherapy drugs and / or pemetrexed can also be found in section 21 above regarding the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or EGFR-TKIs.

[0753] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0754] In some implementations, the non-small cell lung cancer is EGFR-sensitive mutation-positive non-small cell lung cancer. For example, it includes exon 19 deletion mutation (19del) or exon 21 L858R point mutation.

[0755] In some implementations, the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation-positive non-small cell lung cancer that has failed EGFR-TKI treatment. For example, the non-small cell lung cancer has failed first- or second-generation EGFR-TKI treatment and is histologically confirmed to be T790M mutation negative after treatment failure; or, regardless of the T790M mutation status, it has failed third-generation EGFR-TKI treatment.

[0756] In some implementations, the non-small cell lung cancer has not previously received systemic antitumor therapy for locally advanced or metastatic NSCLC other than EGFR-TKI (including systemic therapy in combination with EGFR-TKI, such as chemotherapy and immunotherapy).

[0757] In some implementations, the non-small cell lung cancer is a driver gene-negative non-small cell carcinoma that has not previously received systemic therapy for locally advanced or metastatic stages.

[0758] Combination of protein-drug conjugates and docetaxel

[0759] In a thirtieth aspect, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and docetaxel to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0760] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0761] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, etc. 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6mg / kg, 6.7mg / kg, 6.8m g / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg; preferably 4 mg / kg to 6 mg / kg.

[0762] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0763] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0764] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0765] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0766] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0767] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0768] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0769] In some implementations, the docetaxel can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0770] In some embodiments, the dosage of docetaxel, based on the subject's body surface area, is selected from 50 mg / m². 2 ~100mg / m 2 For example, approximately 50 mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 Preferred concentration: 60 mg / m³ 2 ~75mg / m 2

[0771] In some embodiments, the docetaxel is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the docetaxel. Preferably, the docetaxel is administered on the first day of each cycle.

[0772] It is understood that some or more administrations may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of docetaxel may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0773] In some implementations, the dosing regimen of docetaxel is: 60 mg / m² based on the subject's body surface area. 2 , Q3W.

[0774] In some implementations, the dosing regimen of docetaxel is: 75 mg / m² based on the subject's body surface area. 2 , Q3W.

[0775] In some implementations, the route of administration of docetaxel is intravenous infusion.

[0776] In some implementations, the method involves administering the protein-drug conjugate first, followed by the administration of docetaxel.

[0777] In some implementations, the protein-drug conjugate and the docetaxel are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the docetaxel.

[0778] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0779] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0780] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0781] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0782] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC, preferably locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) NSCLC that is not suitable for radical surgery and / or radical radiotherapy (whether or not it has received concurrent / sequential chemotherapy).

[0783] In some implementations, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has failed standard treatment.

[0784] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has previously failed a platinum-based chemotherapy regimen for locally advanced or metastatic NSCLC.

[0785] In some embodiments, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has failed treatment with a PD-1 / L1 inhibitor and a platinum-based chemotherapy regimen.

[0786] In some implementations, the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer that has failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy.

[0787] In some implementations, the non-small cell lung cancer is an EGFR-sensitive mutation that has failed EGFR-TKI treatment and has failed a platinum-based chemotherapy regimen.

[0788] In some implementations, the failure of EGFR-TKI treatment refers to failure of treatment with a first- or second-generation EGFR-TKI, and subsequent histological confirmation of a negative T790M mutation; or, regardless of the T790M mutation status, failure of treatment with a third-generation EGFR-TKI.

[0789] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has not received docetaxel treatment.

[0790] In some implementations, the non-small cell lung cancer meets one or more of the following characteristics:

[0791] (i) EGFR wild-type and ALK fusion gene negative;

[0792] (ii) No known ROS1 gene fusions or other driver gene alterations for approved first-line targeted therapies;

[0793] (iii) Previously treated with a systemic platinum-based chemotherapy combined with a PD-1 / PD-L1 inhibitor for locally advanced or metastatic NSCLC, and the treatment failed; or previously treated with adjuvant / neoadjuvant chemotherapy (with or without a PD-1 / L1 inhibitor) for the purpose of cure, but the disease progressed within 6 months after the end of the last treatment;

[0794] (iv) At least two cycles of platinum-based chemotherapy and PD-1 / PD-L1 inhibitors have been administered; and / or

[0795] (v) Has not previously received docetaxel treatment.

[0796] In some implementations, the non-small cell lung cancer meets one or more of the following characteristics:

[0797] (i) The presence of EGFR-sensitive mutations, including exon 19 deletion mutations (19del) or exon 21 L858R point mutations;

[0798] (ii) Previously treated with EGFR-TKI for locally advanced or metastatic NSCLC and failed treatment, preferably meeting any of the following requirements: a) failed treatment with a first- or second-generation EGFR-TKI and histologically confirmed negative for T790M mutation; or b) failed treatment with a third-generation EGFR-TKI (regardless of T790M mutation status).

[0799] (iii) Previously received neoadjuvant or adjuvant EGFR-TKI therapy, and disease progression occurred within 12 months of the last treatment;

[0800] (iv) Previously received platinum-based chemotherapy for locally advanced or metastatic NSCLC and failed; or previously received neoadjuvant, adjuvant or radical chemoradiotherapy and the disease progressed within 6 months after the last chemotherapy.

[0801] Optionally, platinum-based chemotherapy may be administered before EGFR-TKI treatment, after treatment failure, or in combination with EGFR-TKI therapy;

[0802] Optionally, platinum-based chemotherapy or EGFR-TKIs can be used in combination with targeted drugs (including but not limited to anti-angiogenic TKIs or monoclonal antibodies);

[0803] Optionally, platinum-based chemotherapy can be combined with immunotherapies (such as PD-1 / PD-L1 monoclonal / dual antibodies);

[0804] (iv) Has not previously received docetaxel treatment.

[0805] In some implementations, the subjects are ≥18 years of age and ≤75 years of age. In some implementations, the subjects have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1.

[0806] In some implementations, the subject has non-small cell lung cancer as defined herein, particularly in this section with respect to aspect thirty-one.

[0807] In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer, preferably a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical treatment. In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical surgery and / or radical radiotherapy (whether or not receiving concurrent / sequential chemotherapy).

[0808] In some implementations, the subjects are patients with locally advanced or metastatic non-small cell lung cancer who have failed standard treatment.

[0809] In some implementations, the subjects are non-small cell lung cancer patients who have previously failed platinum-based chemotherapy for locally advanced or metastatic NSCLC.

[0810] In some implementations, the subjects are EGFR wild-type non-small cell lung cancer patients who have failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy.

[0811] In some implementations, the subjects are non-small cell lung cancer patients with EGFR wild-type and ALK fusion gene negative.

[0812] In some implementations, the subject does not have known ROS1 gene fusions or other known driver gene alterations for first-line targeted therapies.

[0813] In some implementations, the subject had received systemic platinum-based chemotherapy and a PD-1 / L1 inhibitor and had failed the treatment (radiological progression).

[0814] In some implementations, the subject is a non-small cell lung cancer patient with an EGFR-sensitive mutation who has failed EGFR-TKI treatment and has failed one platinum-based chemotherapy.

[0815] In some implementations, EGFR-TKI treatment failure refers to failure of first- or second-generation EGFR-TKI treatment, followed by histological confirmation of T790M mutation negativity; or, regardless of T790M mutation status, failure of third-generation EGFR-TKI treatment. In some implementations, the subject has not received docetaxel treatment.

[0816] In some implementations, the subject meets one or more of the following characteristics (preferably all of them):

[0817] ① EGFR wild-type and ALK fusion gene negative NSCLC, with no known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy;

[0818] ② Previously treated with a systemic platinum-based chemotherapy and PD-1 / L1 inhibitor for locally advanced or metastatic NSCLC and failed (e.g., radiographic progression); or previously treated with adjuvant / neoadjuvant chemotherapy (with or without PD-1 / L1 inhibitor) for the purpose of cure and the disease progression occurred within 6 months after the end of the last treatment;

[0819] Preferably, both the PD-1 / L1 inhibitor and platinum-based chemotherapy should have been used for at least two cycles; and / or

[0820] ③ The patient had not previously received docetaxel treatment.

[0821] In some implementations, the subject meets one or more of the following characteristics (preferably all of them):

[0822] ① The presence of EGFR-sensitive mutations, including exon 19 deletion mutation (19del) or exon 21 L858R point mutation;

[0823] ② Patients who have previously received EGFR-TKI therapy for locally advanced or metastatic NSCLC and have failed the treatment (e.g., radiographic disease progression), preferably meeting any of the following criteria: a) Failure to receive first- or second-generation EGFR-TKI therapy, and histological confirmation of T790M mutation negativity after treatment failure; b) Failure to receive third-generation EGFR-TKI therapy regardless of T790M mutation status; or

[0824] Or have previously received neoadjuvant or adjuvant EGFR-TKI therapy and the disease progression has occurred within 12 months of the last treatment;

[0825] ③ Previously received platinum-based chemotherapy for locally advanced or metastatic NSCLC and failed (e.g., disease progression on imaging); or previously received neoadjuvant or adjuvant therapy or radical chemoradiotherapy and disease progression occurred within 6 months after the last chemotherapy session;

[0826] Optionally, platinum-based chemotherapy may be used before, after, or in combination with EGFR-TKI treatment; targeted therapies (including but not limited to anti-angiogenic TKIs or monoclonal antibodies) may be used in combination with EGFR-TKIs or platinum-based chemotherapy; and / or immunotherapies (including but not limited to monoclonal or bispecific antibodies targeting PD-1 / PD-L1) may be used in combination with platinum-based chemotherapy.

[0827] ④ He has not previously received docetaxel treatment.

[0828] In some embodiments, in said method, for subjects with locally advanced or metastatic NSCLC who have failed standard therapy, antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and docetaxel (60 mg / m²) are administered. 2 Treatment of Q3W).

[0829] In some embodiments, in said method, for subjects with locally advanced or metastatic NSCLC who have failed standard therapy, antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and docetaxel (75 mg / m²) are administered. 2 Treatment of Q3W).

[0830] In some embodiments, in said method, for subjects with locally advanced or metastatic driver gene-negative NSCLC who have failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy, antibody A-ADC (4 mg / kg Q3W) and docetaxel (60 mg / m²) are administered. 2 Treatment of Q3W).

[0831] In some embodiments, in said method, subjects with locally advanced or metastatic driver gene-negative NSCLC who have failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy are given antibody A-ADC (4 mg / kg Q3W) and docetaxel (75 mg / m²). 2 Treatment of Q3W).

[0832] The various implementation schemes described above for aspect 31 also apply to aspects 32 to 40 described below.

[0833] In a 32nd aspect, this disclosure relates to a pharmaceutical combination comprising a protein-drug conjugate and docetaxel, said protein-drug conjugate containing a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0834] In a thirty-third aspect, this disclosure also relates to the use of the protein-drug conjugate in combination with docetaxel in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0835] In a thirty-fourth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in the thirty-second aspect, optionally further comprising pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0836] In the thirty-fifth aspect, this disclosure relates to a pharmaceutical combination of the thirty-second aspect or a medicine box of the thirty-fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0837] In the thirty-sixth aspect, this disclosure relates to the use of the pharmaceutical combination of the thirty-second aspect or the medicament of the thirty-fourth aspect for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0838] In a thirty-seventh aspect, this disclosure relates to the use of the pharmaceutical combination of aspect thirty-two or the medicament of aspect fourteen in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0839] In a thirty-eighth aspect, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0840] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0841] The use of the protein-drug conjugate, which is used in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0842] Thirty-ninthly, this disclosure relates to docetaxel, used in combination with the said protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0843] The use of docetaxel in the preparation of a medicament for use in combination with the protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0844] The use of docetaxel, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with the protein-drug conjugate for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0845] In a fortieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with docetaxel for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0846] In the various aspects described above, the protein-drug conjugate and / or multispecific antigen-binding protein may be referred to as defined in the first aspect or as defined above.

[0847] In the various aspects described above, the definition and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or docetaxel can also be found in the definition and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or docetaxel in aspect 31 above.

[0848] In some implementations, the drug combination is used to treat and / or prevent non-small cell lung cancer (NSCLC).

[0849] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, etc. 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6mg / kg, 6.7mg / kg, 6.8m g / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg; preferably 4 mg / kg to 6 mg / kg.

[0850] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0851] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0852] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0853] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0854] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0855] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0856] In some implementations, the docetaxel can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0857] In some embodiments, the dosage of docetaxel, based on the subject's body surface area, is selected from 50 mg / m². 2 ~100mg / m 2 For example, approximately 50 mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 Preferred concentration: 60 mg / m³ 2 ~75mg / m 2

[0858] In some embodiments, the docetaxel is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the docetaxel. Preferably, the docetaxel is administered on the first day of each cycle.

[0859] It is understood that some or more administrations may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of docetaxel may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0860] In some implementations, the dosing regimen of docetaxel is: 60 mg / m² based on the subject's body surface area. 2 , Q3W.

[0861] In some implementations, the dosing regimen of docetaxel is: 75 mg / m² based on the subject's body surface area. 2 , Q3W.

[0862] In some embodiments, the docetaxel is administered via intravenous infusion. In some embodiments, in the drug combination, the protein-drug conjugate is administered first, followed by docetaxel.

[0863] In some implementations, the protein-drug conjugate and the docetaxel are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the docetaxel.

[0864] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0865] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0866] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0867] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

[0868] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0869] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0870] In some embodiments, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has failed treatment with a PD-1 / L1 inhibitor and a platinum-based chemotherapy regimen.

[0871] In some implementations, the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer that has failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy.

[0872] In some implementations, the non-small cell lung cancer is an EGFR-sensitive mutation that has failed EGFR-TKI treatment and has failed a platinum-based chemotherapy regimen.

[0873] In some implementations, the failure of EGFR-TKI treatment refers to failure of treatment with a first- or second-generation EGFR-TKI, and subsequent histological confirmation of a negative T790M mutation; or, regardless of the T790M mutation status, failure of treatment with a third-generation EGFR-TKI.

[0874] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has not received docetaxel treatment.

[0875] In some implementations, the drug combination is applicable to subjects aged ≥18 years and ≤75 years.

[0876] In some implementations, the drug combination is intended for patients with locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0877] In some implementations, the subject in the drug combination is a patient with locally advanced or metastatic non-small cell lung cancer who has failed standard treatment.

[0878] In some implementations, the subject in the drug combination is an EGFR wild-type non-small cell lung cancer patient who has failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy.

[0879] In some implementations, the subjects are non-small cell lung cancer patients with EGFR wild-type and ALK fusion gene negative.

[0880] In some implementations, the subject does not have known ROS1 gene fusions or other known driver gene alterations for first-line targeted therapies.

[0881] In some implementations, the subject had received systemic platinum-based chemotherapy and a PD-1 / L1 inhibitor and had failed the treatment (radiological progression).

[0882] In some implementations, the subject in the drug combination is a non-small cell lung cancer patient with an EGFR-sensitive mutation who has failed EGFR-TKI treatment and has failed one platinum-based chemotherapy.

[0883] In some implementations, the failure of EGFR-TKI treatment refers to failure of treatment with a first- or second-generation EGFR-TKI, and subsequent histological confirmation of a negative T790M mutation; or, regardless of the T790M mutation status, failure of treatment with a third-generation EGFR-TKI.

[0884] In some implementations, the subjects did not receive docetaxel treatment.

[0885] In some embodiments, the drug combination, for subjects with locally advanced or metastatic NSCLC who have failed standard therapy, includes administration of antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and docetaxel (60 mg / m²). 2 Treatment of Q3W).

[0886] In some embodiments, the drug combination, for subjects with locally advanced or metastatic NSCLC who have failed standard therapy, includes administration of antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and docetaxel (75 mg / m²). 2 Treatment of Q3W).

[0887] In some embodiments, the drug combination, for subjects with locally advanced or metastatic driver gene-negative NSCLC who have failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy, includes antibody A-ADC (4 mg / kg Q3W) and docetaxel (60 mg / m²). 2 Treatment of Q3W).

[0888] In some embodiments, the drug combination, for subjects with locally advanced or metastatic driver gene-negative NSCLC who have failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy, includes antibody A-ADC (4 mg / kg Q3W) and docetaxel (75 mg / m²). 2 Treatment of Q3W).

[0889] In a thirty-third aspect, this disclosure also relates to the use of a protein-drug conjugate in combination with docetaxel in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC), said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0890] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0891] The definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or docetaxel can also be found in section 31 above regarding the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins and / or docetaxel.

[0892] In some implementations, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

[0893] In some embodiments, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has failed treatment with a PD-1 / L1 inhibitor and a platinum-based chemotherapy regimen.

[0894] In some implementations, the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer that has failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor therapy.

[0895] In some implementations, the non-small cell lung cancer is an EGFR-sensitive mutation that has failed EGFR-TKI treatment and has failed a platinum-based chemotherapy regimen.

[0896] In some implementations, the failure of EGFR-TKI treatment refers to failure of treatment with a first- or second-generation EGFR-TKI, and subsequent histological confirmation of a negative T790M mutation; or, regardless of the T790M mutation status, failure of treatment with a third-generation EGFR-TKI.

[0897] In some implementations, the non-small cell lung cancer is non-small cell lung cancer that has not received docetaxel treatment.

[0898] Combination of protein-drug conjugates with PD-1 inhibitors

[0899] In a forty-first aspect, this disclosure relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering to a subject in need a protein-drug conjugate and a PD-1 inhibitor and optionally a diplatin-based chemotherapy drug, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0900] In some embodiments, this disclosure also relates to a method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a PD-1 inhibitor to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0901] The protein-drug conjugate and / or multispecific antigen-binding protein are as defined in the first aspect. Administration of the protein-drug conjugate and / or multispecific antigen-binding protein is also as described in the first aspect above regarding administration of the protein-drug conjugate and / or multispecific antigen-binding protein.

[0902] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg, for example, approximately 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, etc. 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6mg / kg, 6.7mg / kg, 6.8m g / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg; preferably 4 mg / kg to 6 mg / kg.

[0903] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[0904] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the protein-drug conjugate may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0905] In some implementations, the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W.

[0906] In some implementations, the dosing regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks.

[0907] In some implementations, the dosing regimen of the protein-drug conjugate is: 6 mg / kg based on the subject's body weight, Q3W.

[0908] In some implementations, the protein-drug conjugate is administered via intravenous infusion.

[0909] In some implementations, the protein-drug conjugate is administered in one or more cycles or once or multiple times until disease remission, disease progression, or intolerance occurs.

[0910] In some implementations, the PD-1 inhibitor can be administered with any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the US NCCN guidelines, the European ESMO guidelines, the US ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0911] In some implementations, the PD-1 inhibitor is tislelizumab.

[0912] In some embodiments, the dosage of the PD-1 inhibitor is 150 mg to 250 mg, for example, about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg; preferably, the dosage of the PD-1 inhibitor is 200 mg.

[0913] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0914] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0915] In some implementations, the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks.

[0916] In some implementations, the PD-1 inhibitor is administered via intravenous infusion.

[0917] In some implementations, the method involves first administering the protein-drug conjugate, followed by administering the PD-1 inhibitor.

[0918] In some implementations, when the protein-drug conjugate and the PD-1 inhibitor are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the PD-1 inhibitor.

[0919] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0920] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the tislelizumab is: a dose of 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0921] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the tislelizumab is: 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0922] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the tislelizumab is: a dose of 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0923] In some embodiments, the method further includes administering a platinum-based chemotherapy drug, such as carboplatin, to the subject in need, in addition to administering the protein-drug conjugate and the PD-1 inhibitor.

[0924] In some embodiments, the platinum-based chemotherapy drug can be administered in any suitable dosing regimen, particularly according to dosing regimens known in the art or clinically recommended (covering dosage, dose adjustment or discontinuation, route of administration, order of administration, frequency of administration, dosing cycle, duration of treatment and / or Stop-and-Go strategy, etc.), such as following guidelines, such as the Chinese CSCO guidelines, the American NCCN guidelines, the European ESMO guidelines, the American ASCO guidelines, etc., or according to the dosing regimen recommended in the product instructions.

[0925] In some embodiments, the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), is AUC = 4 to 5, for example, approximately 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.

[0926] In some embodiments, the platinum-based chemotherapy drug is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the platinum-based chemotherapy drug. Preferably, the platinum-based chemotherapy drug is administered on the first day of each cycle.

[0927] It is understood that administration of one or more drugs may be delayed or advanced for various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, expressions such as once every two weeks (Q2W), once every three weeks (Q3W), and similar expressions as used herein can each cover the corresponding situation of delay or advancement by 1 day, 2 days, or 3 days. In some embodiments, administration of the platinum-based chemotherapy drug may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or up to 6 weeks.

[0928] In some embodiments, the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles. In some embodiments, the platinum-based chemotherapy drug is administered 1 to 4 times, for example 2, 3, or 4 times, preferably 4 times.

[0929] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 4, once every three weeks for a total of four cycles.

[0930] In some embodiments, the platinum-based chemotherapy drug is carboplatin, administered at a dose with an AUC of 5, once every three weeks for a total of four cycles.

[0931] In some implementations, the platinum-based chemotherapy drug is administered via intravenous infusion.

[0932] In some embodiments, the method involves first administering the protein-drug conjugate, then the PD-1 inhibitor, and finally the platinum-based chemotherapy drug.

[0933] In some implementations, when the protein-drug conjugate, PD-1 inhibitor, and platinum-based chemotherapy drug are administered on the same day, the protein-drug conjugate is administered first, followed by the PD-1 inhibitor, and finally the platinum-based chemotherapy drug.

[0934] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0935] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of carboplatin is AUC=5 every three weeks for a total of 4 cycles.

[0936] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of carboplatin is AUC=5 every three weeks for a total of 4 cycles.

[0937] In some embodiments, the dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the dosing regimen of tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the dosing regimen of carboplatin is AUC=5 every three weeks for a total of 4 cycles.

[0938] In some implementations, the PD-1 inhibitor is pembrolizumab.

[0939] In some embodiments, the dosage of the PD-1 inhibitor is 150 mg to 250 mg, for example, about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg; preferably, the dosage of the PD-1 inhibitor is 200 mg.

[0940] In some embodiments, the PD-1 inhibitor is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the PD-1 inhibitor. Preferably, the PD-1 inhibitor is administered on the first day of each cycle.

[0941] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosure. Therefore, the expressions "once every 2 weeks (Q2W), once every 3 weeks (Q3W)," and similar expressions as used herein can each cover the corresponding situation of a delay or advancement of 1 day, 2 days, or 3 days. In some embodiments, the administration of the PD-1 inhibitor may be delayed, for example, by more than 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or up to 12 weeks.

[0942] In some implementations, the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks.

[0943] In some implementations, the PD-1 inhibitor is administered via intravenous infusion.

[0944] In some implementations, the method involves first administering the protein-drug conjugate, followed by administering the PD-1 inhibitor.

[0945] In some implementations, when the protein-drug conjugate and the PD-1 inhibitor are administered on the same day, for example, the protein-drug conjugate is administered first, followed by the PD-1 inhibitor.

[0946] There is no strict time interval between different medications; it can be determined by local clinical practice or the physician in charge. For example, the time interval between two medications can be from about 1 minute to about 2 hours, or from about 0.5 minutes to about 2 hours.

[0947] In some embodiments, the dosing regimen of the protein-drug conjugate is: 4 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the pembrolizumab is: a dose of 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0948] In some embodiments, the dosing regimen of the protein-drug conjugate is: 5 mg / kg of body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the pembrolizumab is: 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

[0949] In some embodiments, the dosing regimen of the protein-drug conjugate is: 6 mg / kg of the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the pembrolizumab is: a dose of 200 mg, administered once or multiple times every three weeks (preferably until disease remission, disease progression or intolerance).

[0950] In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer, preferably locally advanced (IIIB / IIIC) or metastatic (stage IV) NSCLC that is not suitable for radical treatment. In some embodiments, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) NSCLC that is not suitable for radical surgery and / or radical radiotherapy (whether or not it is treated with concurrent / sequential chemotherapy).

[0951] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer.

[0952] In some implementations, the PD-L1 TPS of the non-small cell lung cancer is ≥1%.

[0953] In some implementations, the non-small cell lung cancer has not received systemic treatment, such as systemic treatment for locally advanced or metastatic stages.

[0954] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

[0955] In some implementations, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer with PD-L1 TPS ≥1% and no prior systemic therapy for locally advanced or metastatic stages.

[0956] In some embodiments, the non-small cell lung cancer meets any one or all of the following characteristics, preferably all of them:

[0957] (i) EGFR wild-type and ALK fusion-negative NSCLC, without known ROS1 gene fusions or other known driver gene alterations approved for first-line targeted therapy; and / or

[0958] (ii) Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; or

[0959] For non-metastatic disease, patients have received adjuvant / neoadjuvant therapy with the aim of curative treatment, or for locally advanced disease, patients have received radical treatment, and disease progression occurs ≥6 months after the end of the last treatment.

[0960] In some implementations, the non-small cell lung cancer meets any one or more of the following characteristics:

[0961] (i) EGFR wild-type and ALK fusion-negative NSCLC, without known ROS1 gene fusions or other known driver gene alterations approved for first-line targeted therapy; and / or

[0962] (ii) Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; or

[0963] Patients who have received adjuvant / neoadjuvant therapy for non-metastatic disease with a curative purpose, or who have received radical therapy for locally advanced disease, and whose disease progression occurred ≥6 months after the end of their last treatment; and / or

[0964] (iii) Positive PD-L1 expression (preferably, PD-L1 TPS ≥ 1%).

[0965] In some implementations, the subjects are ≥18 years of age and ≤75 years of age. In some implementations, the subjects have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1.

[0966] In some implementations, the subject has non-small cell lung cancer as defined herein, particularly in this section with respect to aspect thirty-one.

[0967] In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer, preferably a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical treatment. In some embodiments, the subject is a patient with locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer who is not suitable for radical surgery and / or radical radiotherapy (whether or not receiving concurrent / sequential chemotherapy).

[0968] In some implementations, the subjects are non-small cell lung cancer patients with EGFR wild-type and ALK fusion gene negative.

[0969] In some implementations, the subject does not have known ROS1 gene fusions or other known driver gene alterations for first-line targeted therapies.

[0970] In some implementations, the subjects have not previously received systemic antitumor therapy for locally advanced or metastatic stages.

[0971] In some implementations, the subject is PD-L1 positive, for example, PD-L1 TPS ≥ 1%.

[0972] In some implementations, the subject meets one or more of the following characteristics (preferably all of them):

[0973] ① NSCLC with EGFR wild-type and ALK fusion gene negative, without known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy;

[0974] ② Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; and / or

[0975] For subjects who have previously received adjuvant / neoadjuvant therapy for non-metastatic disease with the aim of curative treatment, or who have received radical therapy for locally advanced disease, disease progression occurring ≥6 months after the end of the last treatment is considered to meet the requirements.

[0976] In some implementations, the subject meets one or more of the following characteristics (preferably all of them):

[0977] ① NSCLC with EGFR wild-type and ALK fusion gene negative, without known ROS1 gene fusion or other known driver gene alterations that have been approved for first-line targeted therapy;

[0978] ② Has not previously received systemic antitumor therapy for locally advanced or metastatic stages; or

[0979] For subjects who have previously received adjuvant / neoadjuvant therapy for nonmetastatic disease with a curative purpose, or who have received radical therapy for locally advanced disease, disease progression occurring ≥6 months after the end of their last treatment is considered to meet the criteria; and / or

[0980] ③ PD-L1 expression is positive (e.g., PD-L1 TPS ≥ 1%).

[0981] In some implementations, patients with driver gene-negative NSCLC who have not previously received systemic therapy for locally advanced or metastatic stages are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and tislelizumab (200 mg Q3W).

[0982] In some implementations, patients with driver gene-negative NSCLC who have not previously received systemic therapy for locally advanced or metastatic stages are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W), tislelizumab (200 mg Q3W), and carboplatin (AUC 5 Q3W, 4 cycles).

[0983] In some implementations, NSCLC subjects with driver gene-negative PD-L1 TPS ≥1% and who have not previously received systemic therapy for locally advanced or metastatic stages are treated with antibody A-ADC (4 mg / kg, 5 mg / kg, or 6 mg / kg Q3W) and pembrolizumab (200 mg Q3W).

[0984] The various implementation schemes described above for aspect thirty-one also apply to aspects forty-two to fiftieth as described below.

[0985] In a forty-second aspect, this disclosure relates to a pharmaceutical combination comprising a protein-drug conjugate and a PD-1 inhibitor, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

[0986] In aspect forty-three, this disclosure also relates to the use of the protein-drug conjugate in combination with a PD-1 inhibitor and optionally a diplatin-based chemotherapy drug in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0987] In a forty-fourth aspect, this disclosure relates to a pillbox containing the pharmaceutical combination described in aspect forty-two, optionally, the pillbox further containing pharmaceutical instructions instructing patients in need of the combination to treat and / or prevent non-small cell lung cancer (NSCLC).

[0988] In aspect forty-five, this disclosure relates to a pharmaceutical combination of aspect forty-two or a medicine box of aspect forty-four for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0989] In aspect forty-six, this disclosure relates to the use of the pharmaceutical combination of aspect forty-two or the medicament of aspect forty-four for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0990] In a forty-seventh aspect, this disclosure relates to the use of the pharmaceutical combination of aspect forty-two or the medicament of aspect forty-four in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0991] In aspect forty-eight, this disclosure relates to the aforementioned protein-drug conjugate for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0992] The protein-drug conjugate is intended for use in the preparation of a drug for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy drug for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0993] The use of the protein-drug conjugate, which is used in combination with PD-1 inhibitors and optionally platinum-based chemotherapy drugs for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0994] In aspect forty-nine, this disclosure relates to a PD-1 inhibitor for use in combination with the aforementioned protein-drug conjugate and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0995] Use of PD-1 inhibitors in the preparation of medicaments for use in combination with the protein-drug conjugates, and optionally with platinum-based chemotherapy agents for the treatment and / or prevention of non-small cell lung cancer (NSCLC); or

[0996] Use of the PD-1 inhibitor, wherein the PD-1 inhibitor is used in combination with the protein-drug conjugate and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0997] In a fiftieth aspect, this disclosure relates to a single-dose unit comprising a single effective dose of the protein-drug conjugate for use in combination with a PD-1 inhibitor and optionally a platinum-based chemotherapy agent for the treatment and / or prevention of non-small cell lung cancer (NSCLC).

[0998] In the various aspects described above, the protein-drug conjugate and / or multispecific antigen-binding protein may be referred to as defined in the first aspect or as defined above.

[0999] In the various aspects described above, the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, the platinum-based chemotherapy drugs and / or the PD-1 inhibitors may also refer to the definitions and administration of the protein-drug conjugates and / or multispecific antigen-binding proteins, the platinum-based chemotherapy drugs and / or the PD-1 inhibitors in the first aspect above.

[1000] In some implementations, the drug combination is used to treat and / or prevent non-small cell lung cancer (NSCLC).

[1001] In some embodiments, the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg, for example 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5... .4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6mg / kg, 6.7mg / kg, 6.8m g / kg, 6.9 mg / kg, 7.0 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8.0 mg / kg; preferably 4 mg / kg to 6 mg / kg.

[1002] In some embodiments, the protein-drug conjugate is administered once every three weeks (Q3W). Therefore, in some embodiments, a three-week period is defined as one dosing cycle for the protein-drug conjugate. Preferably, the protein-drug conjugate is administered on the first day of each cycle.

[1003] It is understood that some administrations may be delayed or advanced due to various reasons, such as patient inconvenience, for example, by 1 day (±1 day), 2 days (±2 days), or 3 days (±3 days), which is also covered within the scope of this disclosu...

Claims

1. A method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a platinum-based chemotherapy drug to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

2. The method according to claim 1, wherein the multispecific antigen-binding protein comprises an antibody or an antigen-binding fragment thereof that binds to TROP2.

3. The method according to claim 2, wherein the antibody binding to TROP2 or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region includes: H1CDR1, which contains the amino acid sequence shown in SEQ ID NO: 1; H1CDR2, which contains the amino acid sequence shown in SEQ ID NO: 2; and H1CDR3, which contains the amino acid sequence shown in SEQ ID NO:

3. The light chain variable region comprises: LCDR1, which contains the amino acid sequence shown in SEQ ID NO: 4; LCDR2, which contains the amino acid sequence shown in SEQ ID NO: 5; and LCDR3, which contains the amino acid sequence shown in SEQ ID NO:

6.

4. The method according to claim 2 or 3, wherein the antibody binding to TROP2 or its antigen-binding fragment comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:

7.

5. The method according to any one of claims 2-4, wherein the antibody binding to TROP2 or its antigen-binding fragment comprises a light chain variable region, wherein the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:

8.

6. The method according to any one of claims 2-5, wherein the antibody binding TROP2 or its antigen-binding fragment comprises a heavy chain, the heavy chain further comprising a constant region of human IgG1 or a variant thereof, for example, the constant region of human IgG1 comprising the amino acid sequence shown in SEQ ID NO:

9.

7. The method according to any one of claims 2-6, wherein the antibody binding TROP2 or its antigen-binding fragment comprises a light chain, the light chain further comprising a constant region of human Igκ or a variant thereof, for example, the constant region of human Igκ comprising the amino acid sequence shown in SEQ ID NO:

10.

8. The method according to any one of claims 2-7, wherein the antibody binding to TROP2 or its antigen-binding fragment comprises a heavy chain, the heavy chain comprising the amino acid sequence shown in SEQ ID NO:

11.

9. The method according to any one of claims 2-8, wherein the antibody binding to TROP2 or its antigen-binding fragment comprises a light chain, the light chain comprising the amino acid sequence shown in SEQ ID NO:

12.

10. The method according to any one of claims 1-9, wherein the multispecific antigen-binding protein further comprises a single-domain antibody that binds to HER3.

11. The method of claim 10, wherein the HER3-binding single-domain antibody comprises: H2CDR1 contains the amino acid sequence shown in SEQ ID NO: 13; H2CDR2 contains the amino acid sequence shown in SEQ ID NO: 14; H2CDR3 contains the amino acid sequence shown in SEQ ID NO:

15.

12. The method according to claim 10 or 11, wherein the HER3-binding single-domain antibody comprises the amino acid sequence shown in SEQ ID NO:

16.

13. The method according to any one of claims 10-12, wherein the HER3-binding single-domain antibody is directly or indirectly connected to the TROP2-binding antibody or antigen-binding fragment via a linker, preferably, the C-terminus of the HER3-binding single-domain antibody is connected to the N-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment, more preferably, the C-terminus of the HER3-binding single-domain antibody is indirectly connected to the N-terminus of the heavy chain of the TROP2-binding antibody or antigen-binding fragment via a linker.

14. The method according to claim 1, wherein, The multispecific antigen-binding protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a first heavy chain variable region and a second heavy chain variable region, and the second polypeptide comprises a light chain variable region; wherein: The first heavy chain variable region comprises: H1CDR1, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 1; H1CDR2, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 2; and H1CDR3, which comprises or is composed of the amino acid sequence shown in SEQ ID NO:

3. The second heavy chain variable region comprises: H2CDR1, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 13; H2CDR2, which comprises or is composed of the amino acid sequence shown in SEQ ID NO: 14; and H2CDR3, which comprises or is composed of the amino acid sequence shown in SEQ ID NO:

15. The light chain variable region comprises: LCDR1, which contains or is composed of the amino acid sequence shown in SEQ ID NO: 4; LCDR2, which contains or is composed of the amino acid sequence shown in SEQ ID NO: 5; and LCDR3, which contains or is composed of the amino acid sequence shown in SEQ ID NO:

6.

15. The method of claim 14, wherein the first heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:

7.

16. The method according to claim 14 or 15, wherein the second heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:

16.

17. The method according to any one of claims 14-16, wherein the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:

8.

18. The method according to any one of claims 1-17, wherein the multispecific antigen-binding protein comprises the first polypeptide shown in SEQ ID NO: 17 and the second polypeptide shown in SEQ ID NO:

12.

19. The method according to any one of claims 1-18, wherein the protein-drug conjugate comprises a cytotoxin.

20. The method according to claim 19, wherein the cytotoxin is DXd.

21. The method according to claim 1, wherein the protein-drug conjugate has the structure of formula I: P-(L1-sp1-L2-sp2-D)n(I), in, Protein P comprises the multispecific antigen-binding protein according to any one of claims 1-18, D is a biologically active substance, L1 is a linker for connecting with P, sp1 is a first spacer unit, L2 is a cleavable linker, sp2 is a second spacer unit connected to D, and n = 1 to 20.

22. The method according to claim 21, wherein L1 is selected from: in, Ar represents C 6-10 Aryl groups, optionally coated with halogens and / or C 1-6 Alkyl substitution; R1 is selected from hydrogen, halogen, and C. 1-6 Alkyl group; Z is selected from straight bond, C 2-6 Ethyne group, C 2-6 imidene group, C 6-10 arylene, 5-10 heteroarylene, amide, sulfonamide, imino, and CF2; Optionally, L1 is selected from Preferred selection 23. The method according to claim 21 or 22, wherein the structure of the first spacing unit sp1 is as shown in formula II: in, a1 = 0 or 1, a2 = an integer from 0 to 6, b1 = 0 or 1, b2 = an integer from 0 to 16, b3 = an integer from 0 to 20, for example, an integer from 0 to 16, c = an integer from 0 to 6, and at least one of b2 and b3 is 0.

24. The method according to any one of claims 21-23, wherein the cleavable linker L2 is a dipeptide, tripeptide, or tetrapeptide residue.

25. The method of claim 24, wherein L2 is selected from the following dipeptide residues: -Phe-Lys-, -Val-Ala-, -Val-Lys-, -Val-Cit-, -Ala-Lys-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, -Trp-Cit-, -Gly-Gly-, -Ala-Ala-, -Gly-Val-, and -Gly-Glu-; wherein the left side of the dipeptide residue is connected to sp1 and the right side is connected to sp2.

26. The method according to claim 24, wherein L2 is selected from the following tripeptide residues: -Glu-Val-Ala-, -Glu-Val-Cit-, -αGlu-Val-Ala-, -αGlu-Val-Cit-, -Val-Lys-Gly and -Val-Cit-Gly-; the left side of the tripeptide residue is connected to sp1 and the right side is connected to sp2.

27. The method of claim 24, wherein L2 is selected from the following tetrapeptide residues: -Gly-Gly-Phe-Gly- and -Gly-Phe-Gly-Gly-; the left side of the tetrapeptide residue is connected to sp1 and the right side is connected to sp2.

28. The method according to any one of claims 21-27, wherein the second spacer unit sp2 is absent, or sp2 is selected from: in, R2 is independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, amino, halogen, nitro, cyano d is an integer from 1 to 20, and e is an integer from 1 to 20; R3 and R4 are each independently selected from hydrogen and C. 1-6 alkyl; The alkyl group may optionally be substituted with hydroxyl, amino, halogen, nitro, and cyano groups.

29. The method according to any one of claims 21-28, wherein -L1-sp1-L2-sp2- is selected from the following structures: in, k is an integer from 1 to 20; optionally, k is an integer from 2 to 16, for example, k = 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

30. The method according to any one of claims 21-29, wherein D is a cytotoxin; preferably, D is a camptothecin derivative; more preferably, D is selected from the following structures:

31. The method according to any one of claims 21-30, wherein -L1-sp1-L2-sp2-D is selected from the following structures: in, k is an integer from 1 to 20; for example, k is 2, 3, 4, 5, 6, 7 or 8.

32. The method according to any one of claims 21-31, wherein the linking unit L is linked to the protein P via an oligosaccharide; preferably, the oligosaccharide is derived from the natural sugar chain of the antibody.

33. The method of claim 32, wherein the oligosaccharide is derived from the N-glycan chain of the antibody.

34. The method according to claim 32 or 33, wherein the oligosaccharide has the structure shown in formula V-a' or formula V-b', wherein the side connected to P* is labeled P*, and the side connected to L1 is labeled L1: in, GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, and f is 0 or 1; Gal* is a modified galactose selected from the following structures: The P* binds to HER3 and TROP2, for example, and includes the multispecific antigen-binding protein described in this disclosure.

35. The method of claim 34, wherein the modified galactose is linked to GlcNAc via a β-1,4-glycosidic bond.

36. The method according to any one of claims 1-35, wherein the protein-drug conjugate has the structure shown in Formula VI: in, P* binds to HER3 and TROP2, for example, comprising the multispecific antigen-binding protein according to any one of claims 1-18, where GlcNAc is N-acetylglucosamine, Fuc is fuc, Man is mannose, f is 0 or 1, and j is 1 to 20; Gal* is a modified galactose selected from the following structures: LP is selected from one of the following structures (a) to (d): (a) and / or (b) and / or (c) and / or as well as (d) and / or k is an integer from 1 to 20, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10; The core GlcNAc is directly connected to P*.

37. The method according to any one of claims 1-36, wherein the average DAR value of the protein-drug conjugate is about 1 to about 8, for example, about 2 to about 6, about 2 to about 5, about 2 to about 4; optionally, the average DAR value of the protein-drug conjugate is about 4.

38. The method according to any one of claims 1-37, wherein the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg; preferably 4 mg / kg to 6 mg / kg.

39. The method according to any one of claims 1-38, wherein the protein-drug conjugate is administered once every three weeks (Q3W).

40. The method according to any one of claims 1-39, wherein the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W; or, 5 mg / kg based on the subject's body weight, Q3W; or, 6 mg / kg based on the subject's body weight, Q3W.

41. The method according to any one of claims 1-40, wherein the route of administration of the protein-drug conjugate is intravenous infusion.

42. The method according to any one of claims 1-40, wherein the protein-drug conjugate is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

43. The method according to any one of claims 1-42, wherein the platinum-based chemotherapy drug is carboplatin.

44. The method according to any one of claims 1-43, wherein the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), has an AUC of 4-5.

45. The method according to any one of claims 1-44, wherein the platinum-based chemotherapy drug is administered once every three weeks (Q3W).

46. ​​The method according to any one of claims 1-45, wherein the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles, or administered 2, 3, or 4 times.

47. The method according to any one of claims 1-46, wherein the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 4, once every three weeks for a total of 4 cycles; or, the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 5, once every three weeks for a total of 4 cycles.

48. The method according to any one of claims 1-47, wherein the platinum-based chemotherapy drug is administered via intravenous infusion.

49. The method according to any one of claims 1-47, wherein: The administration regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the platinum-based chemotherapy drug is carboplatin, and the administration regimen of carboplatin is a dose AUC = 4, administered once every three weeks for a total of 4 cycles; The dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), wherein the platinum-based chemotherapy drug is carboplatin, and the carboplatin dosing regimen is an AUC = 4, administered every three weeks for a total of 4 cycles; or The administration regimen of the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the platinum-based chemotherapy drug is carboplatin, and the carboplatin administration regimen is an AUC of 4, administered once every three weeks for a total of 4 cycles.

50. The method according to any one of claims 1-49, wherein the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

51. The method according to any one of claims 1-50, wherein the non-small cell lung cancer is non-small cell lung cancer that has failed standard treatment; preferably, the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer that has failed standard treatment.

52. The method according to any one of claims 1-51, the method further comprising administering a PD-1 inhibitor to a subject in need.

53. The method of claim 52, wherein the PD-1 inhibitor is administered once every three weeks (Q3W).

54. The method according to claim 52 or 53, wherein the PD-1 inhibitor is administered via intravenous infusion.

55. The method according to any one of claims 52 to 54, wherein the PD-1 inhibitor is administered for one or more cycles or once or more until disease remission, disease progression or intolerance.

56. The method according to any one of claims 52 to 55, wherein the PD-1 inhibitor is a bispecific antibody targeting PD-1 / VEGF, preferably ewocizumab.

57. The method according to claim 56, wherein the dosage of the PD-1 inhibitor is 5 mg / kg to 30 mg / kg, or 10 mg / kg to 30 mg / kg, preferably 20 mg / kg, based on the subject's body weight.

58. The method according to claim 56 or 57, wherein the PD-1 inhibitor is evokinemab, and the dosing regimen is 20 mg / kg based on the subject's body weight, once every three weeks.

59. The method according to any one of claims 52 to 58, wherein The dosing regimen of the protein-drug conjugate is 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance). The PD-1 inhibitor is evokimab, which is administered at a dose of 20 mg / kg based on the subject's body weight, once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance). The platinum-based chemotherapy drug is carboplatin, which is administered at a dose AUC = 5, once every three weeks for a total of 4 cycles. The dosing regimen for the protein-drug conjugate is: 5 mg / kg body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance). The PD-1 inhibitor is evosimib, administered as follows: 20 mg / kg body weight, every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance). The platinum-based chemotherapy drug is carboplatin, administered at a dose AUC = 5, every three weeks for a total of 4 cycles; or The dosing regimen for the protein-drug conjugate is 6 mg / kg per subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance). The PD-1 inhibitor is evosimib, administered at a dose of 20 mg / kg per subject's body weight, once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance). The platinum-based chemotherapy drug is carboplatin, administered at a dose AUC = 5, once every three weeks for a total of 4 cycles.

60. The method according to any one of claims 52 to 55, wherein the PD-1 inhibitor is an antibody targeting PD-1, preferably tislelizumab or pembrolizumab.

61. The method according to claim 60, wherein the dosage of the PD-1 inhibitor is 150 mg to 250 mg, preferably 200 mg.

62. The method according to claim 60 or 61, wherein the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks.

63. The method according to any one of claims 52 to 55 and 60 to 62, wherein The dosing regimen for the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5, every three weeks for a total of 4 cycles. The dosing regimen for the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5, every three weeks for a total of 4 cycles; or The dosing regimen for the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5 every three weeks for a total of 4 cycles.

64. The method according to claim 60 or 61, wherein the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks.

65. The method according to any one of claims 52 to 55 and 60, 61 and 64, wherein The dosing regimen for the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5 every three weeks for a total of 4 cycles. The dosing regimen for the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5, every three weeks for a total of 4 cycles; or The dosing regimen for the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5 every three weeks for a total of 4 cycles.

66. The method according to any one of claims 1 to 65, wherein the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

67. A method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

68. The method of claim 67, wherein the protein-drug conjugate and / or multispecific antigen-binding protein is as defined in any one of claims 2-37.

69. The method according to claim 67 or 68, wherein the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg; preferably 4 mg / kg to 6 mg / kg.

70. The method according to any one of claims 67-69, wherein the protein-drug conjugate is administered once every three weeks (Q3W) or once every two weeks (Q2W).

71. The method according to any one of claims 67-70, wherein the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W; or, 5 mg / kg based on the subject's body weight, Q3W; or, 6 mg / kg based on the subject's body weight, Q3W; Alternatively, 4 mg / kg based on the subject's body weight, Q2W; Alternatively, 5 mg / kg based on the subject's body weight, Q2W; Alternatively, 6 mg / kg based on the subject's body weight, Q2W.

72. The method according to any one of claims 67-71, wherein the route of administration of the protein-drug conjugate is intravenous infusion.

73. The method according to any one of claims 67-72, wherein the protein-drug conjugate is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

74. The method according to any one of claims 67-73, wherein the EGFR-TKI is a third-generation EGFR-TKI.

75. The method according to any one of claims 67-74, wherein the EGFR-TKI is vometinib.

76. The method according to any one of claims 67-75, wherein the dosage of the EGFR-TKI is 80 mg to 200 mg; preferably, the dosage of the EGFR-TKI is 80 mg or 160 mg.

77. The method according to any one of claims 67-76, wherein the EGFR-TKI is administered once daily (QD).

78. The method according to any one of claims 67-77, wherein the EGFR-TKI is administered orally, preferably on an empty stomach.

79. The method according to any one of claims 67-78, wherein the EGFR-TKI is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

80. The method according to any one of claims 67-79, wherein the EGFR-TKI is vormetinib, administered at a dose of 160 mg once daily; or at a dose of 80 mg once daily.

81. The method according to any one of claims 67-80, wherein The dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the EGFR-TKI is vormetinib, which is administered at a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance). The dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the EGFR-TKI is vormetinib, which is administered at a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance). The dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the EGFR-TKI is vormetinib, which is administered at a dose of 160 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance). The dosing regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W or Q2W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the EGFR-TKI is vormetinib, which is administered at a dose of 80 mg once daily, administered once or multiple times (preferably until disease remission, disease progression or intolerance). The dosing regimen of the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, administered once or multiple times every 3 weeks or every 2 weeks (preferably until disease remission, disease progression, or intolerance), and the EGFR-TKI is vormetinib, which is administered at a dose of 80 mg once daily, once or multiple times (preferably until disease remission, disease progression, or intolerance); or The dosing regimen of the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, administered once or multiple times every 3 weeks or every 2 weeks (preferably until disease remission, disease progression, or intolerance). The EGFR-TKI is vormetinib, which is administered at a dose of 80 mg once daily, once or multiple times daily (preferably until disease remission, disease progression, or intolerance).

82. The method according to any one of claims 67-81, wherein the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer.

83. The method according to any one of claims 67-82, wherein the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation non-small cell lung cancer that has failed EGFR-TKI treatment; or, the non-small cell lung cancer is EGFR-sensitive mutation non-small cell lung cancer that has not previously received systemic therapy for the locally advanced or metastatic stage.

84. A method for treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering to a subject in need a protein-drug conjugate and a bispecific antibody targeting PD-1 / VEGF, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

85. The method of claim 84, wherein the protein-drug conjugate and / or multispecific antigen-binding protein is as defined in any one of claims 2-37.

86. The method according to claim 84 or 85, wherein the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 6 mg / kg; preferably 4 mg / kg to 6 mg / kg.

87. The method according to any one of claims 84-86, wherein the protein-drug conjugate is administered once every three weeks (Q3W).

88. The method according to any one of claims 84-87, wherein the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W; or, 5 mg / kg based on the subject's body weight, Q3W; or, 6 mg / kg based on the subject's body weight, Q3W.

89. The method according to any one of claims 84-88, wherein the route of administration of the protein-drug conjugate is intravenous infusion.

90. The method according to any one of claims 84-89, wherein the protein-drug conjugate is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

91. The method according to any one of claims 84-90, wherein the bispecific antibody targeting PD-1 / VEGF is evacimab.

92. The method according to any one of claims 84-91, wherein the dosage of the bispecific antibody targeting PD-1 / VEGF is 5 mg / kg to 30 mg / kg or 10 mg / kg to 30 mg / kg based on the subject's body weight; preferably, the dosage of the bispecific antibody targeting PD-1 / VEGF is 20 mg / kg based on the subject's body weight.

93. The method according to any one of claims 84-92, wherein the bispecific antibody targeting PD-1 / VEGF is administered once every three weeks (Q3W).

94. The method according to any one of claims 84-93, wherein the bispecific antibody targeting PD-1 / VEGF is evokinemab, and the dosing regimen is: 20 mg / kg based on the subject's body weight, once every three weeks.

95. The method according to any one of claims 84-94, wherein the administration route of the bispecific antibody targeting PD-1 / VEGF is intravenous infusion.

96. The method according to any one of claims 84-95, wherein the bispecific antibody targeting PD-1 / VEGF is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

97. The method according to any one of claims 84-96, wherein, The administration regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, with the administration regimen of 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance). The administration regimen of the protein-drug conjugate is: 5 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, with the administration regimen of: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); or The administration regimen of the protein-drug conjugate is 6 mg / kg per subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg per subject's body weight, every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance).

98. The method according to any one of claims 84-97, further comprising administering a platinum-based chemotherapy drug, such as carboplatin, to a subject in need, in addition to administering the protein-drug conjugate and the bispecific antibody targeting PD-1 / VEGF.

99. The method according to any one of claims 84-98, wherein the dosage of the platinum-based chemotherapy drug, based on the area under the curve (AUC), has an AUC of 4-5.

100. The method according to any one of claims 84-99, wherein the platinum-based chemotherapy drug is administered once every three weeks (Q3W).

101. The method according to any one of claims 84-100, wherein the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles, or administered 2, 3, or 4 times.

102. The method according to any one of claims 84-101, wherein the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 4, once every three weeks for a total of 4 cycles; or, the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 5, once every three weeks for a total of 4 cycles.

103. The method according to any one of claims 84-102, wherein, The administration regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: dose AUC = 5, administered once every three weeks for a total of 4 cycles; The administration regimen of the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: AUC = 5, administered every three weeks for a total of 4 cycles; or The administration regimen of the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: AUC=5, administered once every three weeks for a total of 4 cycles.

104. The method according to any one of claims 84-102, wherein after the administration of platinum-based chemotherapy drugs is stopped, for example after four cycles of platinum-based chemotherapy drugs, pemetrexed is started in the next cycle.

105. The method according to claim 104, wherein the dosage of pemetrexed is 250 mg / m² based on the subject's body surface area. 2 ~750mg / m 2 Preferably 500 mg / m 2 .

106. The method according to claim 104 or 105, wherein the pemetrexed is administered once every three weeks (Q3W).

107. The method according to any one of claims 104-106, wherein the pemetrexed administration regimen is 500 mg / m² based on the subject's body surface area. 2 Once every three weeks.

108. The method according to any one of claims 104-107, wherein the pemetrexed is administered via intravenous infusion.

109. The method according to any one of claims 104-108, wherein the pemetrexed is administered once or multiple times until the disease is relieved, the disease progresses, or it becomes intolerable.

110. The method according to any one of claims 104-109, wherein The administration regimen of the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, pemetrexed is administered on the first day of the next cycle after carboplatin discontinuation, at a dose of 500 mg / m² based on the subject's body surface area. 2 Administer once every three weeks, once or more (preferably until disease remission, disease progression or intolerance); The administration regimen of the protein-drug conjugate is as follows: 5 mg / kg body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the bispecific antibody targeting PD-1 / VEGF is evokimab, administered as follows: 20 mg / kg body weight, every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: AUC = 5, every three weeks for 4 cycles; subsequently, pemetrexed is administered on the first day of the next cycle after carboplatin discontinuation, at a dose of 500 mg / m² based on the subject's body surface area. 2 Administer once or more every three weeks (preferably until disease remission, disease progression, or intolerance); or The administration regimen of the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the bispecific antibody targeting PD-1 / VEGF is evosimib, administered as follows: 20 mg / kg based on the subject's body weight, administered once or multiple times every three weeks (preferably until disease remission, disease progression, or intolerance); and the platinum-based chemotherapy drug is carboplatin, administered as follows: AUC = 5, administered every three weeks for a total of 4 cycles; subsequently, pemetrexed is administered on the first day of the next cycle after carboplatin discontinuation, at a dose of 500 mg / m² based on the subject's body surface area. 2 Apply once or more every three weeks (preferably until disease remission, disease progression or intolerance).

111. The method according to any one of claims 84-110, wherein the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (IV) non-small cell lung cancer.

112. The method according to any one of claims 84-111, wherein the non-small cell lung cancer is locally advanced or metastatic EGFR-sensitive mutation non-small cell lung cancer that has failed EGFR-TKI treatment; or, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for the locally advanced or metastatic stage; or the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has failed standard treatment.

113. A method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and docetaxel to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

114. The method of claim 113, wherein the protein-drug conjugate and / or multispecific antigen-binding protein is as defined in any one of claims 2-37.

115. The method according to claim 113 or 114, wherein the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg; preferably 4 mg / kg to 6 mg / kg.

116. The method according to any one of claims 113-115, wherein the protein-drug conjugate is administered once every three weeks (Q3W).

117. The method according to any one of claims 113-116, wherein the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W; or, 6 mg / kg based on the subject's body weight, Q3W.

118. The method according to any one of claims 113-117, wherein the route of administration of the protein-drug conjugate is intravenous infusion.

119. The method according to any one of claims 113-118, wherein the protein-drug conjugate is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

120. The method according to any one of claims 113-119, wherein the dosage of docetaxel, based on the subject's body surface area, is selected from 50 mg / m². 2 ~100mg / m 2 Preferred concentration: 60 mg / m³ 2 ~75mg / m 2 .

121. The method according to any one of claims 113-120, wherein the docetaxel is administered once every three weeks (Q3W).

122. The method according to any one of claims 113-121, wherein the docetaxel administration regimen is: 60 mg / m² based on the subject's body surface area. 2 Q3W; or, 75 mg / m² based on the subject's body surface area. 2 , Q3W.

123. The method according to any one of claims 113-122, wherein the docetaxel is administered via intravenous infusion.

124. The method according to any one of claims 113-123, wherein the docetaxel is administered once or multiple times until the disease is relieved, the disease progresses, or it becomes intolerable.

125. The method according to any one of claims 113-124, wherein The dosing regimen for the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); or The dosing regimen for the protein-drug conjugate is 6 mg / kg based on the subject's body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the docetaxel dosing regimen is 60 mg / m² based on the subject's body surface area. 2 Q3W, administer once or multiple times (preferably until disease remission, disease progression or intolerance).

126. The method according to any one of claims 113-125, wherein the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

127. The method according to any one of claims 113-126, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer that has failed standard treatment; preferably, the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer that has failed systemic platinum-based chemotherapy and PD-1 / L1 inhibitor treatment; or EGFR-sensitive mutation non-small cell lung cancer that has failed EGFR-TKI treatment and has failed platinum-based chemotherapy.

128. A method of treating and / or preventing non-small cell lung cancer (NSCLC), comprising administering a protein-drug conjugate and a PD-1 inhibitor to a subject in need, said protein-drug conjugate comprising a multispecific antigen-binding protein that targets human epidermal growth factor receptor 3 (HER3) and trophoblast cell surface antigen 2 (TROP2).

129. The method of claim 128, wherein the protein-drug conjugate and / or multispecific antigen-binding protein is as defined in any one of claims 2-37.

130. The method according to claim 128 or 129, wherein the dosage of the protein-drug conjugate, based on the subject's body weight, is selected from 3 mg / kg to 8 mg / kg; preferably 4 mg / kg to 6 mg / kg.

131. The method according to any one of claims 128-130, wherein the protein-drug conjugate is administered once every three weeks (Q3W).

132. The method according to any one of claims 128-131, wherein the dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W; or, 5 mg / kg based on the subject's body weight, Q3W; or, 6 mg / kg based on the subject's body weight, Q3W.

133. The method according to any one of claims 128-132, wherein the route of administration of the protein-drug conjugate is intravenous infusion.

134. The method according to any one of claims 128-133, wherein the protein-drug conjugate is administered once or multiple times until disease remission, disease progression, or intolerance occurs.

135. The method according to any one of claims 128-134, wherein the dosage of the PD-1 inhibitor is 150 mg to 250 mg; preferably, the dosage of the PD-1 inhibitor is 200 mg.

136. The method according to any one of claims 128-135, wherein the PD-1 inhibitor is administered once every three weeks (Q3W).

137. The method according to any one of claims 128-136, wherein the PD-1 inhibitor is administered via intravenous infusion.

138. The method according to any one of claims 128-137, wherein the PD-1 inhibitor is administered once or multiple times until disease remission, disease progression, or intolerance.

139. The method according to any one of claims 128-138, wherein the PD-1 inhibitor is tislelizumab.

140. The method according to any one of claims 128-139, wherein the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks.

141. The method according to claim 139 or 140, wherein The dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the tislelizumab is: 200 mg, administered once or multiple times every three weeks (preferably until disease remission, disease progression or intolerance). The dosing regimen for the protein-drug conjugate is 5 mg / kg of body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen for tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); or The dosing regimen for the protein-drug conjugate is 6 mg / kg per subject, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen for tislelizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance).

142. The method according to any one of claims 128-141, further comprising administering a platinum-based chemotherapy drug, such as carboplatin, to a subject in need, in addition to administering the protein-drug conjugate and the PD-1 inhibitor.

143. The method according to claim 142, wherein the dosage of the platinum-based chemotherapy drug, measured by the area under the curve (AUC), has an AUC of 4 to 5.

144. The method according to claim 142 or 143, wherein the platinum-based chemotherapy drug is administered once every three weeks (Q3W).

145. The method according to any one of claims 142-144, wherein the platinum-based chemotherapy drug is administered for 2, 3, or 4 cycles.

146. The method according to any one of claims 142-145, wherein the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 4, once every three weeks for a total of 4 cycles; or, the platinum-based chemotherapy drug is carboplatin, administered at a dose of AUC = 5, once every three weeks for a total of 4 cycles.

147. The method according to any one of claims 142-146, wherein the platinum-based chemotherapy drug is administered via intravenous infusion.

148. The method according to any one of claims 142-147, wherein The dosing regimen for the protein-drug conjugate is as follows: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5 every three weeks for a total of 4 cycles. The dosing regimen for the protein-drug conjugate is as follows: 5 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5, every three weeks for a total of 4 cycles; or The dosing regimen for the protein-drug conjugate is as follows: 6 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); the PD-1 inhibitor is tislelizumab, administered at a dose of 200 mg every three weeks, once or multiple times (preferably until disease remission, disease progression, or intolerance); and the platinum compound is carboplatin, administered at a dose with an AUC of 5 every three weeks for a total of 4 cycles.

149. The method according to any one of claims 128-138, wherein the PD-1 inhibitor is pembrolizumab.

150. The method according to claim 149, wherein the PD-1 inhibitor is pembrolizumab, administered at a dose of 200 mg every three weeks.

151. The method according to claim 149 or 150, wherein The dosing regimen of the protein-drug conjugate is: 4 mg / kg based on the subject's body weight, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the pembrolizumab is: 200 mg, administered once or multiple times every three weeks (preferably until disease remission, disease progression or intolerance). The dosing regimen for the protein-drug conjugate is: 5 mg / kg of body weight, every 3 weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance), and the dosing regimen for pembrolizumab is: 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression, or intolerance); or The dosing regimen of the protein-drug conjugate is 6 mg / kg per subject, Q3W, administered once or multiple times (preferably until disease remission, disease progression or intolerance), and the dosing regimen of the pembrolizumab is 200 mg every three weeks, administered once or multiple times (preferably until disease remission, disease progression or intolerance).

152. The method according to any one of claims 128-151, wherein the non-small cell lung cancer is locally advanced (IIIB / IIIC) or metastatic (stage IV) non-small cell lung cancer.

153. The method according to any one of claims 128-152, wherein the non-small cell lung cancer is driver gene-negative non-small cell lung cancer.

154. The method according to any one of claims 128-153, wherein the PD-L1 TPS of the non-small cell lung cancer is ≥1%.

155. The method according to any one of claims 128-154, wherein the non-small cell lung cancer has not received systemic treatment, for example, no systemic treatment for locally advanced or metastatic stages.

156. The method according to any one of claims 128-155, wherein the non-small cell lung cancer is driver gene-negative non-small cell lung cancer that has not previously received systemic therapy for locally advanced or metastatic stages.

157. The method according to any one of claims 128-156, wherein the non-small cell lung cancer is driver gene-negative non-small cell lung cancer with PD-L1 TPS ≥ 1% and has not previously received systemic therapy for locally advanced or metastatic stages.

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