Treatment of non-small cell lung cancer using salcetuzumab-govitecan and anti-PD-1 antibodies or antigen-binding fragments thereof

Abstract

The present disclosure relates to a method of treating untreated metastatic NSCLC in a patient, the method comprising administering a salcetuzumab-govitecan (SG) and an anti-PD-1 antibody or antigen binding fragment thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 604,632, filed November 30, 2023; U.S. Provisional Patent Application No. 63 / 592,031, filed October 20, 2023; U.S. Provisional Patent Application No. 63 / 581,239, filed September 7, 2023; U.S. Provisional Patent Application No. 63 / 519,818, filed August 15, 2023; and U.S. Provisional Patent Application No. 63 / 564,626, filed March 13, 2024, the entire contents of which are incorporated herein by reference.

[0003] By referencing and incorporating into the sequence list

[0004] This application includes a sequence list, which is submitted electronically in XML file format and incorporated herein by reference in its entirety. The XML copy was created on August 13, 2024, named 210196-304006_PCT_SL.xml, and is 19,960 bytes in size. Technical Field

[0005] This disclosure relates to a method of treating non-small cell lung cancer using sacituzumab govitecan (“SG”) and an anti-PD-1 antibody or an antigen-binding fragment thereof. Background Technology

[0006] Lung cancer (small cell lung cancer and non-small cell lung cancer) is the second most common cancer among men and women in the United States (excluding skin cancer). Approximately 10% to 15% of all lung cancers are small cell lung cancers, while approximately 80% to 85% of all lung cancers are non-small cell lung cancers (www.cancer.org).

[0007] Programmed death (ligand) 1 (PD-[L]1) inhibitor-based regimens are the first-line standard of care for metastatic non-small cell lung cancer (“NSCLC”); however, additional therapies are needed to further improve outcomes.

[0008] Sacituzumab-gavitenac (“SG”) is an antibody-drug conjugate (“ADC”) consisting of: (a) a humanized monoclonal antibody that binds to the cell surface receptor Trop 2 (“hRS7”), (b) a payload that acts as a topoisomerase I inhibitor (“SN-38”), and (c) a linker that conjugates the antibody to the payload (“CL2A”). Trop 2 is highly expressed in non-small cell lung cancer.

[0009] The high expression of Trop 2 in non-small cell lung cancer, coupled with unmet demand, led to the design of the phase 2, open-label, multi-cohort Ph 2 EVOKE-02 study (NCT05186974), which evaluates SG plus pembrolizumab ± platinum as first-line treatment for metastatic NSCLC.

[0010] SG is marketed under the name TRODELVY and is indicated for (1) adult patients with unresectable locally advanced or metastatic HR+ / HER2- breast cancer who have received endocrine-based therapy and, in the metastatic case, at least two additional systemic therapies; (2) adult patients with unresectable locally advanced or mTNBC who have received two or more prior systemic therapies (at least one of which was for metastatic disease); and (3) adult patients with locally advanced or mUC who have previously received platinum-based chemotherapy and a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor (accelerated approval only).

[0011] PD-1 is considered an important molecule for immune regulation and maintaining peripheral tolerance. PD-1 is moderately expressed on primary T, B, and NKT cells and is upregulated through T / B cell receptor signaling on lymphocytes, monocytes, and myeloid cells (Sharpe, Arlene H et al., The function of programmed cell death 1 and its ligands inregulating autoimmunity and infection. Nature Immunology (2007); 8:239-245).

[0012] Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers originating from various tissues. In large datasets of cancers (e.g., ovarian cancer, renal cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma), PD-L1 expression has been shown to be associated with poor prognosis and reduced overall survival, but not with subsequent treatment (Dong, Haidong et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug; 8(8):793-800; Yang, Wanhua et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci. 2008 Jun; 49(6 (2008): 49: 2518-2525; Ghebeh, Hazem et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltratingductal carcinoma: correlation). with important high-risk prognostic factors.Neoplasia (2006) 8: 190-198; Hamanishi, Junzo et al., Programmed cell death 1ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA (2007): 104: 3360-3365; Thompson, R Houston and Eugene D Kwon, Significance of B7-H1 overexpression inkidney cancer.Clinical genitourin Cancer (2006): 5: 206-211; Nomi, Takeo et al., Clinical significance and therapeutic potential of the programmed death-1 ligand / programmed death-1 pathway in human pancreatic cancer. Clinical Cancer Research (2007); 13:2151-2157; Ohigashi, Yuichiro et al., Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer. Clin. Cancer Research (2005): 11: 2947-2953; Inman, Brant A et al., PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer (2007): 109: 1499-1505; Shimauchi, Takatoshi et al., Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia / Lymphoma. Int. J. Cancer (2007): 121: 2585-2590; Gao, Qiang et al., Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.Clinical Cancer Research (2009) 15: 971-979; Nakanishi, Juro et al., Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer ImmunolImmunother. (2007) 56: 1173-1182; Hino et al., Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma. Cancer (2010): 00:1-9). Similarly, PD-1 expression on tumor-infiltrating lymphocytes has been found to mark dysfunctional T cells in breast cancer and melanoma (Ghebeh, Hazem et al., Foxp3+ tregs and B7-H1+ / PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer. 2008 Feb 23; 8:57; Ahmadzadeh, Mojgan et al., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood (2009) 114: 1537-1544) and is associated with poor prognosis in renal cell carcinoma (Thompson, R Houston et al., PD-1 is expressed by tumor-infiltrating cells and is associated with poor outcome for patients with renal carcinoma).Clinical Cancer Research (2007) 15: 1757-1761. Therefore, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells to attenuate T cell activation and immune surveillance evasion, thereby leading to a compromised immune response against the tumor.

[0013] Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 have been approved for cancer treatment. Pembrolizumab (KEYTRUDA) ® pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity for binding to the programmed cell death 1 (PD-1) receptor, thereby inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab demonstrates high affinity and potent receptor-blocking activity against PD-1. ® Pembrolizumab is indicated for the treatment of multiple conditions and is suitable as first-line therapy for patients with unresectable or metastatic CRC with high microsatellite instability or mismatch repair deficient (MSI-H / dMMR). Pembrolizumab is the current standard of care for first-line MSI-H / dMMR mCRC. Summary of the Invention

[0014] One aspect of this disclosure provides a method for treating a patient with treatment-naïve metastatic non-small cell lung cancer (NSCLC), the method comprising: (a) administering 10 mg / kg sacitrus-glavotecan (SG) via intravenous infusion once weekly on days 1 and 8 of one or more 21-day treatment cycles; and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4, and 5, and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9, and 10.

[0015] Another aspect of this disclosure provides a method for treating a patient with metastatic NSCLC, wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0016] In some implementations, the patient's PD-L1 tumor proportion score is ≥50%.

[0017] In some other implementations, the patient's PD-L1 tumor proportion score is <50%. In some implementations, the patient's PD-L1 tumor proportion score is between 1% and 49%. In some implementations, the patient's PD-L1 tumor proportion score is <1%.

[0018] In some implementations, the patient achieves a partial response.

[0019] Another aspect of this disclosure provides a method for treating a patient with untreated metastatic NSCLC, wherein the patient's PD-L1 tumor proportion score is ≥50%, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0020] Another aspect of this disclosure provides a method for treating a patient with metastatic NSCLC, wherein the patient has a PD-L1 tumor proportion score ≥50% and wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0021] In some implementations, when the method is used to treat metastatic NSCLC in a patient population, it achieves an objective response rate of approximately 75% or higher.

[0022] Another aspect of this disclosure provides a method for treating a patient with untreated metastatic NSCLC, wherein the patient's PD-L1 tumor proportion score is <50%, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0023] Another aspect of this disclosure provides a method for treating a patient with metastatic NSCLC, wherein the patient's PD-L1 tumor proportion score is <50%, and wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the method achieves a complete or partial response in the patient, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4, and 5, and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9, and 10.

[0024] In some implementations, when the method is used to treat metastatic NSCLC in a patient population, it achieves an objective response rate of approximately 44%.

[0025] Another aspect of this disclosure provides a method for achieving a partial or complete response, the method comprising administering to a subject in need: (a) once weekly via intravenous infusion of 10 mg / kg SG on days 1 and 8 of one or more 21-day treatment cycles, and (b) via intravenous infusion of 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof on day 1 of one or more 21-day treatment cycles, wherein the patient has treatment-naïve metastatic NSCLC, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0026] Another aspect of the invention provides a method for achieving a partial or complete response, the method comprising administering to a patient in need: (a) 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles, and (b) 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the patient has metastatic NSCLC, wherein the patient has not received prior systemic therapy for metastatic NSCLC, and wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0027] In one implementation plan, the patient's PD-L1 tumor proportion score is ≥50%.

[0028] In one other implementation, the patient's PD-L1 tumor proportion score is <50%. In some implementations, the patient's PD-L1 tumor proportion score is between 1% and 49%. In some implementations, the patient's PD-L1 tumor proportion score is <1%.

[0029] In some implementations, when the method is used to treat a patient population with metastatic NSCLC, the objective response rate is approximately 54%.

[0030] However, another aspect of this disclosure provides a method for achieving an objective response rate of at least 44% in a patient population with treatment-naïve metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles; and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5, and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0031] Another aspect of this disclosure provides a method for achieving an objective response rate of at least 44% in a patient population with metastatic NSCLC, wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles; and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0032] In some implementations, patients have a PD-L1 tumor proportion score ≥50% and an objective response rate of approximately 75%.

[0033] However, another aspect of this disclosure provides a method for achieving a partial response in a patient population with metastatic NSCLC who has not received prior systemic therapy for metastatic NSCLC, the method comprising: (a) administering 10 mg / kg SG once weekly via intravenous infusion on days 1 and 8 of one or more 21-day treatment cycles; and (b) administering 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof via intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 8, 9 and 10.

[0034] In some implementations, the patient's PD-L1 tumor proportion score is <50%. In some implementations, the patient's PD-L1 tumor proportion score is between 1% and 49%. In some implementations, the patient's PD-L1 tumor proportion score is <1%.

[0035] In some implementations, the method does not include the administration of platinum-based chemotherapy.

[0036] In some implementations, patients do not receive platinum-based chemotherapy during one or more 21-day treatment cycles.

[0037] In some implementations, the anti-PD-1 antibody or its antigen-binding fragment is administered for up to 35 cycles.

[0038] In some implementations, the patient has non-squamous NSCLC. In some other implementations, the patient has squamous NSCLC.

[0039] In some implementations, patients do not have operable genomic alterations in EGFR, ALK, and PD-L1.

[0040] In some implementations, patients do not have known operable genomic alterations in ROS1, NTRK, BRAF, and RET.

[0041] In some implementations, the patient has no operable genomic alterations in EGFR and ALK.

[0042] In some implementations, patients do not receive carboplatin, paclitaxel, or paclitaxel protein-bound during one or more 21-day treatment cycles.

[0043] In some implementations, when the method is used to treat a patient population with metastatic NSCLC of all PD-L1 scores, the disease control rate (DCR) is approximately 81% after at least 6 weeks.

[0044] In some implementations, when the method is used to treat a patient population with metastatic NSCLC and a PD-L1 tumor proportion score ≥50%, the disease control rate (DCR) is greater than or equal to about 88% after at least 6 weeks.

[0045] In some implementations, when the method is used to treat a patient population with metastatic NSCLC and a PD-L1 tumor proportion score <50%, the disease control rate (DCR) is greater than or equal to about 78% after at least 6 weeks.

[0046] In some implementations, when the method is used to treat a patient population with metastatic NSCLC, the duration of response (DOR) is approximately 88% at approximately 6 months.

[0047] In some implementations, the patient has stage IV metastatic NSCLC.

[0048] In some implementations, the method is used to treat metastatic NSCLC in a patient population, achieving a serious treatment-emergent adverse effect (TEAE) rate of less than about 10%.

[0049] In some implementations, the method is used to treat metastatic NSCLC in a patient population, achieving a severe TEAE rate of less than approximately 9%.

[0050] In some implementations, the method is used to treat metastatic NSCLC in a patient population, achieving less than about 25% of ≥ grade 3 TEAEs.

[0051] In some implementations, the method is used to treat metastatic NSCLC in a patient population, achieving less than about 24% of ≥ grade 3 TEAEs.

[0052] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region containing SEQ ID NO: 6 or a variant thereof and a heavy chain variable region containing SEQ ID NO: 11.

[0053] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO: 12.

[0054] In some implementations, the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab or a variant thereof.

[0055] In some specific implementations, the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab.

[0056] Another aspect of this disclosure provides the use of a therapeutic combination comprising sacitrus-glavotecan (SG) and an anti-PD-1 antibody or an antigen-binding fragment thereof for use in the methods described herein.

[0057] Another aspect of this disclosure provides a therapeutic combination comprising sacitrus-glavotecan (SG) and an anti-PD-1 antibody or an antigen-binding fragment thereof for use in the methods described herein.

[0058] In some implementations, the method does not include the administration of anti-TIGIT antibodies.

[0059] In some implementations, patients do not receive anti-TIGIT antibodies during one or more 21-day treatment cycles.

[0060] In some embodiments, this document discloses a method of treating patients with NSCLC who have not previously received systemic therapy for metastatic NSCLC, the method comprising co-administering: (a) 10 mg / kg of an antibody-drug conjugate (ADC) comprising an anti-Trop-2 antibody or an antigen-binding fragment thereof, administered intravenously on days 1 and 8 of one or more 21-day treatment cycles, wherein the anti-Trop-2 antibody or the antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing the amino acid sequences shown in SEQ ID NO: 13, 14, and 15 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 16, 17, and 18, and wherein the ADC has the formula MAb-CL2A-SN-38, wherein the formula is represented as follows:

[0061]

[0062] (b) 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, administered by intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a light chain CDR containing the amino acid sequences shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 8, 9 and 10; and wherein the method achieves a complete or partial response in the patient.

[0063] In some embodiments, the method does not include the administration of additional and / or third anticancer agents. In some embodiments, the patient maintains a partial response from baseline for at least about 13 weeks or longer. In some embodiments, the patient's PD-L1 TPS score is <50%, and a partial response is defined as one or more measurable tumor size reductions of about 60% or more from baseline over about 13 weeks or longer. In some embodiments, the patient's PD-L1 TPS is <1%, and a partial response is defined as one or more measurable tumor size reductions of about 50% or more from baseline over about 13 weeks or longer. In some embodiments, the patient's PD-L1 TPS is 1% to 49%, and a partial response is defined as one or more measurable tumor size reductions of about 60% or more from baseline over about 13 weeks or longer. In some embodiments, the patient has no operable genetic alterations in EGFR, ALK, and PD-L1. In some embodiments, the patient has no known operable genetic alterations in ROS1, NTRK, BRAF, and RET. In some embodiments, the patient has no operable genetic alterations in EGFR and ALK. In some implementations, the patient has not received prior targeted therapy for metastatic NSCLC. In some implementations, the patient has not received prior chemotherapy for metastatic NSCLC. In some implementations, the patient maintains a partial response for at least approximately 48 weeks from baseline to baseline.

[0064] In some embodiments, the anti-Trop-2 antibody or its antigen-binding fragment comprises a heavy chain variable region containing SEQ ID NO: 19 and a light chain variable region containing SEQ ID NO: 20.

[0065] In some embodiments, the anti-Trop-2 antibody comprises a heavy chain containing SEQ ID NO: 1 and a light chain containing SEQ ID NO: 2.

[0066] In some implementations, the anti-Trop-2 antibody is sacitrus.

[0067] In some other implementations, the ADC is sacitrus-glavotecan (SG).

[0068] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region containing SEQ ID NO: 6 or a variant thereof, and a heavy chain variable region containing SEQ ID NO: 11.

[0069] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO: 12.

[0070] In some implementations, the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab or a variant thereof.

[0071] In some implementations, the PD-1 antibody or its antigen fragment is pembrolizumab.

[0072] In some implementations, the ADC is SG and the PD-1 antibody or its antigen fragment is pembrolizumab.

[0073] In some implementations, the patient's PD-L1 tumor proportion score (TPS) is ≥50%. In some other implementations, the patient's PD-L1 TPS is <50%.

[0074] In some implementations, the patient has non-squamous NSCLC. In some other implementations, the patient has squamous NSCLC.

[0075] In some embodiments, the method does not include concomitant administration of chemotherapy. In some embodiments, the method does not include concomitant administration of platinum-based chemotherapy. In some embodiments, the method does not include concomitant administration of anti-TGIT antibody.

[0076] In some embodiments, a partial response is a reduction of about 50% or more in the size of one or more measurable tumors from baseline to a reduction of about 60% or more in the size of one or more measurable tumors from baseline to a reduction of about 60% or more in the size of one or more measurable tumors to a reduction of about 13 weeks or more from baseline. In some embodiments, the patient's PD-L1 TPS is 1% to 49%. In some embodiments, the patient's PD-L1 TPS is <1%.

[0077] In some implementations, when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS ≥ 50%, the method achieves a partial response rate of approximately 69% or higher. In some other implementations, when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS < 50%, the method achieves a partial response rate of approximately 44% or higher.

[0078] In some embodiments, when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS of 1% to 49%, the method achieves an ORR of approximately 53%. In some embodiments, the method achieves a partial response of approximately 47% to 53%. In some embodiments, the method achieves a partial response of approximately 47%. In some embodiments, the method achieves a partial response of approximately 53%.

[0079] In some implementations, when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS <1%, the method achieves an ORR of approximately 35%. In some implementations, the method achieves a partial response of approximately 29% to 35%. In some implementations, the method achieves a partial response of approximately 29%. In some implementations, the method achieves a partial response of approximately 35%.

[0080] In some implementations, when the method is used to treat metastatic NSCLC in a patient population, it achieves a partial response of approximately 56% or higher, regardless of the patient population's PD-L1 TPS status.

[0081] In some implementations, the method does not include the administration of additional targeted oncology drugs.

[0082] In some embodiments, this document discloses a method for treating a patient population with metastatic NSCLC without concurrent chemotherapy, the method comprising co-administering: (a) 10 mg / kg of an antibody-drug conjugate (ADC) comprising an anti-Trop-2 antibody or an antigen-binding fragment thereof, administered intravenously on days 1 and 8 of one or more 21-day treatment cycles, wherein the anti-Trop-2 antibody or the antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing amino acid sequences as shown in SEQ ID NO: 13, 14, and 15 and a heavy chain CDR containing amino acid sequences as shown in SEQ ID NO: 16, 17, and 18, and wherein the ADC has the formula MAb-CL2A-SN-38, wherein the formula is represented as follows:

[0083]

[0084] (b) 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof, administered by intravenous infusion on day 1 of one or more 21-day treatment cycles, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain CDR containing the amino acid sequences shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 8, 9 and 10; wherein the patient population has not received prior systemic therapy for metastatic NSCLC.

[0085] In some implementations, the patient population has no operable genetic alterations in EGFR, ALK, and PD-L1. In some implementations, the patient population has no known operable genetic alterations in ROS1, NTRK, BRAF, and RET. In some implementations, the patient population has no operable genetic alterations in EGFR and ALK. In some implementations, the patient population maintains a partial response from baseline to at least approximately 48 weeks from baseline.

[0086] In some embodiments, the anti-Trop-2 antibody or its antigen-binding fragment comprises a heavy chain variable region containing SEQ ID NO: 19 and a light chain variable region containing SEQ ID NO: 20.

[0087] In some embodiments, the anti-Trop-2 antibody comprises a heavy chain containing SEQ ID NO: 1 and a light chain containing SEQ ID NO: 2.

[0088] In some implementations, the anti-Trop-2 antibody is sacitrus.

[0089] In some implementations, the ADC is the SG.

[0090] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region containing SEQ ID NO: 6 or a variant thereof, and a heavy chain variable region containing SEQ ID NO: 11.

[0091] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO: 12.

[0092] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab or a variant thereof. In some other embodiments, the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab.

[0093] In some implementations, the PD-1 antibody or its antigen-binding fragment is pembrolizumab, and the ADC is SG.

[0094] In some implementations, the PD-L1 TPS of the patient population is ≥50%. In some other implementations, the PD-L1 TPS of the patient population is <50%. In some implementations, the PD-L1 TPS of the patient population is 1% to 49%. In some implementations, the PD-L1 TPS of the patient population is <1%.

[0095] In some implementations, the patient population has non-squamous NSCLC. In some other implementations, the patient population has squamous NSCLC.

[0096] In some implementations, treatment includes the achievement of clinical efficacy.

[0097] In some implementations, the ORR is approximately 69%. In some other implementations, the ORR is approximately 44%.

[0098] In some implementations, the DCR is approximately 86%. In some other implementations, the DCR is approximately 78%.

[0099] In some implementations, the DOR is approximately 88% at about 6 months from baseline.

[0100] In some implementations, the method achieves less than about 10% of serious treatment-emergent adverse events (TEAEs). In some other implementations, the method achieves less than about 9% of serious TEAEs.

[0101] In some implementations, the method achieves less than about 25% of ≥3 level TEAEs. In some other implementations, the method achieves less than about 24% of ≥3 level TEAEs.

[0102] In some implementations, TEAE includes one or more of the following: stomatitis, anemia, leukopenia, rash, and thrombocytopenia.

[0103] In some implementations, TEAE includes interstitial lung disease (ILD).

[0104] In some implementations, ILD was observed in less than about 10% of patients. In some other implementations, ILD was observed in less than about 9% of patients. In some other implementations, ILD was observed in less than about 5% of patients.

[0105] In some implementations, ILD was not observed in patients.

[0106] In some embodiments, the method does not include concomitant administration of platinum-based chemotherapy. In some embodiments, the method does not include concomitant administration of anti-TGIT antibody.

[0107] In some implementations, the method achieves a partial response rate of approximately 69% or higher when the patient population has PD-L1 TPS ≥ 50%.

[0108] In some implementations, the method achieves a partial response rate of approximately 44% or higher when the PD-L1 TPS of the patient population is <50%.

[0109] In some implementations, the method achieves a partial response rate of approximately 56% or higher, regardless of the PD-L1TPS status of the patient population.

[0110] In some implementations, the method does not include determining the PD-L1 TPS status of the patient population.

[0111] In some implementations, the method does not include the administration of additional targeted oncology drugs.

[0112] In some implementations, a partial response is one or more tumors whose size has decreased by about 30% or more from baseline to a point approximately 13 weeks or more from baseline.

[0113] In some implementations, a partial response is one or more tumors whose size has decreased by about 40% or more from baseline to a point approximately 13 weeks or more from baseline.

[0114] In some embodiments, this document discloses a method for improving clinical efficacy in a patient population with metastatic non-squamous or squamous NSCLC without concurrent chemotherapy, compared with administration of anti-PD-L1 antibody monotherapy or with administration of antibody-drug conjugate monotherapy, comprising co-administering: (a) 10 mg / kg SG administered intravenously on days 1 and 8 of one or more 21-day treatment cycles; and (b) 200 mg pembrolizumab administered on day 1 of one or more 21-day treatment cycles; wherein the patient population has not received prior systemic therapy for metastatic NSCLC.

[0115] In some implementations, the patient population has no operable genetic alterations in EGFR, ALK, and PD-L1. In some implementations, patients have no known operable genetic alterations in ROS1, NTRK, BRAF, and RET. In some implementations, patients have no operable genetic alterations in EGFR and ALK. In some implementations, the patient population maintains a partial response from baseline to at least approximately 48 weeks from baseline.

[0116] In some embodiments, the anti-PD-1 antibody comprises a light chain variable region containing SEQ ID NO: 6 or a variant thereof and a heavy chain variable region containing SEQ ID NO: 11.

[0117] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO: 12.

[0118] In some implementations, clinical efficacy is improved regardless of the PD-L1 status of the patient population.

[0119] In some implementations, the patient population has a PD-L1 TPS score ≥50%. In some other implementations, the patient population has a PD-L1 TPS score <50%.

[0120] In some implementations, the anti-PD-L1 antibody monotherapy is pembrolizumab.

[0121] In some implementations, antibody-drug conjugate monotherapy is SG.

[0122] In some implementations, the method does not include determining the PD-L1 TPS status of the patient population. In some implementations, the method does not include administering additional targeted oncology drugs.

[0123] In some implementations, chemotherapy is a platinum-based chemotherapy.

[0124] In some implementations, the patient has non-squamous NSCLC. In some other implementations, the patient has squamous NSCLC.

[0125] In some implementations, the method does not include the concomitant administration of anti-TGIT antibody.

[0126] In some implementations, the method achieves a partial response rate of approximately 69% or higher when the patient population has PD-L1 TPS ≥ 50%.

[0127] In some implementations, the method achieves a partial response rate of approximately 44% or higher when the PD-L1 TPS of the patient population is <50%.

[0128] In some implementations, the method achieves a partial response rate of approximately 56% or higher, regardless of the PD-L1TPS status of the patient population.

[0129] In some implementations, the ORR is approximately 69%. In some other implementations, the ORR is approximately 44%.

[0130] In some implementations, the DCR is approximately 86%. In some other implementations, the DCR is approximately 78%.

[0131] In some implementations, the DOR is approximately 88% at about 6 months from baseline.

[0132] In some implementations, the method achieves less than about 10% of serious treatment-emergent adverse events (TEAEs). In some other implementations, the method achieves less than about 9% of serious TEAEs.

[0133] In some implementations, the method achieves less than about 25% of ≥3 level TEAEs. In some other implementations, the method achieves less than about 24% of ≥3 level TEAEs.

[0134] In some implementations, TEAE includes one or more of the following: stomatitis, anemia, leukopenia, rash, and thrombocytopenia.

[0135] In some implementations, TEAE includes interstitial lung disease (ILD).

[0136] In some implementations, ILD was observed in less than about 10% of patients. In some other implementations, ILD was observed in less than about 9% of patients. In some other implementations, ILD was observed in less than about 5% of patients.

[0137] In some implementations, ILD was not observed in patients.

[0138] In some implementations, a partial response is one or more tumors whose size has decreased by about 30% or more from baseline to a point approximately 13 weeks or more from baseline.

[0139] In some implementations, a partial response is one or more tumors whose size has decreased by about 40% or more from baseline to a point approximately 13 weeks or more from baseline.

[0140] In some embodiments, this document discloses methods for achieving clinical efficacy in patients with metastatic NSCLC regardless of the patient's PD-L1 TPS score, regardless of the patient's NSCLC histology, without concurrent chemotherapy, and wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising co-administration of: (a) 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and (b) 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

[0141] In some implementations, the patient population has a PD-L1 TPS score ≥50%. In some other implementations, the patient population has a PD-L1 TPS score <50%. In some implementations, the patient population has PD-L1 TPS ranging from 1% to 49%. In some implementations, the patient population has PD-L1 TPS <1%.

[0142] In some implementations, the method does not include determining the PD-L1 TPS status of the patient population. In some implementations, the method does not include administering additional targeted oncology drugs.

[0143] In some implementations, chemotherapy is a platinum-based chemotherapy.

[0144] In some implementations, the patient has non-squamous NSCLC. In some other implementations, the patient has squamous NSCLC.

[0145] In some implementations, the method does not include the concomitant administration of anti-TGIT antibody.

[0146] In some implementations, the method achieves a partial response rate of approximately 69% or higher when the patient population has PD-L1 TPS ≥ 50%.

[0147] In some implementations, the method achieves a partial response rate of approximately 44% or higher when the PD-L1 TPS of the patient population is <50%.

[0148] In some implementations, the method achieves a partial response rate of approximately 56% or higher, regardless of the PD-L1TPS status of the patient population.

[0149] In some implementations, the ORR is approximately 69%. In some other implementations, the ORR is approximately 44%.

[0150] In some implementations, the DCR is approximately 86%. In some other implementations, the DCR is approximately 78%.

[0151] In some implementations, the DOR is approximately 88% at about 6 months from baseline.

[0152] In some implementations, the method achieves less than about 10% of serious treatment-emergent adverse events (TEAEs). In some other implementations, the method achieves less than about 9% of serious TEAEs.

[0153] In some implementations, the method achieves less than about 25% of ≥3 level TEAEs. In some other implementations, the method achieves less than about 24% of ≥3 level TEAEs.

[0154] In some implementations, TEAE includes one or more of the following: stomatitis, anemia, leukopenia, rash, and thrombocytopenia.

[0155] In some implementations, TEAE includes interstitial lung disease (ILD).

[0156] In some implementations, ILD was observed in less than about 10% of patients. In some other implementations, ILD was observed in less than about 9% of patients. In some other implementations, ILD was observed in less than about 5% of patients.

[0157] In some implementations, ILD was not observed in patients.

[0158] In some implementations, a partial response is one or more tumors whose size has decreased by about 30% or more from baseline to a point approximately 13 weeks or more from baseline.

[0159] In some implementations, a partial response is one or more tumors whose size has decreased by about 40% or more from baseline to a point approximately 13 weeks or more from baseline.

[0160] In some embodiments, the method does not include concomitant administration of additional and / or third anticancer agents. In some embodiments, the method does not include determining the patient's PD-L1 TPS status. In some embodiments, the patient maintains a partial response for at least approximately 48 weeks from baseline to baseline.

[0161] In some implementations, when the method is used to treat a patient population with metastatic NSCLC, and clinical efficacy includes an objective response rate, an objective response rate (ORR) of approximately 56% or higher is achieved. In some implementations, an ORR of approximately 56% or higher is achieved approximately 13 weeks or longer from baseline.

[0162] In some implementations, the method does not include the accompanying administration of additional targeted oncology drugs.

[0163] In some embodiments, this document discloses the use of a therapeutic combination comprising an antibody-drug conjugate (ADC) containing an anti-Trop-2 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof for use in the methods described herein.

[0164] In some embodiments, this document discloses treatment combinations comprising an antibody-drug conjugate (ADC) containing an anti-Trop-2 antibody or an antigen-binding fragment thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, for use in the methods described herein.

[0165] In some implementations, a partial response is one or more tumors whose size has decreased by about 30% or more from baseline to a point approximately 13 weeks or more from baseline.

[0166] In some implementations, a partial response is one or more tumors whose size has decreased by about 40% or more from baseline to a point approximately 13 weeks or more from baseline.

[0167] In some embodiments, a method is provided to achieve clinical efficacy in patients with metastatic NSCLC, regardless of the patient's PD-L1 TPS, regardless of the patient's NSCLC histology, without concomitant chemotherapy, wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising co-administration of: 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles. In some embodiments, the patient's PD-L1 TPS is <1%. In some embodiments, the method does not include concomitant administration of additional targeted oncology drugs.

[0168] In some embodiments, this document discloses a method of treating patients with squamous metastatic non-small cell lung cancer (NSCLC) who have not received prior systemic therapy for squamous metastatic NSCLC, the method comprising co-administration of: a) 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and b) 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

[0169] In some implementations, the patient's PD-L1 tumor proportion score (TPS) is ≥50%. In other implementations, the patient's PD-L1 TPS is <50%.

[0170] In some embodiments, the method does not include concomitant administration of chemotherapy. In some embodiments, the method does not include concomitant administration of platinum-based chemotherapy.

[0171] In some implementations, the method is used to treat squamous metastatic NSCLC in a patient population with PD-L1 TPS ≥ 50%, achieving a partial response rate of approximately 73% or higher. In some implementations, the method is used to treat squamous metastatic NSCLC in a patient population with PD-L1 TPS < 50%, achieving a partial response rate of approximately 54% or higher.

[0172] In some embodiments, this document provides a method for treating a patient population with squamous metastatic NSCLC without concurrent chemotherapy, the method comprising co-administering: 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles; wherein the patient population has not received prior systemic therapy for squamous metastatic NSCLC.

[0173] In some implementations, the patient population has PD-L1 TPS ≥ 50%. In other implementations, the patient population has PD-L1 TPS < 50%.

[0174] In some implementations, treatment includes the achievement of clinical efficacy.

[0175] In some implementations, the ORR is approximately 73%. In some other implementations, the ORR is approximately 54%.

[0176] In some implementations, the DCR is approximately 82%. In some other implementations, the DCR is approximately 85%.

[0177] In some implementations, the method achieves a partial response rate of approximately 64% to 73%. In some other implementations, the method achieves a partial response rate of approximately 46% to 57%.

[0178] In some embodiments, this article provides a method for achieving clinical efficacy in patients with metastatic squamous NSCLC regardless of the patient's PD-L1 tumor proportion score, without prior chemotherapy, and wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising co-administration of: 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

[0179] In some implementations, the method does not include the accompanying administration of additional targeted oncology drugs.

[0180] In some implementations, the ORR is approximately 73%. In some other implementations, the ORR is approximately 54%.

[0181] In some implementations, the DCR is approximately 82%. In some other implementations, the DCR is approximately 85%.

[0182] In some implementations, the method achieves a partial response rate of approximately 64% to 73%. In some other implementations, the method achieves a partial response rate of approximately 46% to 57%.

[0183] In some implementations, this article provides a method for achieving clinical efficacy in patients with metastatic squamous NSCLC, comprising administering to a patient in need: 10 mg / kg SG, administered on days 1 and 8 of one or more 21-day treatment cycles; and 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles, wherein the patient has a PD-L1 tumor proportion score ≥50%.

[0184] In some embodiments, the methods disclosed herein include administration of SG for a treatment cycle of at least about (12) 21 days. In some embodiments, the methods disclosed herein include administration of SG and pembrolizumab for a treatment cycle of at least about (12) 21 days. In some embodiments, the patient achieves a partial response for at least about 36 weeks. In some embodiments, the methods disclosed herein include administration of SG on days 1 and 8 of a treatment cycle of at least about (12) 21 days, and administration of pembrolizumab on day 1 of a treatment cycle of at least about (12) 21 days.

[0185] In some embodiments, the methods disclosed herein include administration of SG for at least a treatment cycle of about (14) 21 days. In some embodiments, the methods disclosed herein include administration of SG and pembrolizumab for at least a treatment cycle of about (14) 21 days. In some embodiments, the patient achieves a partial response for at least about 42 weeks. In some embodiments, the methods disclosed herein include administration of SG on days 1 and 8 of a treatment cycle of at least about (14) 21 days, and administration of pembrolizumab on day 1 of a treatment cycle of at least about (14) 21 days. Attached Figure Description

[0186] Figure 1 The design of the open-label, multi-cohort phase 2 clinical trial (NCT05186974) is shown, evaluating the combination of sacitrusuzumab-gavitenac (SG) and pembrolizumab (pembro) as first-line treatment for metastatic non-small cell lung cancer (NSCLC), with or without platinum. This clinical trial is designated "EVOKE-02". As used in the figure, NSCLC stands for Non-Small Cell Lung Cancer; RECIST stands for Response Evaluation Criteria for Solid Tumors; ECOG stands for Eastern Cooperative Oncology Group Performance Index; PD-L1 stands for Programmed Death-Ligand 1; TPS stands for Tumor Proportion Score; Sq stands for Squamous Tumors; Nsq stands for Non-Squamous Tumors; IV stands for Intravenous; RP2D stands for Recommended Phase 2 Dose; ORR stands for Objective Response Rate; DLT stands for Dose-Limiting Toxicity; DCR stands for Disease Control Rate; DOR stands for Duration of Response; PFS stands for Progression-Free Survival; and OS stands for Overall Survival.

[0187] Figures 2A-2B The heavy chain sequence (Fig. 2a) and light chain sequence (Fig. 2b) of the antibody (hRS7) in SG are shown. Figure 2A SEQ ID NO: 1 has been disclosed. Figure 2B SEQ ID NO: 2 has been disclosed.

[0188] Figure 3The study procedures for EVOKE-02 are shown. As used in the figure: SG, sacitrus-glavotecan; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; PD-L1, programmed death-ligand 1; PK, pharmacokinetics; CT, computed tomography; MRI, magnetic resonance imaging; 18F-FDG PET, fluorodeoxyglucose F 18 positron emission tomography; AE, adverse events; and SAE, serious adverse events. As of the data cutoff date (June 16, 2023), the median (range) follow-up periods for cohort A and cohort B were 5.0 (1.7–12.0) months and 5.8 (1.0–12.2) months, respectively.

[0189] Figure 4 Exemplary data on the optimal percentage reduction of target lesions in patients in EVOKE-02 are shown. Each column represents one patient. The percentage reduction of target lesions for each patient in cohort A or cohort B of EVOKE-02 is shown. The optimal overall response for each patient is indicated, and each patient is classified as having the optimal overall response corresponding to partial response (triangle), stable disease (square), or progressive disease (circle). Only patients with a follow-up of ≥13 weeks as of the cutoff date (June 16, 2023) were included in the efficacy analysis. Used in the figure: TPS, Tumor Proportion Score.

[0190] Figures 5A-5B Queue A for EVOKE-02 is shown ( Figure 5A ) and queue B ( Figure 5B This is an example of patient response data from treatment initiation to progression. The data shows the percentage change in target lesion measurements relative to baseline over time. Each line corresponds to the individual patient's response progression, and each point represents a time point for response assessment. The last assessment for each patient prior to data collection is indicated by a circle. The best overall response is indicated for each patient, and each patient is categorized as having the best overall response corresponding to partial response (green line), stable disease (blue line), or progressive disease (red line). Only patients with a follow-up of ≥13 weeks as of the cutoff date (June 16, 2023) were included in the efficacy analysis. Used in the figure: TPS, Tumor Proportion Score; PD-L1, Programmed Death Ligand; SG, Sacituzumab-Govitecan; and pembro, Pembrolizumab.

[0191] Figure 6Exemplary data on patient-reported treatment-emergent adverse events (TEAEs) in EVOKE-02 are shown. Each column indicates the percentage of patients reported with the corresponding TEAE out of the total number of evaluable patients in cohorts A and B. Only patients who received ≥1 dose of study treatment were included in the analysis. For each TEAE, the number of patients with a grade 1-2 or grade 3 or higher TEAE is indicated.

[0192] Figure 7 Exemplary data on patient-reported immune-mediated TEAEs in EVOKE-02 are presented. Each column indicates the percentage of patients reported with a TEAE out of the total number of evaluable patients in cohorts A and B. Only patients who received ≥1 dose of study treatment were included in the analysis. For each TEAE, the number of patients with a grade 1-2 or grade 3 or higher TEAE is indicated. Detailed Implementation

[0193] Anti-TROP2 ADC: Sacitocilizumab-Govitecan ("SG")

[0194] SG is a pharmaceutical composition comprising an antibody-drug conjugate (“ADC”) consisting of: (1) a drug (“SN-38”), a topoisomerase 1 inhibitor that is the active metabolite of irinotecan; (2) a linker (“CL2A”); and (3) a humanized monoclonal antibody (“hRS7 IgG”). k (or "Sacitocilizumab"). CL2A conjugates SN-38 to hRS7, and hRS7 binds to Trop-2.

[0195] In some implementations, hRS7 is, for example, in WO2003074566 Figure 3 and Figure 4 The description states that the full text of WO2003074566 is incorporated through citation.

[0196] In some implementations, SG is represented by Equation I as shown below.

[0197] (Formula I)

[0198] In some embodiments, the ADC comprises drug molecules linked to an antibody moiety in various stoichiometric molar ratios, which depend on the antibody configuration and at least in part on the method used to achieve that configuration. In some embodiments, the drug-antibody ratio (“DAR”) is about 7.6. In some embodiments, the DAR is about 7.0 to about 8.0.

[0199] In some embodiments, the hRS7 antibody in the SG comprises a heavy chain as shown in SEQ ID NO.: 1 and a light chain as shown in SEQ ID NO.: 2 (as shown in Table 1 and...). Figures 2A-2B (as shown in SEQ ID NO.: 1). In some embodiments, the hRS7 antibody in the SG comprises two heavy chains, each having a sequence as shown in SEQ ID NO.: 1, and two light chains, each having a sequence as shown in SEQ ID NO.: 2.

[0200] Table 1. Amino acid sequence of hRS7 antibody

[0201]

[0202] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in U.S. Patent Nos. 7,999,083 and 9,028,833, which are incorporated herein by reference in their entirety.

[0203] Anti-PD-1 antibody or its antigen-binding fragment

[0204] Examples of human PD-1-binding monoclonal antibodies (mAbs) that can be used in the therapeutic methods and uses of the present invention are described in US 7,521,051, US 8,008,449, and US 8,354,509. Specific anti-human PD-1 mAbs that can be used as PD-1 antagonists in the therapeutic methods of this disclosure include: pembrolizumab (formerly known as MK-3475, SCH 900475, and lambrolizumab), having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013) and containing... Figure 1 The humanized IgG4 mAb with heavy and light chain amino acid sequences shown, and the humanized antibodies h409A11, h409A16 and h409A17 described in WO2008 / 156712 and Table 2.

[0205] In some embodiments of the methods disclosed herein, the anti-PD-1 antibody or its antigen-binding fragment comprises: (a) a light chain CDR comprising the amino acid sequences shown in SEQ ID NO: 3, 4 and 5, and (b) a heavy chain CDR comprising the amino acid sequences shown in SEQ ID NO: 8, 9 and 10.

[0206] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is a human antibody. In other embodiments, the anti-PD-1 antibody or its antigen-binding fragment is a humanized antibody. In other embodiments, the anti-PD-1 antibody or its antigen-binding fragment is a chimeric antibody. In a specific embodiment, the anti-PD-1 antibody or its antigen-binding fragment is a monoclonal antibody.

[0207] In other embodiments of the treatment methods disclosed herein, an anti-PD-1 antibody or an antigen-binding fragment thereof specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising an amino acid sequence as shown in SEQ ID NO: 11 or a variant thereof, and (b) a light chain variable region comprising an amino acid sequence selected from SEQ ID NO: 6.

[0208] Variants of the heavy chain variable region sequence or full-length heavy chain sequence are identical to the reference sequence except that they have up to 17 conserved amino acid substitutions in the frame region (i.e., outside the CDR), and preferably have fewer than 10, 9, 8, 7, 6, or 5 conserved amino acid substitutions in the frame region. Variants of the light chain variable region sequence or full-length light chain sequence are identical to the reference sequence except that they have up to 5 conserved amino acid substitutions in the frame region (i.e., outside the CDR), and preferably have fewer than 4, 3, or 2 conserved amino acid substitutions in the frame region.

[0209] In another embodiment of the treatment method disclosed herein, the anti-PD-1 antibody or its antigen-binding fragment is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain or a variant thereof comprising an amino acid sequence as shown in SEQ ID NO:12 or composed of such amino acid sequence; and (b) a light chain or a variant thereof comprising an amino acid sequence as shown in SEQ ID NO:7 or composed of such amino acid sequence.

[0210] In another embodiment of the treatment method disclosed herein, the anti-PD-1 antibody or its antigen-binding fragment is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain comprising or consisting of an amino acid sequence as shown in SEQ ID NO:12 and (b) a light chain comprising or consisting of an amino acid sequence as shown in SEQ ID NO:7.

[0211] Table 2. Exemplary PD-1 antibody sequences

[0212]

[0213] In one embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain constant region, such as a human constant region, such as g1, g2, g3, or g4 human heavy chain constant regions or variants thereof. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain constant region, such as a human light chain constant region, such as λ or κ human light chain regions or variants thereof. By way of example and not limitation, the human heavy chain constant region may be g4 and the human light chain constant region may be κ. In an alternative embodiment, the Fc region of the antibody is g4 with the Ser228Pro mutation (Schuurman, J et al., Mol. Immunol. 38: 1-8, 2001). In some embodiments, different constant domains may be attached to humanized VL and VH regions derived from the CDR provided herein. For example, if the particular intended use of the antibody (or fragment) of the present invention requires a modified effector function, a heavy chain constant domain other than human IgG1 may be used, or a hybrid IgG1 / IgG4 may be utilized. Although human IgG1 antibodies offer long half-lives and effector functions such as complement activation and antibody-dependent cytotoxicity, such activities may not be desired for all uses of the antibody. In such cases, for example, the human IgG4 constant domain can be used. This invention includes the use of anti-PD-1 antibodies comprising the IgG4 constant domain or antigen-binding fragments thereof. In one embodiment, the IgG4 constant domain may differ from the native human IgG4 constant domain (Swiss-Prot accession number P01861.1) at a position corresponding to position 228 in the EU system and position 241 in the KABAT system, wherein the native Ser108 is replaced by Pro to prevent potential interchain disulfide bonds between Cys106 and Cys109 (corresponding to positions Cys 226 and Cys 229 in the EU system and positions Cys 239 and Cys 242 in the KABAT system) that could interfere with proper intrachain disulfide bond formation. See Angal et al. (1993) Mol. Imunol. 30:105. In other cases, modified IgG1 constant domains that have been modified to increase half-life or reduce effector function can be used.

[0214] In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment has a variable light chain domain and / or a variable heavy chain domain with at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity to one of the aforementioned variable light chain domains or variable heavy chain domains, and exhibits specific binding to PD-1. In another embodiment of the treatment method of the present invention, the anti-PD-1 antibody or its antigen-binding fragment comprises a variable light chain domain and a variable heavy chain domain having at most 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0215] definition

[0216] Unless the context otherwise specifies, the singular forms “a,” “a,” and “the” include plural references.

[0217] As used herein, ranges and quantities can be expressed as “about” a specific value or range. “About” also includes the exact quantity. Therefore, “about 5 µL” means “about 5 µL” and also “5 µL”. Typically, the term “about” includes quantities expected to be within, for example, 15%, 10%, or 5% of experimental error.

[0218] "Operable genomic alterations" are known in the art as gene being operable if a gene has an established biological role in cancer and there are clinically available drugs that confer sensitivity or resistance to the gene, wherein operability can be applied to all or selected alterations or tumor types.

[0219] "Advanced disease" refers to stage III disease that has not yet spread, or cancer that is unlikely to be cured or controlled long-term with treatment because it has spread to distant locations.

[0220] "Anticancer agents" refer to approved or investigational drugs used for or evaluated in cancer. They can refer to systemic and targeted therapies.

[0221] "Metastatic cancer or disease" is a subcategory of advanced disease. It refers to stage IV disease and / or cancer that is unlikely to be cured or controlled long-term with treatment because it has spread to distant locations.

[0222] As used in this article, "locally advanced disease" refers to a disease state in which cancer cells have begun to spread from their initial site of origin but have not yet spread to other parts of the body.

[0223] "Antibody-drug conjugate" or "ADC" generally refers to a compound comprising an antibody targeting a tumor antigen, optionally linked via a linker, and an anticancer drug or payload. In some embodiments, an ADC is a SG. In some embodiments, an ADC is an ADC approved for NSCLC or clinically evaluated for NSCLC. In some embodiments, an ADC comprises a Trop 2-targeting antibody. In some embodiments, "ADC" refers to a compound of formula I having an anti-Trop-2 antibody (sacituzumab) linked to the drug or payload SN38.

[0224] The term "antibody fragment" or "antigen-binding fragment" refers to a molecule that is distinct from a full-length antibody, but contains a portion of the full-length antibody that binds to the antigen bound by the full-length antibody. Antibody fragments retain the ability to specifically bind to the antigen bound to the full-length antibody, for example, fragments that retain one or more CDR regions (e.g., all six CDRs). Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; bivalent antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0225] An antibody that "specifically binds" to a designated target protein is one that exhibits preferential binding to that target compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered "specific" to its intended target if its binding determines the presence of the target protein in the sample, for example, by not producing undesirable results such as false positives. Antibodies or their binding fragments used in this invention will bind to the target protein with an affinity at least two times, preferably at least ten times, more preferably at least 20 times, and most preferably at least 100 times that of the non-target protein. As used herein, if an antibody binds to a polypeptide containing a given amino acid sequence, such as that of a mature human PD-1 or human PD-L1 molecule, but not to a protein lacking that sequence, the antibody is said to specifically bind to the polypeptide containing that sequence.

[0226] As used herein, “baseline” is a time approximately 28 days prior to the start of treatment, i.e., approximately 28 days prior to day 1 of cycle 1. In some embodiments, the baseline refers to approximately day -28 to day -1 prior to day 1 of cycle 1. In some embodiments, the baseline is a time approximately 28 days + / - 7 days prior to the start of treatment. In some embodiments, the baseline is the time from one measurement to another; that is, the baseline may refer to the initial time point when comparing measurements, i.e., measurements of the lesion, between two time points. In this case, the initial time point does not necessarily correspond to the start of treatment.

[0227] "Blinded Independent Central Review" ("BICR") refers to the process of submitting radiological examinations performed as part of a clinical trial protocol and selected clinical data to a central location for independent review.

[0228] As used in this article, "not having received chemotherapy" means that the patient has not yet received chemotherapy, that is, has not yet received chemotherapy for advanced or metastatic NSCLC.

[0229] "Co-administration" refers to the administration of two or more drugs or therapies to a patient. As used herein, "co-administration" means the administration of two or more drugs within the same time period. In some embodiments, "co-administration" means the administration of two or more drugs during the same dosing cycle. For example, if the dosing cycle is 21 days, "co-administration" could mean administering drug 1 on day 1 and drug 2 on day 1 or any other day within a 21-day dosing cycle. In some embodiments, "co-administration" means the combined administration of two or more drugs within at least one dosing cycle. Co-administration of two therapies can also be via the same or different routes of administration.

[0230] "Clinical efficacy" or "clinical activity" refers to clinical efficacy or activity in human patients. In some embodiments, clinical activity or clinical efficacy refers to a partial or complete response. In some embodiments, when used in the context of a patient population, clinical efficacy or clinical activity includes ORR, DOR, and / or DCR. In some embodiments, when used in the context of a comparison between two or more agents, an improvement in clinical efficacy or clinical activity can be used to describe a clinically meaningful benefit of one agent to a human patient compared to another. As used herein, "clinically meaningful benefit" (or a grammatical variation thereof) means an improvement in the outcome / finding of medical care that results in an individual's physical functioning, his / her mental state, and / or ability to participate in social life. The term "improvement in quality of life in medical care" involves both subjective and objective terms. Objective terms may include the duration of disease remission, etc. Subjective terms may include an improvement in quality of life.

[0231] "Complete response" ("CR") refers to the disappearance of all target lesions.

[0232] Unless otherwise specified, as used herein, “CDR” means the complementarity-determining region in the immunoglobulin variable region as defined using the Kabat numbering system.

[0233] "Concomitant administration" or "parallel administration" are used interchangeably and refer to the administration of two or more drugs or therapies during the same dosing cycle. Each drug may be approved or investigated for an indication of interest.

[0234] The “Disease Control Rate” (“DCR”) is defined as the proportion of patients who achieve CR, PR, or SD (stable disease), as assessed by the IRC according to RECIST version 1.1 and / or by investigator assessment.

[0235] "Response Duration" ("DOR") refers to the time from the start of a response to its progress or death (e.g., months).

[0236] "First-line treatment" as known in the art refers to the initial therapy for a specific disease.

[0237] As used herein, “monoclonal antibody” or “mAb” or “Mab” refers to a substantially homogeneous group of antibodies, meaning that the antibody molecules constituting the group are identical in amino acid sequence except that they may be present in small amounts as naturally occurring mutations. In contrast, conventional (polyclonal) antibody formulations typically comprise a variety of different antibodies having different amino acid sequences in their variable structural domains (particularly their CDRs) that are typically specific to different epitopes. The modifier “monoclonal” indicates the characteristic of antibodies obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, the monoclonal antibody to be used according to the invention can be prepared by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or by a recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, those described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0238] As used in this article, “NSCLC histology” refers to whether NSCLC is squamous or non-squamous.

[0239] The objective response rate (“ORR”) refers to the proportion of subjects who have measurable disease at baseline and achieve a confirmed complete response (CR) or partial response (PR) after at least 4 weeks. In some implementations, the ORR is assessed by an independent review committee (IRC) according to the Evaluation Criteria for Response to Solid Tumors (RECIST) version 1.1. In some implementations, the ORR is assessed by the investigator. In some implementations, as assessed according to RECIST version 1.1, the primary analysis of the ORR is performed by estimating the proportion of patients achieving a confirmed CR or PR in the FAS of each cohort, and is a two-sided confidence interval (“CI”) using the Clopper-Pearson exact method.

[0240] A "partial response" ("PR") is defined as a reduction of >30% in the sum of the longest diameters ("LDs") of the target lesion relative to baseline total LD. In some implementations, the lesion is measured with IV contrast agent via computed tomography or MRI (unless the use of contrast agent is medically contraindicated). This is based on the study procedure (e.g., ...). Figure 3As shown, lesions in the chest, abdomen, pelvis, and any other sites of disease involvement were measured in all patients at baseline and every 6 weeks after the start of study treatment for the first 12 months, then every 9 weeks until the start of subsequent anticancer therapy or termination of the study by the sponsor, whichever occurred first. For patients with evidence of CR or PR, a confirmatory scan was performed at least 4 weeks after the initial response record. In some implementations, tumor response and progression were assessed by the IRC using the Evaluation Criteria for Solid Tumor Response (RECIST) version 1.1. In some implementations, PR is defined as the ability to measure 50% or more of the tumor size.

[0241] As used herein, "patient" or "subject" refers to a person suffering from a specific disease. In some implementations, the patient is an adult patient. In some implementations, the patient is a pediatric patient.

[0242] Pembrolizumab (formerly known as MK-3475, SCH 900475, and rambrizumab), alternatively referred to herein as "pembro," is a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013) and containing the heavy and light chain amino acid sequences described in Table 2. Pembrolizumab has been approved by the US FDA, such as KEYTRUDA. ™ The prescription information is as described in the Merck & Co., Inc., Rahway, NJ, USA; originally approved in the U.S. in 2014, updated in March 2021.

[0243] As used herein, “pembrolizumab variant” or “variants thereof” in relation to the pembrolizumab sequence means a monoclonal antibody containing a heavy and light chain sequence substantially identical to that of pembrolizumab, except for three, two, or one conserved amino acid substitution at a position outside the light chain CDR, and six, five, four, three, two, or one conserved amino acid substitution at a position outside the heavy chain CDR, for example, the variant position being located in the FR region or constant region, and optionally having the deletion of a C-terminal lysine residue of the heavy chain. In other words, pembrolizumab and pembrolizumab variants contain the same CDR sequence but differ from each other due to no more than three or six other conserved amino acid substitutions at other positions in their full-length light and heavy chain sequences, respectively. Pembrolizumab variants are substantially identical to pembrolizumab in the following properties: binding affinity for PD-1 and the ability to block the binding of PD-L1 and PD-L2 to PD-1, respectively.

[0244] "Progression-free survival" ("PFS") refers to the time from the first dose of RECIST 1.1 to the date of disease progression or death (whichever occurs first), as defined by ICR.

[0245] "Refractory" is used to describe a disease that does not respond to treatment or whose response to treatment is short-lived.

[0246] "Relapse" refers to a disease that recurs or grows again after a period of remission.

[0247] As used in this article, “standard of care” refers to the preferred treatment for a specific disease or indication, such as treatment approved by a government regulatory agency for a specific disease or indication.

[0248] "Targeted therapy" refers to small molecule inhibitors, monoclonal antibodies, and treatments for various tumor types in cancer treatment.

[0249] "Therapeutic effective amount" or "effective amount" is defined as the amount of a compound / drug that treats a disease or condition and achieves clinical efficacy.

[0250] "Treatment" (or its grammatical variant) means medical care that produces a clinically meaningful benefit or improvement in a human patient or human subject.

[0251] As used in this article, “treatment-emergent adverse effect” (“TEAE”) refers to an adverse effect reported in patients who have received at least one dose of treatment.

[0252] As used in this article, "untreated" means that the patient has not yet received treatment, that is, has not yet received treatment for advanced or metastatic NSCLC.

[0253] "Tumor proportion score" ("TPS"), or PD-L1 TPS, refers to PD-L1 protein expression as determined by the percentage of live tumor cells stained with partial or complete membranes of any intensity, as known in the art. In some embodiments, an FDA-validated assay may be used to measure TPS. In some embodiments, TPS refers to PD(L)-1 protein expression.

[0254] Recommended dosing regimen

[0255] In some embodiments, SG is administered weekly via intravenous infusion at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle. In some embodiments, SG is administered until disease progression or unacceptable toxicity occurs.

[0256] In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment (e.g., pembrolizumab) is administered to subjects in need approximately every two weeks, approximately every three weeks, or approximately every four weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered to subjects in need approximately every two weeks, approximately every three weeks, approximately every four weeks, or approximately every six weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered to subjects in need every two weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered to subjects in need every three weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered to subjects in need every six weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered to subjects in need every four weeks. In some embodiments, an anti-PD-1 antibody or its antigen-binding fragment is administered approximately every 14, 15, 16, 17, 18, 19, 20, or 21 days.

[0257] In some implementations, the anti-PD-1 antibody or its antigen-binding fragment (e.g., pembrolizumab) is administered at a dose of about 200 mg every 3 weeks, at a dose of about 400 mg every 6 weeks, or at a dose of about 2 mg / kg every 3 weeks (maximum of 200 mg).

[0258] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., pembrolizumab) is administered at a dose of approximately 2 mg / kg. In some embodiments, pembrolizumab is administered at a dose of approximately 2 mg / kg every 3 weeks. In a particular embodiment, the patient is a pediatric patient.

[0259] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., pembrolizumab) is administered via intravenous infusion over 30 minutes (-5 minutes / +10 minutes). In one embodiment, a selected dose of the anti-PD-1 antibody or its antigen-binding fragment is administered via IV infusion over a time period of 25 to 40 minutes or approximately 30 minutes.

[0260] In one aspect, an anti-PD-1 antibody or its antigen-binding fragment (e.g., pembrolizumab) is included in a pharmaceutical composition along with a pharmaceutically acceptable carrier or diluent, and may include additional pharmaceutically acceptable excipients.

[0261] Co-administration regimen

[0262] In some embodiments, SG and pembrolizumab are administered together. In some embodiments, 10 mg / kg SG is administered intravenously on days 1 and 8 of one or more 21-day treatment cycles, and 200 mg pembrolizumab is administered intravenously on day 1 of one or more 21-day treatment cycles. In some embodiments, combination therapy with SG and pembrolizumab begins on the same day of the 21-day dosing cycle, i.e., day 1 of the 21-day dosing cycle. In some embodiments, on the day of treatment when both SG and pembrolizumab are administered, i.e., day 1 of the 21-day dosing cycle, pembrolizumab is administered first, followed by SG. In some embodiments, on the day of treatment when both SG and pembrolizumab are administered, i.e., day 1 of the 21-day dosing cycle, SG is administered first, followed by pembrolizumab. In some embodiments, pembrolizumab is administered for no more than (35) 21-day dosing cycles. In some embodiments, SG is administered until disease progression or unacceptable toxicity occurs. In some embodiments, SG is administered during one or more 21-day dosing cycles prior to co-administration of SG and pembrolizumab. In some embodiments, pembrolizumab is not administered during one or more 21-day dosing cycles prior to co-administration of SG and pembrolizumab.

[0263] Dosage modification for adverse reactions

[0264] In some implementations, as described in Tables 3 and 4, the 10 mg / kg SG dose is stopped, modified, or interrupted to manage adverse reactions. In some implementations, the SG dose is not increased after a dose reduction has been implemented to address adverse reactions.

[0265] Table 3: Dosage modifications for adverse reactions (severe neutropenia)

[0266]

[0267] Table 4. Dosage modifications for adverse reactions (severe non-neutropenia toxicity)

[0268]

[0269] patient group

[0270] In some embodiments, the patient treated with the methods disclosed herein has NSCLC. In some embodiments, the NSCLC is advanced. In some embodiments, the NSCLC is advanced or metastatic. In some embodiments, the NSCLC is metastatic. In some embodiments, the NSCLC is untreated. In some embodiments, the NSCLC is untreated.

[0271] In some embodiments, the methods disclosed herein are used to treat first-line NSCLC. In some embodiments, the methods disclosed herein are used to treat first-line advanced or metastatic NSCLC. In some embodiments, the methods disclosed herein are used to treat first-line metastatic NSCLC.

[0272] In some embodiments, the patient treated with the methods disclosed herein has treatment-naïve NSCLC. In some embodiments, the patient treated with the methods disclosed herein has chemotherapy-naïve NSCLC. In some embodiments, the patient treated with the methods disclosed herein has not received prior therapy for NSCLC. In some embodiments, the patient treated with the methods disclosed herein has not received prior systemic therapy for NSCLC. In some embodiments, the patient has not received prior systemic therapy for metastatic NSCLC. In some embodiments, the patient has received adjuvant or neoadjuvant therapy completed at least 6 months prior to the development of metastatic disease. In some embodiments, the patient has not received adjuvant or neoadjuvant therapy completed at least 6 months prior to the development of metastatic disease. In some embodiments, the patient with advanced or metastatic NSCLC has not received prior therapy for advanced or metastatic NSCLC prior to the co-administration of SG and pembrolizumab as disclosed herein. In some embodiments, the patient has not received targeted therapy (approved or investigational) for NSCLC. In some embodiments, the patient has not received prior systemic therapy for NSCLC. In some implementations, the patient has not received prior systemic therapy for metastatic NSCLC.

[0273] In some embodiments, patients treated with the methods disclosed herein have no genomic alterations in EGFR. In some embodiments, patients have no genomic alterations in ALK. In some embodiments, patients have no operable genomic alterations in EFGR. In some embodiments, patients have no operable genomic alterations in ALK. In some embodiments, patients have no operable genomic alterations in both EGFR and ALK. In some embodiments, testing is required if the patient's status is unknown. In some embodiments, testing is not required if the patient's status is unknown.

[0274] In some implementations, where prior arterial therapy is used in patients treated with the methods disclosed herein, there are no known genomic alterations in ROS1, NTRK, BRAF, RET, and / or other operable driver oncogenes. In some implementations, testing is not required if the patient's condition is unknown.

[0275] In some implementations, patients treated with the methods disclosed herein do not have mixed small cell lung cancer (“SCLC”) / NSCLC histology.

[0276] In some embodiments, the patient treated with the methods disclosed herein has squamous NSCLC. In some embodiments, the patient treated with the methods disclosed herein has non-squamous NSCLC. In some embodiments, the patient treated with the methods disclosed herein has both squamous and non-squamous NSCLC.

[0277] In some embodiments, the methods disclosed herein do not include administration of anti-TIGIT antibodies to the patient. In some embodiments, the patient does not receive anti-TIGIT antibodies during one or more 21-day treatment cycles. In some embodiments, the methods do not include concomitant administration of anti-TGIT antibodies.

[0278] In some embodiments, the methods disclosed herein do not include concomitant administration of anticancer agents. In some embodiments, the methods disclosed herein do not include concomitant administration of chemotherapy. In some embodiments, the methods disclosed herein do not include concomitant administration of platinum-based chemotherapy. In some embodiments, the methods disclosed herein do not include concomitant administration of pemetrexed. In some embodiments, the methods disclosed herein do not include concomitant administration of both pemetrexed and platinum-based chemotherapy. In some embodiments, the methods disclosed herein do not include concomitant administration of carboplatin. In some embodiments, the methods disclosed herein do not include concomitant administration of paclitaxel / paclitaxel protein-bound formulation. In some embodiments, the methods disclosed herein do not include concomitant administration of carboplatin and paclitaxel / paclitaxel protein-bound formulation. In some embodiments, the methods disclosed herein do not include concomitant administration of pemetrexed, platinum-based chemotherapy, carboplatin, and paclitaxel / paclitaxel protein-bound formulation.

[0279] In some embodiments, patients treated with the methods disclosed herein have not previously received platinum-based chemotherapy for NSCLC or metastatic NSCLC. In some embodiments, patients treated with the methods disclosed herein have not previously received immune checkpoint inhibitor therapy for NSCLC or metastatic NSCLC. In some embodiments, patients treated with the methods disclosed herein have not previously received docetaxel therapy for NSCLC. In some embodiments, patients treated with the methods disclosed herein have not previously received docetaxel therapy for metastatic NSCLC.

[0280] In some embodiments, the method further includes administering one or more platinum-based chemotherapy therapies. In some embodiments, the patient receives platinum-based chemotherapy during one or more 21-day treatment cycles. In some embodiments, platinum-based chemotherapy is administered on day 1 of one or more 21-day treatment cycles. In some embodiments, platinum-based chemotherapy continues for up to four cycles.

[0281] Any known platinum-based chemotherapy can be used in this method. In some embodiments, the platinum-based chemotherapy is selected from a list consisting of cisplatin, carboplatin, oxaliplatin, and platinum nanocluster-based (Pt NC) nanomedicines.

[0282] Cisplatin is a first-generation platinum-based anticancer drug, discovered in the late 1960s and approved for cancer treatment in 1978. Cisplatin has therapeutic effects on many malignancies, such as breast cancer, ovarian cancer, and colorectal cancer. Carboplatin, a second-generation platinum-based chemotherapy drug, is developed based on cisplatin. Compared with cisplatin, carboplatin exhibits a lower hydration rate due to its bidentate cyclobutane dicarboxylic acid ligand and has high biocompatibility, while significantly reducing systemic toxicity, including hepatotoxicity, nephrotoxicity, neurotoxicity, and ototoxicity. Due to its lower toxicity, carboplatin can be used as a high-dose chemotherapy for aggressive tumors. Oxaliplatin is a third-generation platinum-based clinical drug. Oxaliplatin has a similar mechanism of action to cisplatin and does not exhibit cross-resistance with cisplatin or carboplatin. Therefore, oxaliplatin and cisplatin can complement each other in clinical anticancer treatment and have been widely used (Zhang et al., Theranostics, 12(5): 2115–2132 (2022)).

[0283] In some implementations, the platinum-based chemotherapy is cisplatin. In some implementations, cisplatin is administered at 75 mg / m². 2 The dosage of the chemotherapy is specified. In other embodiments, the platinum-based chemotherapy is carboplatin. In some embodiments, carboplatin is administered at a dose of AUC5. In some embodiments, cisplatin or cisplatin treatment is continued for up to 4 cycles. Those skilled in the art can adjust the dosage and cycle of the platinum-based chemotherapy based on the subject's condition.

[0284] effect

[0285] In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 44%, approximately 54%, or approximately 75%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 44%, 54%, or 75%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 54%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 75%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 54%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 54%. In some embodiments, treating NSCLC in a patient population with NSCLC achieves an ORR of approximately 75%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 75%.

[0286] In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 44%, approximately 56%, or approximately 69%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 44%, 56%, or 69%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 56%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of at least 69%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 44%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of approximately 56%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 56%. In some embodiments, treating NSCLC in a patient population with NSCLC achieves an ORR of approximately 69%. In some embodiments, treating NSCLC in a patient population with NSCLC using the methods disclosed herein achieves an ORR of 69%.

[0287] In some implementations, treating NSCLC in patient populations with individual NSCLC and individual PD-L1 TPS ≥ 50% achieves an ORR of approximately 75%. In some implementations, treating NSCLC in patient populations with individual NSCLC and individual PD-L1 TPS ≥ 50% achieves an ORR of approximately 69% or higher.

[0288] In some implementations, treating NSCLC in a patient population with individual NSCLC and individual PD-L1 TPS < 50% achieves an ORR of approximately 44%. In some implementations, treating NSCLC in a patient population with individual NSCLC and individual PD-L1 TPS < 50% achieves an ORR of 44%. In some implementations, treating NSCLC in a patient population with individual NSCLC and individual PD-L1 TPS < 50% achieves an ORR of approximately 44% or higher.

[0289] In some implementations, treating NSCLC in a given patient population achieves an ORR of approximately 54%, regardless of PD-L1 TPS status. In some implementations, treating NSCLC in a given patient population achieves an ORR of approximately 54%, regardless of PD-L1 TPS status. In some implementations, treating NSCLC in a given patient population achieves an ORR of approximately 54% or higher. In some implementations, treating NSCLC in a given patient population achieves an ORR of approximately 56% or higher.

[0290] In some implementations, treating squamous metastatic NSCLC in a patient population with individual PD-L1 TPS ≥ 50% achieves an ORR of approximately 73%. In some implementations, treating squamous metastatic NSCLC in a patient population with individual PD-L1 TPS ≥ 50% achieves an ORR of approximately 73% or higher.

[0291] In some implementations, treating squamous metastatic NSCLC in a patient population with individual PD-L1 TPS <50% achieves an ORR of approximately 54%. In some implementations, treating squamous metastatic NSCLC in a patient population with individual PD-L1 TPS <50% achieves an ORR of 54%. In some implementations, treating squamous metastatic NSCLC in a patient population with individual PD-L1 TPS <50% achieves an ORR of approximately 54% or higher.

[0292] In some embodiments, NSCLC patients with PD-L1 TPS ≥ 50% achieve a partial or complete response. In some embodiments, NSCLC patients with PD-L1 TPS < 50% achieve a partial or complete response. In some embodiments, NSCLC patients achieve a partial or complete response. In some embodiments, NSCLC patients with PD-L1 TPS ≥ 50% achieve a partial response. In some embodiments, NSCLC patients with PD-L1 TPS < 50% achieve a partial response. In some embodiments, NSCLC patients achieve a partial response. In some embodiments, NSCLC patients achieve a partial response. In some embodiments, NSCLC patients achieve a reduction of >30% in the sum of target lesion LDs relative to baseline total LD. In some embodiments, NSCLC patients achieve disease stabilization. In some embodiments, a partial response is a reduction of approximately 30% or more in the size of one or more measurable tumors from baseline. In some embodiments, a partial response is a reduction of approximately 40% or more in the size of one or more measurable tumors from baseline. In some embodiments, a partial response is a reduction in the size of one or more measurable tumors from baseline of approximately 50% or more. In some embodiments, a partial response is a reduction in the size of one or more measurable tumors from baseline of approximately 60% or more. In some embodiments, a partial response is measured from baseline to approximately 13 weeks or more from baseline.

[0293] In some embodiments, when the methods disclosed herein are used to treat a patient population with metastatic squamous metastatic NSCLC and PD-L1 TPS ≥ 50%, the partial response rate is approximately 64% to 74%. In some embodiments, when the methods disclosed herein are used to treat a patient population with metastatic squamous metastatic NSCLC and PD-L1 TPS < 50%, the partial response rate is approximately 46% to 54%. In some embodiments, the partial response is measured from baseline to approximately 13 weeks or longer from baseline.

[0294] In some embodiments, when the methods disclosed herein are used to treat a patient population with metastatic NSCLC and PD-L1 TPS ≥ 50%, the partial response rate is approximately 69% or higher. In some embodiments, when the methods disclosed herein are used to treat a patient population with metastatic NSCLC and PD-L1 TPS < 50%, the partial response rate is approximately 44% or higher. In some embodiments, when the methods disclosed herein are used to treat a patient population with metastatic NSCLC, the partial response rate is approximately 56% or higher.

[0295] In some implementations, NSCLC treated with the methods disclosed herein in a patient population with metastatic NSCLC across all PD-L1 TPS scores achieves a disease control rate (DCR) of approximately 82% or higher after at least 6 weeks from baseline. In some implementations, NSCLC treated with the methods disclosed herein in a patient population with metastatic NSCLC across all PD-L1 TPS scores achieves a disease control rate (DCR) of 81% after at least 6 weeks from baseline. In some implementations, NSCLC treated with the methods disclosed herein in a patient population with metastatic NSCLC achieves a disease control rate (DCR) of greater than or equal to approximately 78% after at least 6 weeks from baseline. In some implementations, NSCLC treated with the methods disclosed herein in a patient population with metastatic NSCLC achieves a disease control rate (DCR) of 78% after at least 6 weeks from baseline. In some implementations, NSCLC treated with the methods disclosed herein in a patient population with metastatic NSCLC and a PD-L1 TPS score of ≥50% achieves a DCR of approximately 86% or higher after at least 6 weeks from baseline. In some implementations, treatment of NSCLC in patients with metastatic NSCLC and a PD-L1 TPS score ≥50% achieved a DCR of 86% after at least 6 weeks from baseline.

[0296] In some implementations, treatment of squamous metastatic NSCLC in patients with metastatic squamous NSCLC and a PD-L1 tumor proportion score <50% achieves a disease control rate (DCR) greater than or equal to approximately 82% after at least 6 weeks from baseline. In some implementations, treatment of squamous metastatic NSCLC in patients with metastatic squamous NSCLC and a PD-L1 tumor proportion score <50% achieves a DCR of 82% after at least 6 weeks from baseline. In some implementations, treatment of squamous metastatic NSCLC in patients with metastatic squamous NSCLC and a PD-L1 TPS score ≥50% achieves a DCR of approximately 85% or higher after at least 6 weeks from baseline. In some implementations, treatment of squamous metastatic NSCLC in patients with metastatic squamous NSCLC and a PD-L1 TPS score ≥50% achieves a DCR of 85% after at least 6 weeks from baseline.

[0297] In some embodiments, treatment of NSCLC with metastatic NSCLC and a PD-L1 tumor proportion score <50% using the methods disclosed herein achieves approximately 88% duration of response (DOR) at approximately 6 months from baseline. In some embodiments, treatment of NSCLC with metastatic NSCLC and a PD-L1 tumor proportion score <50% achieves approximately 88% DOR at approximately 6 months from baseline. In some embodiments, treatment of NSCLC with metastatic NSCLC and a PD-L1 TPS ≥50% achieves approximately 88% DOR at approximately 6 months from baseline. In some embodiments, treatment of NSCLC with metastatic NSCLC and a PD-L1 TPS ≥50% achieves 88% DOR at approximately 6 months from baseline. In some embodiments, treatment of NSCLC with metastatic NSCLC with the methods disclosed herein achieves approximately 87% DOR across all PD-L1 TPS scores at approximately 6 months from baseline. In some implementations, treatment of NSCLC in a patient population with metastatic NSCLC using the methods disclosed herein achieved a DOR of 87% across all PD-L1 TPS scores at approximately 6 months from baseline.

[0298] In some embodiments, treating NSCLC with the methods disclosed herein in a patient population with metastatic NSCLC achieves / causes less than about 10% of serious treatment-emergent adverse effects (TEAEs). In some embodiments, treating NSCLC with the methods disclosed herein in a patient population with metastatic NSCLC achieves / causes less than about 9% of serious TEAEs.

[0299] In some implementations, treating NSCLC in a patient population with metastatic NSCLC achieves ≥ Grade 3 TEAEs in less than about 25%. In some implementations, treating NSCLC in a patient population with metastatic NSCLC achieves / results in ≥ Grade 3 TEAEs in less than about 24%.

[0300] In some embodiments, TEAE is interstitial lung disease (ILD). In some embodiments, less than about 10% of patients treated with the methods disclosed herein have been observed to have ILD. In some embodiments, less than about 9% of patients treated with the methods disclosed herein have been observed to have ILD. In some embodiments, less than about 5% of patients treated with the methods disclosed herein have been observed to have ILD. In some embodiments, ILD has not been observed in patients treated with the methods disclosed herein.

[0301] Example

[0302] Example 1

[0303] Ph 1 / 2 IMMU-132-01 Basket Test (NCT01631552)

[0304] In a clinical trial evaluating SG (as monotherapy) in metastatic NSCLC: IMMU-132-01 (completed, 54 patients enrolled). For the NSCLC population, the ORR based on local response assessment was 16.7%; all responses were PR. The median duration of response (DOR) based on local assessment was 6.0 months. The median progression-free survival was 5.2 months, and the median overall survival was 9.5 months.

[0305] Table 5 shows the key efficacy results in patients with NSCLC in the IMM-132-01 basket trial.

[0306] Table 5. Summary of responses from evaluable patients in intention-to-treat analysis for PFS and OS

[0307]

[0308] Example 2

[0309] Phase 2 clinical trial - EVOKE-02 (NCT05186974)

[0310] Adults with previously untreated metastatic NSCLC, no actionable genomic alterations, and an ECOG performance status of 0 or 1 were recruited in Cohort A and Cohort B. Patients with a PD-L1 tumor proportion score ≥50% (Cohort A) and PD-L1 TPS <50% (Cohort B) received SG 10 mg / kg on days 1 and 8 of a 21-day cycle and pembrolizumab 200 mg on day 1. Trial endpoints included objective response rate (ORR; according to RECIST v1.1), progression-free survival, duration of response, disease control rate, overall survival, and safety. Safety outcomes were reported in patients evaluable for safety in those receiving ≥1 dose of study treatment, and efficacy outcomes were reported in patients evaluable for efficacy in those with a follow-up of ≥13.0 weeks.

[0311] Inclusion criteria

[0312] Patients who meet all inclusion criteria outlined below during screening / day-1 are eligible to participate in this study. No waivers are provided or permitted for patient eligibility:

[0313] The patient must be 18 years of age or older and be able to understand and provide written informed consent.

[0314] The patient's life expectancy is ≥3 months.

[0315] The patient has pathologically documented NSCLC. Pathologically documented NSCLC at the time of recruitment is stage IV NSCLC according to the American Joint Committee on Cancer, 8th edition; EGFR and ALK test results are negative; there are no known operable genomic alterations in ROS1, NTRK, BRAF, RET mutations, or other operable driver oncogenes; an approved therapy is available for first-line treatment; and tumor tissue from a non-radiated site prior to biopsy has been provided. If the status of EGFR and ALK or ROS1, NTRK, BRAF, RET, and other operable driver oncogenes is unknown, tumor tissue testing is required. If not performed by an approved 22C3 assay, formalin-fixed samples after the patient has been diagnosed with metastatic disease are preferred for evaluating Trop-2 expression and determining PD-L1 status prior to recruitment. If a recent biopsy is not feasible, a biopsy obtained prior to adjuvant / neoadjuvant chemotherapy is permissible. Bone biopsies and fine-needle aspiration are not accepted as suitable tissue. If no organization is available, new biopsies will be obtained before research can be recruited.

[0316] Patients were diagnosed with a measurable disease as determined by investigators using CT or MRI according to RECIST version 1.1 criteria. Measurable lesions were considered to be located in previously irradiated areas and had shown progression. Historical images from within 28 days of the screening visit were used as screening images if deemed acceptable by the investigators.

[0317] The patient has no prior systemic therapy for metastatic non-small cell lung cancer (mNSCLC). Patients receiving adjuvant or neoadjuvant therapy are eligible if they have completed adjuvant / neoadjuvant therapy at least 6 months prior to the development of metastatic disease for platinum-based treatments.

[0318] The patient's Eastern Cooperative Oncology Group (ECOG) performance status score, assessed within 7 days prior to treatment, was 0 or 1.

[0319] Within 10 days of starting the study drug, patients had adequate hematological counts and did not require blood transfusions or growth factor support (hemoglobin ≥9 g / dL, absolute neutrophil count [ANC] ≥1500 / mm). 3 And platelets ≥100,000 / µL). Hemoglobin levels must be met within the first 2 weeks without pRBC transfusions. Patients can receive a stable dose of erythropoietin (≥approximately 3 months).

[0320] The patient has adequate liver function (bilirubin ≤1.5×ULN, AST and ALT ≤2.5×ULN or ≤5×ULN (if liver metastasis is known), and serum albumin >3g / dL).

[0321] Patients must have a creatinine clearance of at least 30 mL / min, as assessed by the Cockcroft-Gault equation (Cockcroft 1976). For patients assigned to the cisplatin cohort, the creatinine clearance must be at least 60 mL / min.

[0322] Patients with HIV must be receiving antiretroviral therapy (ART) and have well-controlled HIV infection / disease, defined as: (1) patients receiving ART with a CD4+ T cell count >350 cells / mm² at screening. 3 (2) Patients receiving ART must achieve and maintain virological suppression using locally available assays at screening time and for at least 12 weeks prior to screening. Virological suppression is defined as confirmed HIV RNA levels below 50 copies / mL or the lower limit of quantitation (below the limit of detection). (3) Patients receiving ART must have received a stable regimen for at least 4 weeks prior to entering the study without any changes in medication or dosage. (4) The combination ART regimen must not contain any drugs that may interfere with SN-38 metabolism.

[0323] Finally, male and female patients of reproductive potential who participate in heterosexual intercourse must agree to use the contraceptive method specified in the protocol.

[0324] Exclusion criteria

[0325] Patients who meet any of the exclusion criteria outlined below during screening / day-1 are not eligible for this study, and no waiver of eligibility will be offered or permitted:

[0326] The patient had histology of mixed small cell lung cancer (SCLC) and NSCLC.

[0327] The patient has an active second malignancy. Patients with a history of malignancy who have been fully treated for the past 3 years prior to recruitment and show no signs of cancer, or patients with low-risk tumors that have been surgically cured (e.g., non-melanoma skin cancer, histologically confirmed complete resection of carcinoma in situ, or similar cases) are eligible for recruitment.

[0328] The patient has NSCLC that is eligible for definitive local therapy alone.

[0329] Within 7 days prior to the first dose of the study drug, the patient must have been diagnosed with immunodeficiency or be receiving long-term systemic steroid therapy (prednisone equivalent, more than 10 mg daily) or any other form of immunosuppressive therapy. Intermittent use of topical, inhaled, intranasal, and intraocular steroids is permitted.

[0330] The patient has an active autoimmune disease and has required systemic treatment (i.e., the use of disease-modifying agents, corticosteroids, or immunosuppressants) for the past 2 years. Replacement therapies (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of systemic treatment and are permitted.

[0331] The patient has received allogeneic tissue or solid organ transplants.

[0332] The patient has a severe (≥ grade 3) allergic reaction to SG, pembrolizumab, carboplatin or cisplatin, their metabolites or excipients.

[0333] The patient needs to continue treatment with any prohibited medications, or has a history of using any prohibited medications.

[0334] The patient has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents or agents targeting another stimulating or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137) and has discontinued treatment due to a grade 3 or higher immune-related adverse event (irAE).

[0335] The patient had received >30 Gy of lung radiation therapy within 6 months of the first treatment cycle.

[0336] Patients must not have received systemic anticancer therapy within 6 months prior to enrollment, or radiation therapy within 2 weeks prior, or stereotactic radiosurgery within 72 hours prior. Upon enrollment, patients must have recovered from adverse events (AEs) (i.e., >2 grade is considered unrecovered). Patients with any grade of alopecia are an exception to this criterion and are eligible for the study. If patients have undergone major surgery, they must be fully recovered from toxicities and / or complications arising from the intervention before treatment begins. Patients must have recovered from all radiation-related toxicities, without the need for corticosteroids, and without radiation pneumonitis. For palliative radiation therapy (≤2 weeks of radiation therapy) for non-central nervous system (CNS) diseases, a 1-week washout is permitted.

[0337] The patient has previously received any of the following treatments: (1) a topoisomerase 1 inhibitor, or any drug that includes an ADC containing a chemotherapeutic agent that targets topoisomerase 1; or (2) a therapy that targets Trop-2.

[0338] Patients must have been participating in or already participating in a study of the investigational drug or using an investigational medical device within 4 weeks prior to the first dose of the study treatment. Patients entering the follow-up phase of the study may participate, provided it is 4 weeks after the last dose of the previous study drug.

[0339] Patients with clinically severe lung damage caused by concurrent lung disease, including but not limited to any underlying lung condition (i.e., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc. within the past 3 months); any autoimmune, connective tissue, or inflammatory condition involving the lungs (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.); or a history of lung resection.

[0340] Patients had known active CNS metastases and / or carcinomatous meningitis. Patients with previously treated brain metastases were eligible to participate if they had stable CNS disease for at least 4 weeks prior to recruitment, all neurological symptoms had returned to baseline, there was no evidence of new or expanding brain metastases, and they were taking ≤10 mg / day of prednisone or its equivalent. All patients with carcinomatous meningitis were excluded regardless of clinical stability. Patients were clinically stable and taking ≤10 mg / day of prednisone or its equivalent for at least 14 days prior to the first dose of study treatment, as assessed by the investigator.

[0341] Patients must have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of recruitment.

[0342] The patient has a history of (non-infectious) pneumonia / interstitial lung disease requiring steroids or is currently suffering from pneumonia / interstitial lung disease.

[0343] The patient has an active, serious infection that requires antibiotics.

[0344] The patient is HIV-1 or HIV-2 positive and has a history of Kaposi's sarcoma and / or multicentric Citadel Mann disease.

[0345] The patient has active or chronic hepatitis B infection, or is positive for hepatitis B surface antigen. Patients with a positive hepatitis B core antibody test need to undergo quantitative polymerase chain reaction (PCR) to determine hepatitis B virus DNA to confirm active disease.

[0346] The patient was positive for hepatitis C antibodies and had a detectable viral load of hepatitis C virus (HCV).

[0347] The patient has a positive serum pregnancy test or is a woman who is currently lactating.

[0348] The patient has other concurrent medical or psychiatric symptoms that the investigators believe may confuse the interpretation of the study or hinder the completion of the study procedures and follow-up examinations.

[0349] Patients should receive a live virus vaccine within 30 days of the start of planned treatment. Seasonal influenza vaccines without live virus are permitted.

[0350] result

[0351] As of January 13, 2023, 44 patients were recruited (cohort A, n=16; cohort B, n=28) and received SG plus pembrolizumab. The median age was 68 years (range, 47–80 years); 64% of patients had non-squamous histology and 77% had an ECOG performance status of 1. In patients with evaluable efficacy (cohort A, n=8; cohort B, n=18), the investigator-assessed ORR was 75% in cohort A (5 confirmed partial responses [PR] and 1 pending PR) and 44% in cohort B (7 confirmed PRs and 1 pending PR) (as shown in Table 6).

[0352] Table 6. Efficacy Results

[0353]

[0354] In patients with evaluable safety profiles (n=63), the incidence of any grade of treatment-emergent adverse event (TEAE) was 100% (grade 3 / 4, 70%; Table 7). For example... Figure 6 As shown, the most common TEAEs of any grade were diarrhea (86%), anemia (76%), asthenia (60%), and hair loss (59%). The most common immune-mediated TEAEs were pneumonia and hyperthyroidism (13% and 8%, respectively). Figure 7 Grade 3 pneumonia was the highest grade observed and was seen in 2 patients (3%). TEAEs leading to interruption of SG occurred in 18% of patients. TEAEs resulting in death were reported in 4 patients (6%), and only 1 (2%) was considered to be related to study treatment.

[0355] Table 7: Safety Results

[0356]

[0357] Table 8. Efficacy Results

[0358] Table 8 shows the efficacy results obtained through investigator assessment as of the data cutoff date (June 16, 2023). At this data cutoff date, the median (range) follow-up periods for cohort A and cohort B were 5.0 (1.7–12.0) months and 5.8 (1.0–12.2) months, respectively.

[0359] Table 8. Efficacy Results

[0360]

[0361] Table 9. PD-L1 TPS subgroup analysis of cohort B

[0362] Table 9 shows the performance results of queue B as of the data cutoff date (June 16, 2023).

[0363] Table 9. Efficacy Results .

[0364]

[0365] ORR is the best overall response (BOR) for CR+PR. DCR is the BOR for CR+PR+SD at ≥6 weeks. BOR is the best overall response, DCR is the disease control rate, DOR is the duration of response, and SD is disease stability. Other acronyms are defined in this article.

[0366] Table 10 shows the response rates of frontline SG+pembrolizumab in patients with squamous and non-squamous mNSCLC.

[0367] In cohort A, the objective response rate (ORR) was 72.7% (8 / 11) in patients with squamous mNSCLC and 66.7% (12 / 18) in patients with non-squamous mNSCLC (Table 10). In cohort B, the ORRs were 53.8% (7 / 13) in patients with squamous mNSCLC and 36.8% (7 / 19) in patients with non-squamous mNSCLC (Table 10). The median destination of error (DOR) was not reached in either cohort.

[0368] Table 10. Efficacy Results .

[0369]

[0370] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art will make various modifications or changes based on these embodiments and implementations, which are included within the spirit and scope of this application and the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method for treating a patient with metastatic non-small cell lung cancer (NSCLC), wherein the patient has not received prior systemic therapy for metastatic NSCLC, the method comprising co-administering: a. An antibody-drug conjugate (ADC) comprising 10 mg / kg of an anti-Trop-2 antibody or an antigen-binding fragment thereof, said antibody-drug conjugate being administered intravenously on days 1 and 8 of one or more 21-day treatment cycles, wherein said anti-Trop-2 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing the amino acid sequences shown in SEQ ID NO: 13, 14 and 15 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 16, 17 and 18, and wherein said ADC has the formula MAb-CL2A-SN-38, wherein said formula is represented as follows: as well as b. 200 mg of anti-PD-1 antibody or its antigen-binding fragment, administered intravenously on day 1 of one or more of the 21-day treatment cycles. The anti-PD-1 antibody or its antigen-binding fragment comprises a light chain CDR containing the amino acid sequences shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 8, 9 and 10; and the method achieves a complete or partial response in the patient.

2. The method according to claim 1, wherein the anti-Trop-2 antibody is sacitrus antibody.

3. The method according to any one of claims 1 to 2, wherein the ADC is sacitrus-glavotecan (SG).

4. The method according to any one of claims 1 to 3, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region containing SEQ ID NO: 6 or a variant thereof, and a heavy chain variable region containing SEQ ID NO:

11.

5. The method according to any one of claims 1 to 4, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO:

12.

6. The method according to any one of claims 1 to 5, wherein the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab or a variant thereof.

7. The method of claim 6, wherein the anti-PD-1 antibody or its antigen fragment is pembrolizumab.

8. The method of claim 1, wherein the ADC is SG and the anti-PD-1 antibody or its antigen fragment is pembrolizumab.

9. The method according to any one of claims 1 to 8, wherein the patient's PD-L1 tumor proportion score (TPS) is ≥50%.

10. The method according to any one of claims 1 to 8, wherein the patient's PD-L1 TPS < 50%.

11. The method according to any one of claims 1 to 10, wherein the patient has non-squamous NSCLC.

12. The method according to any one of claims 1 to 10, wherein the patient has squamous NSCLC.

13. The method according to any one of claims 1 to 12, wherein the method does not include concomitant chemotherapy.

14. The method of claim 13, wherein the method does not include the concurrent administration of platinum-based chemotherapy.

15. The method according to any one of claims 1 to 14, wherein the method does not include the concomitant administration of anti-TGIT antibody.

16. The method of claim 8, wherein the partial response is one or more measures that the size of the tumor decreases by about 50% or more from baseline to a distance of about 13 weeks or more from baseline.

17. The method of claim 16, wherein the partial response is a reduction in the size of one or more of the measurable tumors by about 60% or more from baseline to a distance of about 13 weeks or more from baseline.

18. The method of claim 8, wherein when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS ≥ 50%, the method achieves a partial response rate of approximately 69% or higher.

19. The method of claim 8, wherein when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS < 50%, the method achieves a partial response rate of approximately 44% or higher.

20. The method of claim 8, wherein when the method is used to treat metastatic NSCLC in a patient population, the method achieves a partial response of about 56% or higher, regardless of the PD-L1 TPS status of the patient population.

21. A method for treating a patient population with metastatic NSCLC without concurrent chemotherapy, said method comprising co-administering: a. An antibody-drug conjugate (ADC) comprising 10 mg / kg of an anti-Trop-2 antibody or an antigen-binding fragment thereof, said antibody-drug conjugate being administered intravenously on days 1 and 8 of one or more 21-day treatment cycles, wherein said anti-Trop-2 antibody or an antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) containing the amino acid sequences shown in SEQ ID NO: 13, 14 and 15 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 16, 17 and 18, and wherein said ADC has the formula MAb-CL2A-SN-38, wherein said formula is represented as follows: as well as b. 200 mg of anti-PD-1 antibody or its antigen-binding fragment, administered intravenously on day 1 of one or more of the 21-day treatment cycles. The anti-PD-1 antibody or its antigen-binding fragment comprises a light chain CDR containing the amino acid sequences shown in SEQ ID NO: 3, 4 and 5 and a heavy chain CDR containing the amino acid sequences shown in SEQ ID NO: 8, 9 and 10; wherein the patient population has not received prior systemic therapy for metastatic NSCLC.

22. The method of claim 21, wherein the anti-Trop-2 antibody is sacitrus antibody.

23. The method according to any one of claims 21 to 22, wherein the ADC is an SG.

24. The method according to any one of claims 21 to 23, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region containing SEQ ID NO:6 or a variant thereof, and a heavy chain variable region containing SEQ ID NO:

11.

25. The method according to any one of claims 21 to 24, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain containing SEQ ID NO: 7 and a heavy chain containing SEQ ID NO:

12.

26. The method according to any one of claims 21 to 25, wherein the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab or a variant thereof.

27. The method of claim 26, wherein the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab.

28. The method of claim 21, wherein the anti-PD-1 antibody or its antigen-binding fragment is pembrolizumab and the ADC is SG.

29. The method of claim 28, wherein the PD-L1 TPS of the patient population is ≥50%.

30. The method of claim 28, wherein the PD-L1 TPS of the patient population is <50%.

31. The method according to any one of claims 21 to 30, wherein the patient population has non-squamous NSCLC.

32. The method according to any one of claims 21 to 30, wherein the patient population has squamous NSCLC.

33. The method of claim 28, wherein the treatment includes the achievement of clinical efficacy.

34. The method of claim 29, wherein the ORR is about 69%.

35. The method of claim 30, wherein the ORR is about 44%.

36. The method of claim 29, wherein the DCR is about 86%.

37. The method of claim 30, wherein the DCR is about 78%.

38. The method of claim 29, wherein the DOR is approximately 88% at approximately 6 months from the baseline.

39. The method of claim 30, wherein the DOR is approximately 88% at approximately 6 months from the baseline.

40. The method of claim 28, wherein the method achieves a serious treatment-emergent adverse event (TEAE) rate of less than about 10%.

41. The method of claim 40, wherein the method achieves less than about 9% of severe TEAEs.

42. The method of claim 28, wherein the method achieves less than about 25% of ≥3 levels of TEAE.

43. The method of claim 42, wherein the method achieves less than about 24% of ≥3 levels of TEAE.

44. The method according to any one of claims 40 to 43, wherein the TEAE includes one or more of the following: stomatitis, anemia, leukopenia, rash, and thrombocytopenia.

45. The method of claim 28, wherein TEAE includes interstitial lung disease (ILD).

46. ​​The method of claim 45, wherein ILD is observed in less than about 10% of said patients.

47. The method of claim 46, wherein ILD is observed in less than about 9% of said patients.

48. The method of claim 47, wherein ILD is observed in less than about 5% of said patients.

49. The method of claim 28, wherein no ILD was observed in the patient.

50. A method for improving clinical efficacy in a patient population with metastatic non-squamous or squamous NSCLC without concurrent chemotherapy, compared with administration of anti-PD-L1 antibody monotherapy or with administration of antibody-drug conjugate monotherapy, said method comprising co-administration: a. 10 mg / kg SG, administered intravenously on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles; wherein the patient population has not received prior systemic therapy for metastatic NSCLC.

51. The method of claim 50, wherein clinical efficacy is improved regardless of the PD-L1 status of the patient population.

52. The method of claim 50, wherein the PD-L1 TPS score of the patient population is ≥50%.

53. The method of claim 50, wherein the PD-L1 TPS score of the patient population is <50%.

54. The method of claim 50, wherein the anti-PD-L1 antibody monotherapy is pembrolizumab.

55. The method of claim 50, wherein the antibody-drug conjugate monotherapy is SG.

56. The method of claim 50, wherein the method does not include determining the PD-L1 TPS status of the patient population.

57. The method of claim 50, wherein the chemotherapy is a platinum-based chemotherapy.

58. The method of claim 50, wherein the method does not include the administration of additional targeted oncology drugs.

59. A method for achieving clinical efficacy in patients with metastatic NSCLC, the method comprising, regardless of the patient's PD-L1 tumor proportion score, regardless of the patient's NSCLC histology, without concurrent chemotherapy, and wherein the patient has not previously received systemic therapy for metastatic NSCLC, the method comprising co-administering: a. 10 mg / kg SG, said SG being administered on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

60. The method of claim 59, wherein the method does not include the concurrent administration of additional targeted oncology drugs.

61. The use of a treatment combination for the method according to any one of claims 1 to 49, the treatment combination comprising the antibody-drug conjugate (ADC) containing the anti-Trop-2 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof.

62. A treatment combination comprising an antibody-drug conjugate (ADC) containing an anti-Trop-2 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, for use in the method according to any one of claims 1 to 49.

63. The method of claim 8, wherein the partial response is one or more measures that the size of the tumor decreases by about 30% or more from baseline to a distance of about 13 weeks or more from baseline.

64. The method of claim 61, wherein the partial response is one or more measures that the size of the tumor decreases by about 40% or more from baseline to a distance of about 13 weeks or more from baseline.

65. The method according to claims 10 to 15, wherein the patient's PD-L1 TPS is 1% to 49%.

66. The method according to claims 10 to 15, wherein the patient's PD-L1 TPS < 1%.

67. The method of claim 66, wherein the patient achieves a partial response, and wherein the partial response is one or more measures that reduce the size of the tumor from baseline to a reduction of about 50% or more over a period of about 13 weeks or more from baseline.

68. The method of claim 67, wherein the partial response is one or more measures that can measure the size of a tumor as decreasing by about 60% or more from baseline to a distance of about 13 weeks or more from baseline.

69. The method of claim 65, wherein when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS of 1% to 49%, the method achieves an ORR of approximately 53%.

70. The method of claim 66, wherein when the method is used to treat metastatic NSCLC in a patient population with PD-L1 TPS < 1%, the method achieves an ORR of approximately 35%.

71. The method of claim 69, wherein the method achieves approximately 47% to 53% partial response.

72. The method of claim 70, wherein the method achieves approximately 29% to 35% partial response.

73. The method of claim 60, wherein the patient's PD-L1 TPS < 1%.

74. The method according to claims 53 to 58, wherein the PD-L1 TPS score of the patient population is <1%.

75. A method for treating a patient with squamous metastatic non-small cell lung cancer (NSCLC), wherein the patient has not received prior systemic therapy for squamous metastatic NSCLC, the method comprising co-administering: a. 10 mg / kg SG, said SG being administered on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

76. The method of claim 75, wherein the patient’s PD-L1 tumor proportion score (TPS) is ≥50%.

77. The method of claim 75, wherein the patient’s PD-L1 TPS < 50%.

78. The method according to any one of claims 75 to 77, wherein the method does not include concomitant chemotherapy.

79. The method of claim 78, wherein the method does not include concomitant administration of platinum-based chemotherapy.

80. The method according to any one of claims 75 to 76 and 78 to 79, wherein when the method is used to treat squamous metastatic NSCLC in a patient population with PD-L1 TPS ≥ 50%, the method achieves a partial response rate of about 73% or higher.

81. The method according to any one of claims 75 and 77 to 79, wherein when the method is used to treat squamous metastatic NSCLC in a patient population with PD-L1TPS <50%, the method achieves a partial response rate of about 54% or higher.

82. A method for treating a patient population with squamous metastatic NSCLC without concurrent chemotherapy, said method comprising co-administering: a. 10 mg / kg SG, said SG being administered on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more of the 21-day treatment cycles; wherein the patient population has not received prior systemic therapy for squamous metastatic NSCLC.

83. The method of claim 82, wherein the PD-L1 TPS of the patient population is ≥50%.

84. The method of claim 82, wherein the PD-L1 TPS of the patient population is <50%.

85. The method of claim 82, wherein the treatment includes the achievement of clinical efficacy.

86. The method of claim 83, wherein the ORR is about 73%.

87. The method of claim 84, wherein the ORR is about 54%.

88. The method of claim 83, wherein the DCR is about 82%.

89. The method of claim 84, wherein the DCR is about 85%.

90. The method of claim 83, wherein the method achieves approximately 64% to 73% partial response.

91. The method of claim 84, wherein the method achieves approximately 46% to 57% partial response.

92. A method for achieving clinical efficacy in patients with metastatic squamous NSCLC, the method being performed without chemotherapy regardless of the patient's PD-L1 tumor proportion score, and wherein the patient has not previously received systemic therapy for metastatic NSCLC, the method comprising co-administration of: a. 10 mg / kg SG, said SG being administered on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles.

93. The method of claim 92, wherein the method does not include the concurrent administration of additional targeted oncology drugs.

94. The method of claim 92, wherein the ORR is about 73%.

95. The method of claim 92, wherein the ORR is about 54%.

96. The method of claim 92, wherein the DCR is about 82%.

97. The method of claim 92, wherein the DCR is about 85%.

98. The method of claim 92, wherein the method achieves approximately 64% to 73% partial response.

99. The method of claim 92, wherein the method achieves approximately 46% to 57% partial response.

100. A method for achieving clinical efficacy in patients with metastatic squamous NSCLC, the method comprising administering to the patients in need: a. 10 mg / kg SG, said SG being administered on days 1 and 8 of one or more 21-day treatment cycles; and b. 200 mg pembrolizumab, administered on day 1 of one or more 21-day treatment cycles, wherein the patient’s PD-L1 tumor proportion score is ≥50%.

101. The method according to any one of the preceding claims, wherein SG is applied on day 1 and day 8 of a treatment cycle of at least about (14) 21 days.

102. The method of claim 101, wherein pembrolizumab is administered on day 1 of the at least about (14) 21-day treatment cycle.

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