Treatment methods for non-small cell lung cancer

Abstract

This disclosure provides a method for treating EGFR-positive non-small cell lung cancer (NSCLC) in subjects whose disease has progressed during or after treatment with at least one prior tyrosine kinase inhibitor (TKI).

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 536,575, filed September 5, 2023, and U.S. Provisional Application No. 63 / 564,664, filed March 13, 2024, the disclosure of each of which is incorporated herein by reference in its entirety.

[0003] sequence list

[0004] This application contains a sequence list that has been electronically submitted in XML format, and is incorporated herein by reference in its entirety. This XML copy was created on September 3, 2024, named JBI6835_SeqListing.xml, and is 20,480 bytes in size. Technical Field

[0005] This disclosure provides a method for treating epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) in subjects whose disease has progressed during or after treatment with at least one prior tyrosine kinase inhibitor (TKI). Background Technology

[0006] Stratification of advanced non-small cell lung cancer (NSCLC) based on oncogenic driver gene mutations has improved overall survival and quality of life for patients with actionable driver gene mutations, as well as the effectiveness of targeted therapies for solid tumors. In NSCLC, specific mutations in the EGFR gene are associated with high response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs). While most NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, virtually all of them acquire resistance that blocks durable responses. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors show increased expression of hepatocyte growth factor receptor (c-Met), amplification of the c-Met gene, or an increase in its only known ligand, hepatocyte growth factor (Turke et al., Cancer Cell, 17:77-88, 2010).

[0007] The progression of acquired resistance to EGFR-TKIs (such as osimertinib) in epidermal growth factor receptor mutant (EGFRm) NSCLC can be caused by complex and heterogeneous resistance patterns along with the co-occurrence of multiple resistance mechanisms, and therefore the details of these mechanisms remain elusive. Consequently, the duration and durability of responses to targeted therapies present unique challenges, and new treatment paradigms are still needed for patients with NSCLC who have disease progression during or after treatment with at least one prior tyrosine kinase inhibitor (TKI). Summary of the Invention

[0008] In one aspect, this article provides a method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), the method comprising administering to the subject population a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a subject reference population with NSCLC harboring one or more EGFR mutations, whose NSCLC progresses during or after treatment with at least one prior TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody has not been administered.

[0009] In another aspect, this article provides a method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), the method comprising administering to this subject population a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of lazazeinib. (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who have progressed during or after treatment with at least one prior TKI, who have been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody, nor the latezatinib or its pharmaceutically acceptable salt or hydrate. In some embodiments, latezatinib or its pharmaceutically acceptable salt or hydrate is latezatinib mesylate. In some embodiments, latezatinib or its pharmaceutically acceptable salt or hydrate is latezatinib mesylate monohydrate. In some embodiments, latezatinib or its pharmaceutically acceptable salt or hydrate is administered orally once daily at a dose of about 240 mg.

[0010] In some embodiments of any of the methods disclosed above, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0011] In some embodiments of any of the methods described above in this disclosure, one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0012] In some embodiments of any of the methods disclosed above, the at least one prior TKI comprises a first-generation EGFR TKI. In some embodiments of any of the methods disclosed above, the at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments of any of the methods disclosed above, the at least one prior TKI comprises a third-generation EGFR TKI. In some embodiments of any of the methods disclosed above, the at least one prior TKI comprises osimertinib.

[0013] In some embodiments of any of the methods described above in this disclosure, administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

[0014] In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody is administered intravenously. In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0015] In some embodiments of any of the methods described above in this disclosure, the method includes administering a bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg. In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody is administered in amounts of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

[0016] In some embodiments of any of the methods described above in this disclosure, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2. In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody dose on day 1 of cycle 1 is administered as a fractionated dose on days 1 and 2.

[0017] In some embodiments of any of the methods described above in this disclosure, if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0018] In some embodiments of any of the methods described above in this disclosure, if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2. In some embodiments of any of the methods described above in this disclosure, the bispecific anti-EGFR / c-Met antibody dose on day 1 of cycle 1 is administered as a fractionated dose on days 1 and 2.

[0019] In some embodiments of any of the methods described above in this disclosure, if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0020] In some embodiments of any of the methods described above in this disclosure, the method includes administering carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

[0021] In some embodiments of any of the methods described above in this disclosure, the method includes administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 Administer pemetrexed at a dose for up to 4 cycles, then as maintenance until disease progression.

[0022] In some embodiments of any of the methods disclosed above, the method includes: a) (i) If the subject weighs less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2; or (ii) If the subject weighs less than 80 kg, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or (iii) If the subject weighs 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2; or (iv) If the subject weighs 80 kg or more, administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3; and b) administer a bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on day 1 of each 21-day cycle. Administer carboplatin at a dose of 5 for up to 4 cycles; and c) administer carboplatin along with approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The dose of pemetrexed is administered for up to four cycles, followed by maintenance until disease progression. In some embodiments of any of the methods described above in this disclosure, the dose for day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0023] In some embodiments of the methods disclosed above, the combination therapy achieves a median PFS improvement of at least two weeks. In some embodiments of the methods disclosed above, the combination therapy achieves a median PFS improvement of at least one month. In some embodiments of the methods disclosed above, the combination therapy achieves a median PFS improvement of at least 1.5 months. In some embodiments of the methods disclosed above, the combination therapy achieves a median PFS improvement of at least two months. In some embodiments of the methods disclosed above, the subject demonstrates a PFS of at least 4.5 months. In some embodiments of the methods disclosed above, the subject demonstrates a PFS of at least 5 months. In some embodiments of the methods disclosed above, the subject demonstrates a progression-free survival of at least 5.5 months. In some embodiments of the methods disclosed above, the subject demonstrates a PFS of at least 6 months. In some embodiments of the methods disclosed above, the subject demonstrates a progression-free survival of at least 10 months. In some embodiments of the methods disclosed above, the subject demonstrates a PFS of at least 12 months. In some embodiments of any of the methods described above in this disclosure, the subject exhibits a progression-free survival (PFS) of at least 14 months.

[0024] In some embodiments of the methods described above in this disclosure, the combination therapy further improves the objective response relative to the reference population. In some embodiments of the methods described above in this disclosure, the combination therapy further improves overall survival (OS) relative to the reference population. In some embodiments of the methods described above in this disclosure, the combination therapy further improves the duration of response (DoR) relative to the reference population. In some embodiments of the methods described above in this disclosure, the combination therapy further improves the time required for subsequent therapy relative to the reference population. In some embodiments of the methods described above in this disclosure, the combination therapy further improves progression-free survival (PFS) after the first subsequent therapy (PFS2) relative to the reference population. In some embodiments of the methods described above in this disclosure, the combination therapy further improves the median intracranial PFS relative to the reference population.

[0025] In one aspect, this article provides a method for improving median overall survival (OS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, whose NSCLC has progressed during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), the method comprising administering to the subject population a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed, wherein the improvement in median OS is relative to the median OS of a subject reference population with NSCLC harboring one or more EGFR mutations, whose NSCLC has progressed during or after treatment with at least one prior TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody has not been administered.

[0026] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises: a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0027] In some implementations, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0028] In some implementations, one or more EGFR mutations involve deletions of one or more exon 19. In some implementations, one or more EGFR mutations involve exon 21 L858R substitutions.

[0029] In some embodiments, the at least one prior TKI comprises a first-generation EGFR TKI. In some embodiments, the at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments, the at least one prior TKI comprises a third-generation EGFR TKI. In some embodiments, the at least one prior TKI comprises osimertinib.

[0030] In some implementations, the combination therapy is administered starting on day 1 of cycle 1 of the first 21-day cycle and continues in subsequent 21-day cycles.

[0031] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0032] In some implementations, the method includes administering a bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

[0033] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at doses of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

[0034] In some implementations, if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0035] In some implementations, the bispecific anti-EGFR / c-Met antibody dose on day 1 of cycle 1 is administered as a fractionated dose on days 1 and 2.

[0036] In some implementations, if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0037] In some implementations, if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0038] In some implementations, the bispecific anti-EGFR / c-Met antibody dose on day 1 of cycle 1 is administered as a fractionated dose on days 1 and 2.

[0039] In some implementations, if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0040] In some implementations, the method includes administering carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to four cycles.

[0041] In some implementations, the method includes administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 Administer pemetrexed at a dose for up to 4 cycles, then as maintenance until disease progression.

[0042] In some implementations, the method includes:

[0043] a)(i) If the subject weighs less than 80 kg, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0044] (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or

[0045] (iii) If the subject weighs 80 kg or more, administer the bispecific anti-EGFR / c-Met antibody at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0046] (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0047] as well as

[0048] b) Administer carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles;

[0049] as well as

[0050] c) On day 1 of each 21-day cycle, administer with carboplatin at approximately 500 mg / m².2 Administer pemetrexed at a dose for up to 4 cycles, then as maintenance until disease progression.

[0051] In some implementations, the bispecific anti-EGFR / c-Met antibody dose on day 1 of cycle 1 is administered as a fractionated dose on days 1 and 2.

[0052] In some implementation schemes, combination therapy achieves at least a two-month improvement in median overall survival (OS).

[0053] In some implementations, the combination therapy achieves a median OS improvement of at least 2.4 months.

[0054] In some implementations, combination therapy achieves a median OS improvement of approximately 2.4 months.

[0055] In some implementations, subjects demonstrated an overall survival of at least 17 months.

[0056] In some implementations, subjects demonstrated an overall survival of at least approximately 17.7 months.

[0057] In some implementations, subjects showed an overall survival of approximately 17.7 months.

[0058] In some implementations, the combination therapy further improves the time to symptomatic progression (TTSP) relative to the reference group.

[0059] In some implementations, the combination therapy further improves the time to follow-up therapy (TTST) relative to the reference group.

[0060] In some implementations, the combination therapy further improves PFS (PFS2) after the first follow-up therapy, relative to the reference population.

[0061] In some implementations, the combination therapy further improves treatment interruption time (TTD) relative to the reference population. Attached Figure Description

[0062] Figure 1 An exemplary schematic overview of the study is shown.

[0063] Figure 2 The MARIPOSA-2 study design is shown. a- The analysis was further stratified based on osimertinib therapy line, history of brain metastases, and ethnicity (Asian vs. non-Asian). ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer; OS, overall survival.

[0064] Figure 3 Overall survival is shown. Ami, ervantuzumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; OS, overall survival.

[0065] Figure 4 The time to symptomatic progression (TTSP) is shown. Ami, ervantuzumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; TTSP, time to symptomatic progression.

[0066] Figure 5 The treatment interruption time is shown. Ami, ervantuzumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; PD, disease progression; TTD, treatment interruption time.

[0067] Figure 6 The timeframe for subsequent therapy is indicated. Ami, ervantuzumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; TTST, timeframe for subsequent therapy.

[0068] Figure 7 The PFS following the first follow-up therapy is shown. Ami, ervantumab; chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; PFS2, progression-free survival following the first follow-up therapy. Detailed Implementation

[0069] definition

[0070] All publications cited in this specification, including but not limited to patents and patent applications, are incorporated herein by reference as if they were given in their entirety.

[0071] It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0072] While any methods and materials similar to or equivalent to those described herein may be used in the practice of testing the invention, exemplary materials and methods are described herein. The following terminology will be used in describing and claiming the invention.

[0073] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0074] As used in this specification and the appended claims, unless otherwise expressly stated, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, a reference to “a cell” includes a combination of two or more cells, and so on.

[0075] The connecting term "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, in the case where two elements are connected by "and / or," the first option means applying the first element in the absence of the second element. The second option means applying the second element in the absence of the first element. The third option means applying both the first and second elements together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0076] The transitional terms “comprising,” “substantially consisting of,” and “consisting of” are intended to imply their accepted meaning in patent terminology; that is, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open at the end, and does not exclude additional, unlisted elements or method steps; (ii) “consisting of” excludes any element, step, or component not specified in the claims; and (iii) “substantially consisting of” limits the scope of the claims to the specified material or step “and material or step that does not substantially affect the essential and novel features of the invention protected by the claims.” Embodiments described with the phrase “comprising” (or its equivalents) are also provided, as are those described independently with “consisting of” and “substantially consisting of”.

[0077] "Together with", "in combination with", "in combination with", "in combination with", etc., encompass the administration of selected therapeutic agents or drugs to a single patient and are intended to include treatment regimens in which these therapeutic agents or drugs are administered via the same or different routes of administration or at the same or different times.

[0078] "Isolated" refers to a homogeneous group of molecules (such as synthetic polynucleotides, polypeptide carriers, or viruses) that have been substantially isolated and / or purified from other components of the system that produced the molecules (such as recombinant cells), as well as proteins that have undergone at least one purification or isolation step. "Isolated" also refers to molecules that are substantially free of other cellular material and / or chemicals, and encompasses molecules isolated to higher purities (such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity).

[0079] "Treating" a disease or condition such as cancer means achieving one or more of the following: reducing the severity and / or duration of the condition, inhibiting the worsening of characteristic symptoms of the treated condition, limiting or preventing the recurrence of the condition in a subject who previously had the condition, or limiting or preventing the recurrence of symptoms in a subject who previously had symptoms of the condition.

[0080] "Prevention" of disease or symptom means preventing the development of symptoms in the test subjects.

[0081] "Diagnosis" refers to the method of determining whether a subject has a given disease or condition, whether it is likely to develop into a given disease or condition in the future, or whether it is likely to respond to treatment for a previously diagnosed disease or condition (i.e., stratifying a patient population based on the likelihood of responding to treatment). Diagnosis is usually made by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating the subject's likely response to a particular treatment.

[0082] "Response", "responsiveness" or "probable response" means any type of improvement or positive response, such as the reduction or improvement of one or more symptoms, a decrease in the severity of the disease, a stabilization of the disease state (i.e., no worsening), prevention of the spread of the disease, a delay or slowing of the progression of the disease, an improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable.

[0083] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective dose can vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0084] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably in this document.

[0085] “About” means within the acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or implementation, unless otherwise expressly stated in the implementation or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) in accordance with convention in the art.

[0086] "Cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread) to other areas of the patient's body.

[0087] "Cancer expressing EGFR or c-Met" refers to cancer with detectable EGFR or c-Met expression or with EGFR or c-Met mutations or amplifications. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemistry, flow cytometry, or Western blotting.

[0088] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) with the amino acid sequence shown in GenBank accession number NP_005219, as well as its naturally occurring variants.

[0089] As used herein, “hepatocyte growth factor receptor” or “c-Met” refers to human c-Met and its natural variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0090] "Bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody that has a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. The domains that specifically bind to EGFR and c-Met are usually a VH / VL pair, and the bispecific anti-EGFR / c-Met antibody is monovalent in binding to both EGFR and c-Met.

[0091] "Specific binding," "specifically binding," or simply "binding" refers to an antibody binding to an antigen or an epitope within an antigen with a higher affinity than it would to other antigens. Typically, the binding of an antibody to an antigen or an epitope within an antigen occurs at an equilibrium dissociation constant (K). D It is approximately 5x10 -8 M or lower, for example, about 1x10 -9 M or lower, approximately 1x10 -10 M or lower, approximately 1x10 -11 M or lower, or approximately 1x10 -12 M or lower, usually K D Compared to its binding to non-specific antigens (such as BSA, casein), K D At least one hundred times lower. The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may be cross-reactive to other related antigens, for example, to the same antigen from other species (homologous) (such as humans or monkeys, such as cynomolgus (cyno) or chimpanzee (chimp)). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0092] "Antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of immunoglobulin molecules containing an antigen-binding site with desired specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, and their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0093] A “biosimilar” (referring to an approved reference product / biologic, i.e., a reference marketed drug) is a biologic that is highly similar to a reference drug based on data from studies in which there are no clinically significant differences in safety, purity, and efficacy between the biosimilar and the reference drug: (a) analytical studies demonstrating a high degree of similarity between the biologic and the reference drug; (b) animal studies (including assessments of toxicity); and / or (c) one or more clinical studies (including assessments of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate the safety, purity, and efficacy of the reference product under one or more appropriate conditions of use, intended for use, and for which a license to use the biosimilar is sought. A biosimilar may be an interchangeable product that can replace the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional criterion of “interchangeability,” a biosimilar should be expected to produce the same clinical outcomes as the reference product in any given patient, and if the biosimilar is administered to an individual more than once, the risk of reduced safety or efficacy from substitution or exchange between the use of the biosimilar and the reference product is no greater than the risk of using the reference product without such substitution or exchange. Biosimilars utilize the same mechanisms of action as the reference product under the proposed conditions of use, provided that these mechanisms are known to the reference product. One or more conditions of use specified, recommended, or suggested in the proposed labeling of the biosimilar have previously been approved for use with the reference product. The biosimilar has the same route of administration, dosage form, and / or strength as the reference product and is manufactured, processed, packaged, or stored in a facility that meets standards designed to ensure that the biosimilar remains safe, pure, and potent. When compared to the reference product, biosimilars may include minor modifications to the amino acid sequence, such as N-terminal or C-terminal truncation that is not expected to alter the biosimilar's properties.

[0094] The complementarity-determining region (CDR) is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al., (1970) J Exp Med 132: 211-50) (Kabat et al., "Sequences of Proteins of Immunological Interest", 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al., (2003) Dev Comp Immunol 27: 55-77), and AbM (Martin and Thornton (1996), J Bmol Biol 263: 800-15). The correspondence between various depictions and variable area numbers is described (see, for example, Lefranc et al., (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun (2001), J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resource, http: / / imgt_org). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include the CDR as defined by any of the methods described above (Kabat, Chothia, IMGT, or AbM).

[0095] Immunoglobulins can be classified into five major types based on the amino acid sequence of their heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, the antibody light chain of any vertebrate species can be designated as one of two distinct types: κ and λ.

[0096] An "antigen-binding fragment" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtained, or genetically engineered polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; humped VH domains; and minimal recognition units consisting of amino acid residues from CDRs of analog antibodies, such as FR3-CDR3-FR4, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs. Where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0097] Monoclonal antibodies are antibodies derived from a substantially homogeneous population of antibody molecules, meaning that the individual antibodies within that population are identical, differing only in possible well-known modifications, such as removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can exhibit heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0098] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, formed, or isolated through recombination when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins.

[0099] "Bispecific" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may be cross-reactive to other related antigens, for example, to the same antigen from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques or pantroglodytes), or they may bind to epitopes shared between two or more different antigens.

[0100] An "antagonist" or "inhibitor" is a molecule that, when bound to a cellular protein, inhibits at least one response or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one response or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than when at least one response or activity is inhibited in the absence of an antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of an antagonist.

[0101] "Biosample" refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within the subject's body. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleural fluid, pericardial fluid, peritoneal fluid, peritoneal fluid and other body cavity fluids, fluids collected by bronchoalveolar lavage fluid, synovial fluid, liquid solutions in contact with the subject or biological sources (e.g., cell and organ culture media (including cell or organ conditioned media), lavage fluid, etc.), tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine-needle aspirates, surgically removed tissue, organ cultures, or cell cultures. As a non-limiting example, a biological sample is a blood sample. As another non-limiting example, a biological sample is a plasma sample. As yet another non-limiting example, a biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA), which can be isolated from a variety of other biological samples disclosed herein, such as, but not limited to, blood or plasma samples. In some embodiments, the biological sample is tumor DNA that can be isolated from, for example, a tumor sample.

[0102] As used in this application, "low fucose" or "low fucose content" means that the fucose content of the antibody is about 1% to 15%.

[0103] As used in this article, "normal fucose" or "normal fucose content" refers to an antibody with a fucose content of approximately 50%, typically approximately 80% or 85%.

[0104] As used in this article, "treatment-naïve" refers to a subject diagnosed with locally advanced or metastatic NSCLC who has not yet received anti-cancer therapy for NSCLC; therefore, the subject is someone who has never received chemotherapy and has never received TKI therapy, for example, has not received chemotherapy or tyrosine kinase inhibitors (including first-generation, second-generation, or third-generation TKIs) or other anti-NSCLC therapy. Treatment of treatment-naïve subjects may also be referred to as first-line or front-line therapy.

[0105] As used herein, RECIST v1.1 criteria refer to publicly available guidelines for evaluating responses in solid tumors as described in the following literature: Eisenhauer EA, Therasse P, Bogaerts J et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-247, which is incorporated herein by reference. Eisenhauer et al. provided the following definition of criteria for determining objective tumor responses to target lesions:

[0106] - Complete response (CR): Disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must show a reduction in short axis to <10 mm.

[0107] - Partial response (PR): The total diameter of the target lesions is reduced by at least 30%, with the total diameter of the baseline as a reference.

[0108] - Progressive disease (PD): The sum of the diameters of target lesions increases by at least 20%, using the minimum sum in the study as a reference (if the baseline sum is the minimum in the study, then the baseline sum is included). In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression).

[0109] - Stable disease (SD): Neither sufficient for reduction to meet PR criteria nor sufficient for increase to meet PD criteria; the sum of the smallest diameters in the study is used as a reference.

[0110] As used in this article, a partial response or better response refers to a partial response (PR) or a complete response (CR).

[0111] As used in this article, progression-free survival (PFS) refers to the time from randomization in a clinical trial to an objective date of disease progression or death (whichever occurs first), based on a blinded independent central review (BICR) using the Responsive Evaluation Criteria for Solid Tumors (RECIST) v1.1.

[0112] As used in this article, overall response (OR) is defined as those participants who achieve PR or CR as their best response in a clinical trial, as defined by BICR using RECIST v1.1.

[0113] As used in this article, overall survival (OS) is defined as the time from the date of randomization in a clinical trial to the date of death from any cause.

[0114] As used in this article, Duration of Response (DoR) is defined for participants with PR or CR as the time from the date a response (PR or CR) is first recorded in the clinical trial to the date of progression or death (whichever occurs first).

[0115] As used in this article, the time to follow-up therapy (TTST) is defined as the time from the date of randomization in the clinical trial to the date of initiation of follow-up anticancer therapy after interruption of study treatment or death (whichever occurs first).

[0116] As used in this article, progression-free survival (PFS2) after the first follow-up therapy is defined as the time from randomization in a clinical trial up to the date of the second objective disease progression or death following the initiation of follow-up anticancer therapy based on researcher assessment (after the assessment used for PFS), whichever occurs first.

[0117] As used in this article, the time to symptomatic progression (TTSP) is defined as the time from randomization in a clinical trial to the occurrence of any of the following (whichever occurs first): a new symptom or symptom exacerbation that researchers consider relevant to lung cancer and requires changes in anticancer treatment and / or clinical intervention to manage the symptoms.

[0118] As used in this article, intracranial progression-free survival (Intracranial PFS) is defined as the time from randomization in a clinical trial to the date of objective intracranial disease progression or death (whichever occurs first), based on the BICR using RECIST v1.1. Specifically, intracranial disease progression is defined as progression with brain metastases or the occurrence of new brain lesions.

[0119] The method disclosed herein

[0120] Resistance to osimertinib is diverse, polyclonal, and difficult to treat. Currently, there are no approved targeted therapies in the post-osimertinib scenario. Recently, two studies of immunotherapy-chemotherapy regimens failed to demonstrate efficacy in the TKI-resistant scenario. Currently, six other phase 3 studies (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) are investigating targeted therapy combinations versus chemotherapy as second-line (or later) treatment for EGFR-mutant advanced NSCLC, highlighting unmet needs in this patient population.

[0121] This invention relates to novel regimens for treating patients with EGFR-mutant advanced NSCLC whose disease has progressed during or after TKI therapy (such as osimertinib). Embodiments of the invention provide methods for significantly improving progression-free survival in patients with EGFR-mutant advanced NSCLC compared to chemotherapy with epantadine chemotherapy and epantadine-lazetinib-chemotherapy, whose disease has progressed during or after osimertinib monotherapy.

[0122] According to one embodiment of the invention, a method for improving median PFS in a subject population with locally advanced or metastatic NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with at least one prior TKI (i.e., the subjects were not untreated but had previously received TKI therapy) comprises administering a combination therapy to the subject population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a subject reference population with NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with a prior TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody has not been administered.

[0123] According to another embodiment of the invention, an improvement in median PFS for a subject population with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations, whose NSCLC progressed during or after treatment with a prior TKI (i.e., the subjects were not untreated but had previously received TKI therapy) comprises administering a combination therapy to the subject population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of lazaitinib or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a reference subject population with NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with a third-generation TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody and lazaitinib or a pharmaceutically acceptable salt or hydrate thereof have not been administered.

[0124] According to one embodiment of the invention, a method for improving median intracranial PFS in a subject population with locally advanced or metastatic NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with at least one prior TKI (i.e., the subjects were not untreated but had previously received TKI therapy) comprises administering a combination therapy to the subject population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of carboplatin, and (iii) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a subject reference population with NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with a prior TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody has not been administered.

[0125] According to another embodiment of the invention, a method for improving median intracranial PFS in a subject population with locally advanced or metastatic NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with a prior TKI (i.e., the subjects were not untreated but had previously received TKI therapy) comprises administering a combination therapy to the subject population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of latezatitinib or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein the improvement in median PFS is relative to the median PFS of a reference subject population with NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after treatment with a third-generation TKI, to which carboplatin and pemetrexed have been administered, but the bispecific anti-EGFR / c-Met antibody and latezatitinib or a pharmaceutically acceptable salt or hydrate thereof have not been administered.

[0126] According to another embodiment of the invention, a method for treating a subject with locally advanced or metastatic NSCLC carrying one or more EGFR mutations, whose NSCLC progressed during or after prior TKI treatment (i.e., the subject is not untreated but has previously received TKI therapy) comprises administering a combination therapy to the subject comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, (ii) a therapeutically effective amount of lazalatinib or a pharmaceutically acceptable salt or hydrate thereof, (iii) a therapeutically effective amount of carboplatin, and (iv) a therapeutically effective amount of pemetrexed, wherein administration of the combination therapy begins on day 1 of cycle 1 of the first 21-day cycle and continues in subsequent 21-day cycles, and wherein the method comprises administering lazalatinib or a pharmaceutically acceptable salt or hydrate thereof after carboplatin administration (e.g., wherein the method comprises: (a) administering lazalatinib at AUC on day 1 of each 21-day cycle). (a) administer carboplatin at a dose of 5 for up to 4 cycles, and (b) begin oral administration of lazatinib or its pharmaceutically acceptable salts or hydrates once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

[0127] In some embodiments, latezatitinib or a pharmaceutically acceptable salt or hydrate thereof is latezatitinib mesylate. In some embodiments, latezatitinib or a pharmaceutically acceptable salt or hydrate thereof is latezatitinib mesylate monohydrate.

[0128] In some implementations, the method involves oral administration of lazatinib or its pharmaceutically acceptable salt or hydrate once daily at a dose of about 240 mg.

[0129] In some implementations, the method includes oral administration of lazatinib or its pharmaceutically acceptable salt or hydrate once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

[0130] In some embodiments, one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. In some embodiments, one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments, one or more EGFR mutations comprise exon 21 L858R substitutions.

[0131] In some embodiments, at least one prior TKI comprises a first-generation EGFR TKI. In some embodiments, at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments, at least one prior TKI comprises a second-generation EGFR TKI. In some embodiments, at least one prior TKI comprises osimertinib. EGFR-TKIs are EGFR targets that interfere with EGFR signaling. To date, three different generations of EGFR-TKIs are available, but all still exhibit resistance mechanisms. First-generation TKIs (e.g., erlotinib, gefitinib, and itotinib) act by causing reversible ATP binding site blockade, thereby terminating downstream signaling. Second-generation TKIs (e.g., afatinib and dacominitib) provide an alternative for patients with acquired resistance to first-generation TKIs. Third-generation TKIs (e.g., osimertinib, rociletinib, olmutinib, lazetinib) provide treatment for patients with acquired resistance to first- and second-generation TKIs. See, for example, Caponnetto et al., J. Mol. Pathol. 2021, 2(1), 1-10.

[0132] In some embodiments, the method includes oral administration of lazalatinib or a pharmaceutically acceptable saline or hydrate thereof once daily in a dose of about 80 mg to about 320 mg. In some embodiments, the method includes oral administration of lazalatinib or a pharmaceutically acceptable saline or hydrate thereof once daily in a dose of about 240 mg. In some embodiments, the method includes oral administration of lazalatinib or a pharmaceutically acceptable saline or hydrate thereof once daily in a dose of about 240 mg, starting from day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

[0133] In some implementations, the combination therapy is administered starting on day 1 of cycle 1 of the first 21-day cycle and continues in subsequent 21-day cycles.

[0134] In some implementations, the method induces a clinical response in subjects according to RECIST v1.1 criteria. In some implementations, the method achieves a partial response or better in subjects according to RECIST v1.1 criteria. In some implementations, the combination therapy achieves a median PFS improvement of at least two weeks. In some implementations, the combination therapy achieves a median PFS improvement of at least one month. In some implementations, the combination therapy achieves a median PFS improvement of at least 1.5 months. In some implementations, the combination therapy achieves a median PFS improvement of at least two months. In some implementations, subjects demonstrate a PFS of at least 4.5 months. In some implementations, subjects demonstrate a PFS of at least 5 months. In some implementations, subjects demonstrate a PFS of at least 5.5 months. In some implementations, subjects demonstrate a PFS of at least 6 months, or at least 10 months, or at least 12 months, or at least 14 months. In some implementations, the combination therapy further achieves an improvement in objective response relative to the reference population. In some implementations, the combination therapy further achieves an improvement in overall survival (OS) relative to the reference population. In some implementations, the improvement in OS is at least two months relative to the reference population. In some embodiments, the improvement in OS relative to the reference group is at least about 2.4 months. In some embodiments, the improvement in OS relative to the reference group is about 2.2 months. In some embodiments, the improvement in OS relative to the reference group is about 2.3 months. In some embodiments, the improvement in OS relative to the reference group is about 2.4 months. In some embodiments, the improvement in OS relative to the reference group is about 2.5 months. In some embodiments, the improvement in OS relative to the reference group is about 2.6 months. In some embodiments, the combination therapy further improves the duration of response (DoR) relative to the reference group. In some embodiments, the combination therapy further improves the time to subsequent therapy relative to the reference group. In some embodiments, the combination therapy further improves the progression-free survival (PFS2) after the first subsequent therapy relative to the reference group. In some embodiments, the combination therapy further improves the median intracranial PFS relative to the reference group. In some embodiments, the improvement in PFS2 relative to the reference group is at least two months. In some embodiments, the improvement in PFS2 relative to the reference group is at least about 4.4 months. In some implementations, the improvement in PFS2 relative to the reference group is approximately 4.5 months. In some implementations, the improvement in PFS2 relative to the reference group is approximately 5 months. In some implementations, the combination therapy further achieves an improvement in time to symptomatic progression (TTSP) relative to the reference group.In some embodiments, the improvement in TTSP relative to the reference population is at least about 4 months. In some embodiments, the improvement in TTSP relative to the reference population is at least about 4.2 months. In some embodiments, the improvement in TTSP relative to the reference population is at least about 4.5 months. In some embodiments, the combination therapy further improves the time to treatment interruption (TTD) relative to the reference population. In some embodiments, the improvement in TTD relative to the reference population is at least about 5.5 months. In some embodiments, the improvement in TTD relative to the reference population is at least about 5.9 months. In some embodiments, the improvement in TTD relative to the reference population is at least about 6 months. In some embodiments, the combination therapy further improves the time to follow-up therapy (TTST) relative to the reference population. In some embodiments, the improvement in TTST relative to the reference population is at least about 5 months. In some embodiments, the improvement in TTST relative to the reference population is at least about 5.5 months. In some embodiments, the improvement in TTST relative to the reference population is at least about 5.6 months. In some implementations, the improvement in TTST relative to the reference group is at least about 6 months.

[0135] In some implementations, subjects are progression-free after at least 20 months. In some implementations, subjects are progression-free after at least 30 months. In some implementations, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and / or 51% at 36 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more EGFR mutations.

[0136] In some implementations, the overall survival (OS) of the subjects is at least 17 months. In some implementations, the overall survival (OS) of the subjects is at least 17.7 months. In some implementations, the overall survival (OS) of the subjects is approximately 17 months. In some implementations, the overall survival (OS) of the subjects is at least 17.5 months. In some implementations, the overall survival (OS) of the subjects is at least 18 months.

[0137] In some implementations, the time to follow-up therapy (TTST) is at least 12 months. In some implementations, the time to follow-up therapy (TTST) is at least 12.2 months.

[0138] In some implementations, the time to symptomatic progression (TTSP) is at least 16 months. In other implementations, the time to symptomatic progression (TTSP) is approximately 16 months.

[0139] In some implementations, the treatment interruption period (TTD) for the subject is at least 10 months. In some implementations, the treatment interruption period (TTD) for the subject is at least 10.4 months. In some implementations, the treatment interruption period (TTD) for the subject is approximately 10.4 months.

[0140] In some implementations, the progression-free survival (PFS2) of the subject after the first follow-up therapy is at least 16 months. In some implementations, the progression-free survival (PFS2) of the subject after the first follow-up therapy is approximately 16 months.

[0141] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises: a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain specifically binding to EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0142] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at doses of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg. According to some embodiments, the method includes administering the dose weekly for four weeks, followed by administration every two weeks starting from week five, wherein the dose is 1050 mg for a baseline weight of less than 80 kg and 1400 mg for a baseline weight of 80 kg or more. In some embodiments, the initial dose is administered as a fractionated infusion on days 1 and 2 of week 1. In some embodiments, the initial dose is administered on day 1 of week 1.

[0143] In some embodiments, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2. In some embodiments, the initial dose is administered as a fractionated infusion on days 1 and 2 of week 1. In some embodiments, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3. In some embodiments, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2. In some embodiments, the initial dose is administered as a fractionated infusion on days 1 and 2 of week 1. In some implementations, if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0144] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0145] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises: a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. In some embodiments, the first domain that specifically binds to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0146] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0147] In some implementations, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0148] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 1% to about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 2% to about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 3% to about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 4% to about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 15%.

[0149] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI), such as, but not limited to, epidermal growth factor receptor (EGFR TKI). Non-limiting examples of TKIs include erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazatinib, poziotinib, critinib, cabozantinib, carmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein may be administered in combination with lazatinib.

[0150] Lazatinib is an oral third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is being developed for the treatment of non-small cell lung cancer (NSCLC).

[0151] Lazazinib is described in WO 2016 / 060443 as N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinylphenyl)acrylamide, and is described below as a compound of formula I.

[0152] Formula I

[0153] In addition, WO2018 / 194356 describes its salt, hydrate and crystalline forms; and WO2019 / 022485, WO2019 / 022486 and WO2019 / 022487 disclose methods for producing lazatinib.

[0154] Lazazinib mesylate monohydrate is described below as a compound of formula Ia.

[0155] Formula Ia,

[0156] It can be called N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-(morpholin-4-yl)phenyl]acrylamide methanesulfonate hydrate.

[0157] In some implementations, the method includes administering carboplatin at an AUC 5 dose on day 1 of each 21-day cycle for up to four cycles. Carboplatin can be administered at an AUC 5 dose according to a commercially available method approved by a healthcare institution.

[0158] In some implementations, the method includes administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2Administer pemetrexed at a dose for up to 4 cycles, then as maintenance until disease progression.

[0159] application

[0160] Bispecific anti-EGFR / c-Met antibodies can be administered in pharmaceutically acceptable carriers. "Carrier" refers to the diluent, adjuvant, excipient, or medium with which the antibodies of this invention are administered. Such mediators can be liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR / c-Met antibodies. These solutions are sterile and generally free of particulate matter. They can be sterilized using conventional, known sterilization techniques, such as filtration. For parenteral administration, the carrier may comprise sterile water, and other excipients may be added to increase solubility or preservative properties. Injectable suspensions or solutions can also be prepared using water-based carriers along with suitable additives. Suitable mediators and formulations containing other human proteins (e.g., human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Troy, DB editor, Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing, pp. 691-1092 (see especially pp. 958-989).

[0161] The administration method can be any suitable route for delivering the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, for example, intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, nasal, vaginal, rectal), using formulations in tablet, capsule, solution, powder, gel, or granule form; and contained in a syringe, implantation device, osmotic pump, cartridge, micropump; or other methods as understood by a person skilled in the art. Site-specific administration can be achieved through methods such as intratumoral, extraintestinal, intrabronchial, intraperitoneal, intracystic, intracartilaginous, intracavitary, intrabody cavity, intracerebellum, intravenous, intracolonic, intracervical, intrastomal, intracervical canal, intrastomal, intrahepatic, intracardiac, intraosseous, intrapelvic, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intrabladder, intralesional, vaginal, rectal, oral, sublingual, intranasal, or percutaneous delivery.

[0162] In some implementations, bispecific anti-EGFR / c-Met antibodies are administered intravenously.

[0163] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. The bispecific anti-EGFR / c-Met antibody can be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0164] In some implementations, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous preparation as disclosed in PCT International Publication No. WO2022 / 224187A1.

[0165] In some embodiments, the method includes administering the dose weekly for four weeks, followed by administration every two weeks starting from week five, wherein the dose is 1050 mg for a baseline weight of less than 80 kg and 1400 mg for a baseline weight of 80 kg or more. In some embodiments, the initial dose is administered as a fractionated infusion on days 1 and 2 of week 1.

[0166] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 1400 mg and about 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 1400 mg and about 1750 mg.

[0167] In some implementations, the bispecific anti-EGFR / c-Met antibody is available in doses of approximately 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, and 510 mg. mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 620mg, approximately 630mg, approximately 640mg, approximately 650mg, approximately 660mg, approximately 670mg, approximately 680mg, approximately 690mg, approximately 700mg, approximately 710mg, approximately 720mg, approximately 730mg, approximately 740mg, approximately 750mg, approximately 760mg, approximately 770mg, approximately 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg, approximately 840mg, approximately 850mg, approximately 860mg, approximately 870mg, approximately 880mg, approximately 890mg, approximately 900mg, approximately 910mg, approximately 920mg, approximately 930mg, approximately 940mg, approximately 950mg, approximately 960mg, approximately 970mg, approximately 980mg, approximately 990mg, approximately 1000mg, approximately 1010mg, approximately 1020mg, approximately 1030mg, approximately 1040mg, approximately 1050mg, approximately 1060mg, approximately 1070mg, approximately 1080mg, approximately 1090mg, approximately 1100mg, approximately 1110mg, approximately 1120mg, approximately 1130mg, approximately 1140mg, approximately 1150mg, approximately 1160mg, approximately 1170mg, approximately 1180mg, approximately 1190mg Approximately 1200mg, approximately 1210mg, approximately 1220mg, approximately 1230mg, approximately 1240mg, approximately 1250mg, approximately 1260mg, approximately 1270mg, approximately 1280mg, approximately 1290mg, approximately 1300mg, approximately 1310mg, approximately 1320mg, approximately 1330mg, approximately 1340mg, approximately 1350mg, approximately 1360mg, approximately 1370mg, approximately 1380mg, approximately 1390mg, approximately 1400mg, approximately 1410mg, approximately 1420mg, approximately 1430mg, approximately 1440mg, approximately 1450mg, approximately 1460mg, approximately 1470mg, approximately 1480mg, approximately 1490mg, approximately 1500mg.Approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, 1575mg, approximately 1580mg, approximately 1590mg, approximately 1600mg, approximately 1610mg, 1620mg, approximately 1630mg, approximately 1640mg, approximately 1650mg, approximately 1660mg, approximately 1670mg, approximately 1680mg, approximately 1690mg. Approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, approximately 1860mg, approximately 1870mg, approximately 1880mg, 1890mg Approximately 1900mg, approximately 1910mg, approximately 1920mg, approximately 1930mg, approximately 1940mg, approximately 1950mg, approximately 1960mg, approximately 1970mg, approximately 1980mg, approximately 1990mg, approximately 2000mg, 2100mg, 2110mg, 2120mg, 2130mg, 2140mg, 2150mg, 2160mg, 2170mg, 2180mg, 2190mg, Administer at doses of 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, or 2410 mg.

[0168] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, about 1400 mg, about 1750 mg, or about 2100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg.

[0169] In some embodiments, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2. In some embodiments, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1 / 2 of cycle 1 (divided into two doses), days 8 and 15 of cycle 1, and day 1 of cycle 2.

[0170] In some implementations, if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0171] In some embodiments, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2. In some embodiments, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1 / 2 of cycle 1 (divided into two doses), days 8 and 15 of cycle 1, and day 1 of cycle 2.

[0172] In some implementations, if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0173] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice weekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once weekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every three weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every four weeks.

[0174] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0175] In some embodiments, a suitable route of administration for delivering lazatinib to a subject may be oral administration, such as oral tablets. Lazatinib tablet formulations suitable for oral administration according to the invention are described, for example, in WO2021 / 209893 and WO2020 / 079637, which are incorporated herein by reference.

[0176] In some embodiments, latezolitinib is administered at a dose ranging from about 10 mg to about 400 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 20 mg to about 320 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 50 mg to about 300 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 100 mg to about 300 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 150 mg to about 280 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 200 mg to about 250 mg. In some embodiments, latezolitinib is administered at a dose ranging from about 220 mg to about 250 mg.

[0177] In some embodiments, lazatinib is administered at doses of approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, or approximately 400 mg. In some embodiments, lazatinib is administered at a dose of approximately 240 mg.

[0178] In some implementations, lazatinib is administered daily. In some implementations, lazatinib is administered twice weekly. In some implementations, lazatinib is administered once weekly. In some implementations, lazatinib is administered once every two weeks. In some implementations, lazatinib is administered once every three weeks. In some implementations, lazatinib is administered once every four weeks.

[0179] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazatinib, which may be administered using any of the doses and dosage forms disclosed herein. In some embodiments, lazatinib is administered at a dose ranging from about 10 mg to about 400 mg. In some embodiments, lazatinib is administered at a dose ranging from about 20 mg to about 320 mg. In some embodiments, lazatinib is administered at doses of approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, or approximately 400 mg. In some embodiments, lazatinib is administered at a dose of approximately 240 mg.

[0180] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein can be administered in combination with lazatinib at any of the doses and formulations disclosed herein. As a non-limiting example, 1400 mg of etanercept can be administered in combination with 240 mg of lazatinib. As a non-limiting example, 1750 mg of etanercept can be administered in combination with 240 mg of lazatinib. As a non-limiting example, 2100 mg of etanercept can be administered in combination with 240 mg of lazatinib.

[0181] In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lavatinib, wherein lavatinib is administered daily, every other day, twice weekly, or once weekly. In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lavatinib, wherein lavatinib is administered daily. In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lavatinib, wherein lavatinib is administered orally.

[0182] In some implementations, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with carboplatin.

[0183] In some implementations, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with pemetrexed.

[0184] In some implementations, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lazatinib, carboplatin, and pemetrexed.

[0185] In some implementations, combination therapies comprising bispecific anti-EGFR / c-Met bispecific antibodies and EGFR TKIs may further include one or more other anticancer therapies.

[0186] In some embodiments, the methods of this disclosure include administering a cancer therapy to a subject, excluding a combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI disclosed herein. In some embodiments, the cancer therapy may include any of the therapies described herein. As a non-limiting example, cancer therapies that may be administered in the methods of this disclosure may include any number of various platinum-based chemotherapy therapies or combinations thereof. As a non-limiting example, platinum-based chemotherapy therapies include carboplatin, cisplatin, or combinations thereof.

[0187] Additional anticancer therapies that can be applied in the methods of this disclosure may include any one or more of chemotherapeutic agents or other anticancer agents known to those skilled in the art. Chemotherapy agents are chemical compounds that can be used to treat cancer and include growth inhibitors or other cytotoxic agents, including alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, etc. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN). ®Alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imines and methyl melamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; nitrogen mustards, such as chlornaphazine, cholophosphamide, estradiol, ifosfamide, dichloroethylmethylamine, and mechlorethamine. Oxygen hydrochloride, melphalan, novobichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorpromazine, fotemustine, lomustine, nimustine, ranimnustine;Antibiotics, such as aclacinomysins, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycins, and mycophenolic acid. Drugs containing 5-amino acids, such as nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-FU; and folic acid analogues, such as denoposide, methotrexate, and pteroxate. Terin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluorouridine; and androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergic drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone.Aldophosphamide glycoside; aminolevulinic acid; bestrabucil; bisantrene; idatrax; defofamide; demecolcine; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; londamine; mitoguazone; mitoantrone; mopidanmol; nitrarine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazine; procarbazine; PSK; ® Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2′,2″-Trichlorotriethylamine; Urethan; Vinpocetine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactalol; Pipobroman; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Members of the taxane family of novel taxanes, such as Taxol (TAXOL) ® Dorsetase (TAXOTERE) ® ( ) and its analogues; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; norvincristine; novantrone; teniposide; danomycin; aminopterin; capecitabine; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; receptor tyrosine kinase and / or angiogenesis inhibitors, including sorafenib (NEXAVAR) ®Sunitinib ® ), pazopanib (VOTRIENT™), tocinivib (PALLADIA™), vandetanib (ZACTIMA™), sildenafil (RECENTIN) ® ), Regorafenib (BAY 73-4506), Axitinib (AG013736), Lettatinib (CEP-701), Erlotinib (TARCEVA) ® gefitinib (IRESSA) ® Afatinib (BIBW 2992), Lapatinib (TYKERB) ® ), neratinib (HKI-272), and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. This definition also includes anti-hormonal agents used to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trivoxifen, keoxifene, LY117018, onaspirone, and toremifene (FARESTON). ® ); and antiandrogen drugs, such as flutamide, nilumet, bicalutamide, leuprorelin, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. Other conventional cytotoxic chemical compounds, such as those disclosed in Wiemann et al., 1985, in Medical Oncology (edited by Calabresi et al.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0188] Generation of bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure

[0189] An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of this disclosure is ervantumab. Evantumab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164, the entire contents of which are incorporated herein by reference. Evantumab is characterized by the following amino acid sequence:

[0190] EGFR conjugate arm

[0191] >SEQ ID NO: 1 (HCDR1, EGFR binding arm)

[0192] TYGMH

[0193] >SEQ ID NO: 2 (HCDR2, EGFR binding arm)

[0194] VIWDDGSYKYYGDSVKG

[0195] >SEQ ID NO: 3 (HCDR3, EGFR binding arm)

[0196] DGITMVRGVMKDYFDY

[0197] >SEQ ID NO: 4 (LCDR1, EGFR binding arm)

[0198] RASQDISSALV

[0199] >SEQ ID NO: 5 (LCDR2, EGFR binding arm)

[0200] DASSLES

[0201] >SEQ ID NO: 6 (LCDR3, EGFR binding arm)

[0202] QQFNSYPLT

[0203] >SEQ ID NO: 7 (HCDR1, c-Met binding arm)

[0204] SYGIS

[0205] >SEQ ID NO: 8 (HCDR2, c-Met binding arm)

[0206] WISAYNGYTNYAQKLQG

[0207] >SEQ ID NO:9 (HCDR3, c-Met binding arm)

[0208] DLRGTNYFDY

[0209] >SEQ ID NO: 10 (LCDR1, c-Met binding arm)

[0210] RASQGISNWLA

[0211] >SEQ ID NO: 11 (LCDR2, c-Met binding arm)

[0212] AASSLLS

[0213] >SEQ ID NO: 12 (LCDR3, c-Met binding arm)

[0214] QQANSFPIT

[0215] >SEQ ID NO: 13 (VH, EGFR binding arm)

[0216] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS

[0217] >SEQ ID NO: 14 (VL, EGFR binding arm)

[0218] AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK

[0219] >SEQ ID NO:15 (VH, c-Met binding arm)

[0220] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS

[0221] >SEQ ID NO:16 (VL, c-Met binding arm)

[0222] DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK

[0223] >SEQ ID NO: 17 HC1

[0224] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0225] >SEQ ID NO: 18 LC1

[0226] AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0227] >SEQ ID NO: 19 HC2

[0228] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0229] >SEQ ID NO: 20 LC2

[0230] DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0231] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and the second domain comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0232] In some embodiments, the first domain that specifically binds to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14; and the second domain that specifically binds to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0233] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0234] In some implementations, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0235] In some implementations, the bispecific anti-EGFR / c-Met antibody is ervantuzumab.

[0236] In some implementations, the bispecific anti-EGFR / c-Met antibody is a biosimilar of ervantomab.

[0237] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: https: / / us.proteogenix_science / product / amivantamab-biosimilar-anti-egfr-me-rccp2-mab-research-grade / .

[0238] In some implementations, non-limiting examples of biosimilars of evatumab can be found in publicly available online resources: https: / / www_thermofisher_com / antibody / product / Amivantamab-Antibody-Recombinant-Monoclonal / MA5-42260.

[0239] In some implementations, non-limiting examples of biosimilars of ervantumab can be found in publicly available online resources: https: / / www_genemedi.net / i / biologics-biosimilar-GMP-Bios-ab-021.

[0240] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: https: / / www_prosci-inc_com / product / amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966 / .

[0241] In some implementations, non-limiting examples of biosimilars of ervantomab can be found in publicly available online resources: https: / / www_antibodysystem_com / product / 6201.html.

[0242] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: https: / / www_biorbyt_com / amivantamab-biosimilar-antibody-orb1140752.html.

[0243] In one implementation, the bispecific anti-EGFR / c-Met antibody contains one or more Fc silencing mutations.

[0244] In one implementation, one or more Fc silencing mutations reduce affinity for the Fcγ receptor.

[0245] In one implementation, one or more Fc silencing mutations include V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0246] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%. Antibodies with reduced fucose content can be prepared using various methods reported for the successful expression of relatively high defucosylation antibodies with bibranched complex-type Fc oligosaccharides. These methods include controlling culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012), using the variant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; pre-printed electronic version; PMID:20562582), using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introducing specific antibodies against α Small interfering RNA of the 1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosyltransferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitors such as chifrine (Ferrara et al., JBiol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, reducing the fucose content in the antibody glycan enhances antibody-mediated cytotoxicity (ADCC).

[0247] Other publicly available bispecific anti-EGFR / c-Met antibodies may also be used in the methods of this disclosure, provided they exhibit similar properties when compared to ervantuzumab, as described in U.S. Patent No. 9,593,164. Bispecific anti-EGFR / c-Met antibodies that can be used in the methods of this disclosure may also be generated by binding publicly available EGFR-binding VH / VL domains and c-Met-binding VH / VL domains and testing the resulting bispecific antibody for characteristics, as described in U.S. Patent No. 9,593,164. In some embodiments, the anti-EGFR / c-Met antibody is a biosimilar of the anti-EGFR / c-Met antibody as described in U.S. Patent No. 9,593,164.

[0248] The bispecific anti-EGFR / c-Met antibody in the method of this disclosure can be generated, for example, by Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies, in the following manner: substitution is introduced at the heavy chain CH3 junction in each half-molecule to facilitate the formation of heterodimers of two antibody half-molecules with different specificities in an in vitro cell-free environment or by co-expression. The Fab arm exchange reaction is the result of disulfide bond isomerization and CH3 domain dissociation-association. The heavy chain disulfide bond in the hinge region of the parent monospecific antibody is reduced. The resulting free cysteine ​​of one parent monospecific antibody forms an inter-heavy chain disulfide bond with the cysteine ​​residue of the second parent monospecific antibody molecule, while the CH3 domain of the parent antibody is released and reformed through dissociation-association. The CH3 domain of the Fab arm can be engineered to better support heterodimerization compared to homodimerization. The resulting product is a bispecific antibody with two Fab arms or half-molecules, each binding to different epitopes (i.e., an epitope on EGFR and an epitope on c-Met). For example, the bispecific antibody of the present invention can be generated using the technique described in International Patent Publication WO2011 / 131746. In the case of IgG1 antibodies, a mutant F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild-type IgG2 and IgG4 antibodies with F405L and R409K substitutions can be used. For IgG4 antibodies, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions can be used. To generate bispecific antibodies, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, and the antibodies are incubated together under reducing conditions sufficient to allow disulfide isomerization of cysteine ​​in the hinge region; thereby generating bispecific antibodies through Fab arm exchange. Ideally, the incubation conditions can be restored to non-reducing conditions. Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation for at least 90 minutes at a pH of 5-8, such as pH 7.0 or pH 7.4, in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a temperature of at least 20°C.

[0249] The bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure can also be generated using designs such as Knob-in-Hole (Genentech), CrossMAb (Roche), electrostatic matching (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange engineered domain body (SEEDbody) (EMDSerono), and Biclonic (Merus).

[0250] In the "mortar and pestle" strategy (see, for example, International Publication WO 2006 / 028936), selected amino acids at the interface forming the CH3 domain in human IgG can be mutated at sites affecting CH3 domain interactions, thereby promoting heterodimer formation. Amino acids with small side chains (mortars) are introduced into the heavy chain of an antibody that specifically binds to the first antigen, and amino acids with large side chains (mortars) are introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, heterodimers are formed due to the preferential interaction between the heavy chains with "mortars" and those with "mortars". The exemplary CH3 substitution pairs forming the pestle and mortar (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain) are: T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0251] In addition to using a "mortar and pestle" strategy to facilitate Fab wall exchange, the CrossMAb technology also utilizes the replacement of the CH1 / CL domain in one half-arm to ensure the correct light chain pairing of the resulting bispecific antibody (see, for example, U.S. Patent No. 8,242,247).

[0252] Other exchange strategies can be used to generate the full-length bispecific antibody of the present invention as follows: in one or both arms of the bispecific antibody, a variable domain or a constant domain, or both, can be exchanged between or within the heavy chain and the light chain. These exchanges include, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1, as described in International Patent Publications WO2009 / 080254, WO2009 / 080251, WO2009 / 018386, and WO2009 / 080252.

[0253] Other strategies can also be used, such as promoting heavy chain heterodimerization by electrostatic interactions through substitution of positively charged residues on one CH3 surface and substitution of negatively charged residues on a second CH3 surface, as described in U.S. Patent Publication No. US2010 / 0015133, U.S. Patent Publication No. US2009 / 0182127, U.S. Patent Publication No. US2010 / 028637, or U.S. Patent Publication No. US2011 / 0123532. In other strategies, heterodimerization can be promoted by the following substitutions (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_ Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in U.S. Patent Publication No. US2012 / 0149876 or U.S. Patent Publication No. US2013 / 0195849.

[0254] SEEDbody technology can be used to generate the bispecific antibodies of the present invention. SEEDbody has selected IgG residues substituted with IgA residues in its constant domain to facilitate heterodimerization, as described in U.S. Patent No. US20070287170.

[0255] Standard methods are typically used to mutate molecules (such as the constant result domain of antibodies) at the DNA level.

[0256] Exemplary Implementation

[0257] 1. A method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising:

[0258] (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody

[0259] (ii) Treatment with an effective dose of carboplatin, and

[0260] (iii) Treat with an effective dose of pemetrexed.

[0261] The improvement in median PFS is relative to the median PFS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, and who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

[0262] 2. According to the embodiment of claim 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0263] 3. The method according to embodiment 1 or embodiment 2, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0264] 4. The method according to embodiment 3, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

[0265] 5. The method according to embodiment 3, wherein the one or more EGFR mutations comprise exon 21L858R substitution.

[0266] 6. The method according to any one of embodiments 1 to 5, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

[0267] 7. The method according to any one of embodiments 1 to 5, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

[0268] 8. The method according to any one of embodiments 1 to 5, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

[0269] 9. The method according to any one of embodiments 1 to 5, wherein the at least one prior TKI comprises osimertinib.

[0270] 10. The method according to any one of embodiments 1 to 9, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

[0271] 11. The method according to any one of embodiments 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0272] 12. The method according to any one of embodiments 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0273] 13. The method according to embodiments 1 to 12, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

[0274] 14. The method according to embodiment 13, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

[0275] 15. The method according to embodiment 14, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0276] 16. The method according to embodiment 15, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0277] 17. The method according to embodiment 14, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0278] 18. The method according to embodiment 14, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0279] 19. The method according to embodiment 18, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0280] 20. The method according to embodiment 14, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0281] 21. The method according to any one of embodiments 1 to 20, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

[0282] 22. The method according to any one of embodiments 1 to 21, wherein the method comprises administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0283] 23. The method of claim 22, wherein the method comprises:

[0284] a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0285] (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or

[0286] (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0287] (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0288] as well as

[0289] b) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles;

[0290] as well as

[0291] c) On day 1 of each 21-day cycle, administer with the aforementioned carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0292] 24. The method according to embodiment 23, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0293] 25. The method according to any one of embodiments 1 to 24, wherein the combination therapy achieves the median PFS improvement for at least two weeks.

[0294] 26. The method according to embodiment 25, wherein the combination therapy achieves at least one month of improvement in median PFS.

[0295] 27. The method according to embodiment 26, wherein the combination therapy achieves at least 1.5 months of improvement in median PFS.

[0296] 28. The method according to embodiment 27, wherein the combination therapy achieves at least 2 months of improvement in median PFS.

[0297] 29. The method according to embodiment 28, wherein at least one subject in the subject population exhibits a progression-free survival of at least 4.5 months.

[0298] 30. The method according to embodiment 29, wherein at least one subject in the subject population exhibits at least 5 months of progression-free survival.

[0299] 31. The method according to embodiment 30, wherein at least one subject in the subject population exhibits a progression-free survival of at least 5.5 months.

[0300] 32. The method according to embodiment 31, wherein at least one subject in the subject population exhibits at least 6 months of progression-free survival.

[0301] 33. The method according to embodiment 32, wherein at least one subject in the subject population exhibits at least 10 months of progression-free survival.

[0302] 34. The method according to embodiment 33, wherein at least one subject in the subject population exhibits at least 12 months of progression-free survival.

[0303] 35. The method according to embodiment 34, wherein at least one subject in the subject population exhibits at least 14 months of progression-free survival.

[0304] 36. The method according to any one of embodiments 1 to 35, wherein the combination therapy further achieves an improvement in objective response relative to the reference population (e.g., wherein the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%).

[0305] 37. The method according to any one of embodiments 1 to 36, wherein the combination therapy further improves overall survival (OS) relative to the reference population.

[0306] 38. The method according to any one of embodiments 1 to 37, wherein the combination therapy further improves the duration of response (DoR) relative to the reference population (e.g., wherein the combination therapy achieves a median DoR of at least about 6 months, or at least about 7 months, or at least about 8 months, or at least about 9 months).

[0307] 39. The method according to any one of embodiments 1 to 38, wherein the combination therapy further achieves an improvement in the time to follow-up therapy (TTST) relative to the reference group (e.g., wherein the combination therapy achieves a median TTST of at least about 7 months, or at least about 8 months, or at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).

[0308] 40. The method according to any one of embodiments 1 to 39, wherein the combination therapy further achieves an improvement in PFS (PFS2) after the first follow-up therapy relative to the reference population (e.g., wherein the combination therapy achieves a median PFS2 of at least about 12 months, or at least about 13 months, or at least about 14 months).

[0309] 41. The method according to any one of embodiments 1 to 40, wherein the combination therapy further improves the median intracranial PFS relative to the reference population (e.g., wherein the combination therapy achieves a median intracranial PFS of at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).

[0310] 42. A method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising:

[0311] (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody

[0312] (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate.

[0313] (iii) Treatment with an effective dose of carboplatin, and

[0314] (iv) Treat with an effective dose of pemetrexed.

[0315] The improvement in median PFS is relative to the median PFS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody, nor lazatinib or its pharmaceutically acceptable salts or hydrates.

[0316] 43. The method according to embodiment 42, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and wherein the second domain binding c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0317] 44. The method according to embodiment 42 or embodiment 43, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0318] 45. The method according to embodiment 44, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

[0319] 46. ​​The method according to embodiment 44, wherein the one or more EGFR mutations comprise exon 21L858R substitution.

[0320] 47. The method according to any one of embodiments 42 to 46, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

[0321] 48. The method according to any one of embodiments 42 to 46, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

[0322] 49. The method according to any one of embodiments 42 to 46, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

[0323] 50. The method according to any one of embodiments 42 to 46, wherein the at least one prior TKI comprises osimertinib.

[0324] 51. The method according to any one of embodiments 42 to 50, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

[0325] 52. The method according to any one of embodiments 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0326] 53. The method according to any one of embodiments 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0327] 54. The method according to any one of embodiments 42 to 53, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

[0328] 55. The method according to embodiment 54, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

[0329] 56. The method according to embodiment 55, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0330] 57. The method according to embodiment 56, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0331] 58. The method according to embodiment 55, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0332] 59. The method according to embodiment 55, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0333] 60. The method according to embodiment 59, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0334] 61. The method according to embodiment 55, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0335] 62. The method according to any one of embodiments 42 to 61, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate.

[0336] 63. The method according to any one of embodiments 42 to 61, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate monohydrate.

[0337] 64. The method according to any one of embodiments 42 to 63, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily at a dose of about 240 mg.

[0338] 65. The method according to embodiment 64, wherein the method comprises orally administering lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily at a dose of approximately 240 mg, starting from day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

[0339] 66. The method according to any one of embodiments 42 to 65, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

[0340] 67. The method according to any one of embodiments 42 to 66, wherein the method comprises administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0341] 68. The method according to embodiment 67, wherein the method comprises:

[0342] a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0343] (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or

[0344] (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0345] (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0346] as well as

[0347] b)(i) Administer the lazazetinib or its pharmaceutically acceptable salt or hydrate orally once daily at a dose of approximately 240 mg; or

[0348] (ii) Begin oral administration of lazatinib or its pharmaceutically acceptable salt or hydrate once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

[0349] as well as

[0350] c) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles;

[0351] as well as

[0352] d) On day 1 of each 21-day cycle, administer carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0353] 69. The method according to embodiment 68, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0354] 70. The method according to any one of embodiments 42 to 69, wherein the combination therapy achieves the median PFS improvement for at least two weeks.

[0355] 71. The method according to embodiment 70, wherein the combination therapy achieves at least one month of improvement in median PFS.

[0356] 72. The method according to embodiment 71, wherein the combination therapy achieves at least 1.5 months of improvement in median PFS.

[0357] 73. The method according to embodiment 72, wherein the combination therapy achieves at least a 2-month improvement in median PFS.

[0358] 74. The method according to embodiment 73, wherein at least one subject in the subject population exhibits a progression-free survival of at least 4.5 months.

[0359] 75. The method according to embodiment 74, wherein at least one subject in the subject population exhibits at least 5 months of progression-free survival.

[0360] 76. The method according to embodiment 75, wherein at least one subject in the subject population exhibits a progression-free survival of at least 5.5 months.

[0361] 77. The method according to embodiment 76, wherein at least one subject in the subject population exhibits at least 6 months of progression-free survival.

[0362] 78. The method according to embodiment 77, wherein at least one subject in the subject population exhibits at least 10 months of progression-free survival.

[0363] 79. The method according to embodiment 78, wherein at least one subject in the subject population exhibits at least 12 months of progression-free survival.

[0364] 80. The method according to embodiment 79, wherein at least one subject in the subject population exhibits at least 14 months of progression-free survival.

[0365] 81. The method according to any one of embodiments 42 to 80, wherein the combination therapy further achieves an improvement in objective response relative to the reference population (e.g., wherein the combination therapy achieves an ORR of at least about 60%, or at least about 61%, or at least about 62%).

[0366] 82. The method according to any one of embodiments 42 to 81, wherein the combination therapy further improves overall survival (OS) relative to the reference population.

[0367] 83. The method according to any one of embodiments 42 to 82, wherein the combination therapy further achieves an improvement in duration of response (DoR) relative to the reference population (e.g., wherein the combination therapy achieves a median DoR of at least about 6 months, or at least about 7 months, or at least about 8 months, or at least about 9 months).

[0368] 84. The method according to any one of embodiments 42 to 83, wherein the combination therapy further achieves an improvement in the time to follow-up therapy (TTST) relative to the reference population (e.g., wherein the combination therapy achieves a median TTST of at least about 7 months, or at least about 8 months, or at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).

[0369] 85. The method according to any one of embodiments 42 to 84, wherein the combination therapy further achieves an improvement in PFS (PFS2) after the first follow-up therapy relative to the reference population (e.g., wherein the combination therapy achieves a median PFS2 of at least about 12 months, or at least about 13 months, or at least about 14 months).

[0370] 86. The method according to any one of embodiments 42 to 85, wherein the combination therapy further improves the median intracranial PFS relative to the reference population (e.g., wherein the combination therapy achieves a median intracranial PFS of at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months).

[0371] 87. The method according to any one of embodiments 1 to 86, wherein the bispecific anti-EGFR / c-Met antibody is ervantumab.

[0372] 88. The method according to any one of embodiments 1 to 86, wherein the bispecific anti-EGFR / c-Met antibody is a biosimilar of ervantomab.

[0373] 89. The method according to any one of embodiments 1 to 41, wherein, relative to the reference population, the combination therapy further achieves improvements in TTD, TTST, and PFS2 (e.g., wherein the combination therapy achieves a median TTD of more than 4.5 months, or at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or at least about 11 months; and wherein the combination therapy achieves a median TTST of more than 6.6 months, or at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months; and wherein the combination therapy achieves a median PFS2 of more than 11.3 months, or at least about 12 months, or at least about 13 months).

[0374] 90. The method according to any one of embodiments 1 to 41, wherein the combination therapy further achieves an improvement in the time to symptomatic progression (TTSP) relative to the reference population (e.g., greater than 13 months, or at least 13.5 months, or at least 14 months).

[0375] 91. A method for improving median overall survival (OS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising:

[0376] (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody

[0377] (ii) Treatment with an effective dose of carboplatin, and

[0378] (iii) Treat with an effective dose of pemetrexed.

[0379] The improvement in median OS is relative to the median OS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, and who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

[0380] 92. The method according to embodiment 91, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and wherein the second domain binding c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0381] 93. The method according to embodiment 91 or embodiment 92, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0382] 94. The method according to embodiment 93, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

[0383] 95. The method according to embodiment 93, wherein the one or more EGFR mutations comprise exon 21L858R substitution.

[0384] 96. The method according to any one of embodiments 91 to 95, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

[0385] 97. The method according to any one of embodiments 91 to 95, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

[0386] 98. The method according to any one of embodiments 91 to 95, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

[0387] 99. The method according to any one of embodiments 91 to 95, wherein the at least one prior TKI comprises osimertinib.

[0388] 100. The method according to any one of embodiments 91 to 99, wherein the improvement in median OS at 18 months is greater in the subject population receiving the combination therapy than in the reference population.

[0389] 101. The method according to any one of embodiments 91 to 100, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

[0390] 102. The method according to any one of embodiments 91 to 101, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0391] 103. The method according to any one of embodiments 91 to 101, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0392] 104. The method according to any one of embodiments 91 to 103, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

[0393] 105. The method according to embodiment 104, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

[0394] 106. The method according to embodiment 105, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0395] 107. The method according to embodiment 106, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0396] 108. The method according to embodiment 105, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0397] 109. The method according to embodiment 105, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

[0398] 110. The method according to embodiment 109, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0399] 111. The method according to embodiment 105, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0400] 112. The method according to any one of embodiments 91 to 111, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

[0401] 113. The method according to any one of embodiments 91 to 112, wherein the method comprises administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0402] 114. The method according to embodiment 113, wherein the method comprises:

[0403] a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0404] (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or

[0405] (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or

[0406] (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

[0407] as well as

[0408] b) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles;

[0409] as well as

[0410] c) On day 1 of each 21-day cycle, administer with the aforementioned carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

[0411] 115. The method according to embodiment 114, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

[0412] 116. The method according to any one of embodiments 91 to 115, wherein the subject population receiving the combination therapy achieves at least two months of median OS improvement relative to the reference population.

[0413] 117. The method according to embodiment 116, wherein the subject population receiving the combination therapy achieves the median OS improvement for at least about 2.2 months, 2.3 months, 2.4 months, 2.5 months, or 2.6 months relative to the reference population.

[0414] 118. The method according to embodiment 116, wherein the subject population receiving the combination therapy achieved the median OS improvement of approximately 2.4 months relative to the reference population.

[0415] 119. The method according to embodiment 116, wherein the subject population receiving the combination therapy exhibits an overall survival of at least 17 months.

[0416] 120. The method according to embodiment 119, wherein the subject exhibits an overall survival of at least about 17.2 months, about 17.4 months, about 17.6 months, about 17.7 months, about 17.8 months, or about 18 months.

[0417] 121. The method according to implementation scheme 119, wherein the subject exhibits an overall survival of approximately 17.7 months.

[0418] 122. The method according to any one of embodiments 91 to 121, wherein the subject population receiving the combination therapy further achieves an improvement in the time to subsequent therapy (TTST) relative to the reference population.

[0419] 123. The method according to any one of embodiments 91 to 121, wherein, relative to the reference group, the subject group receiving the combination therapy further achieves an improvement in the time to symptomatic progression (TTSP).

[0420] 124. The method according to any one of embodiments 91 to 121, wherein the subject population receiving the combination therapy further achieves an improvement in PFS (PFS2) after the first follow-up therapy, relative to the reference population.

[0421] 125. The method according to any one of embodiments 91 to 121, wherein the subject population receiving the combination therapy further achieves an improvement in treatment interruption time (TTD) relative to the reference population.

[0422] 126. The method according to embodiment 122, wherein the subject population receiving the combination therapy achieves an improvement in TTST for at least about 5 months, about 5.5 months, about 5.6 months, about 6 months, about 6.5 months, or about 7 months, relative to the reference population.

[0423] 127. The method according to embodiment 122, wherein the subject population receiving the combination therapy exhibits at least approximately 12 months of TTST.

[0424] 128. The method according to embodiment 122, wherein the subject population receiving the combination therapy exhibits TTST for approximately 12 months, approximately 12.2 months, or approximately 12.5 months.

[0425] 129. The method according to embodiment 122, wherein the subject population receiving the combination therapy exhibits approximately 12.2 months of TTST.

[0426] 130. The method according to embodiment 122, wherein the subject population receiving the combination therapy exhibited approximately twice the TTST of the reference population at 18 months.

[0427] 131. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieves an improvement in TTSP for at least about 4 months relative to the reference population.

[0428] 132. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieves TTSP improvement for approximately 4 months, approximately 4.2 months, or approximately 4.5 months relative to the reference population.

[0429] 133. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieves approximately 4 months of TTSP improvement relative to the reference population.

[0430] 134. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieves approximately 4.2 months of TTSP improvement relative to the reference population.

[0431] 135. The method according to embodiment 123, wherein the subject population receiving the combination therapy exhibits TTSP for at least about 16 months.

[0432] 136. The method according to embodiment 123, wherein the subject population receiving the combination therapy exhibits TTSP for approximately 16 months.

[0433] 137. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieves a reduction of approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, or approximately 30% of TTSP relative to the reference population.

[0434] 138. The method according to embodiment 123, wherein the subject population receiving the combination therapy achieved a TTSP reduction of approximately 27% at 18 months relative to the reference population.

[0435] 139. The method according to embodiment 124, wherein the subject population receiving the combination therapy achieves a PFS2 improvement of at least about 4 months, about 4.2 months, about 4.4 months, about 4.5 months, about 4.6 months, about 4.8 months, or about 5 months relative to the reference population.

[0436] 140. The method according to embodiment 124, wherein the subject population receiving the combination therapy achieves an improvement in PFS2 for approximately 4 months, approximately 4.2 months, approximately 4.4 months, approximately 4.5 months, approximately 4.6 months, approximately 4.8 months, or approximately 5 months, relative to the reference population.

[0437] 141. The method according to embodiment 124, wherein the subject population receiving the combination therapy achieved an improvement in PFS2 of approximately 4.4 months relative to the reference population.

[0438] 142. The method according to embodiment 124, wherein the subject exhibits PFS2 for at least about 16 months.

[0439] 143. The method according to embodiment 124, wherein the subject exhibits PFS2 for approximately 16 months.

[0440] 144. The method according to embodiment 124, wherein the subject population receiving the combination therapy exhibited a greater PFS2 at 18 months relative to the reference population.

[0441] 145. The method according to embodiment 125, wherein the subject population receiving the combination therapy achieves TTD improvement for at least about 5 months, about 5.3 months, about 5.5 months, about 5.7 months, about 5.9 months, or about 6 months relative to the reference population.

[0442] 146. The method according to embodiment 125, wherein the subject population receiving the combination therapy achieves TTD improvement for approximately 5 months, approximately 5.3 months, approximately 5.5 months, approximately 5.7 months, approximately 5.9 months, or approximately 6 months relative to the reference population.

[0443] 147. The method according to embodiment 125, wherein the subject population receiving the combination therapy exhibits a time to treatment duration (TTD) of at least about 10 months, about 10.2 months, about 10.4 months, about 10.6 months, about 10.8 months, or about 11 months.

[0444] 148. The method according to embodiment 125, wherein the subject population receiving the combination therapy exhibits a time to treatment duration (TTD) of approximately 10 months, approximately 10.2 months, approximately 10.4 months, approximately 10.6 months, approximately 10.8 months, or approximately 11 months.

[0445] 149. The method according to embodiment 125, wherein the number of subjects treated in the subject population administering the combination therapy at 18 months is approximately 5 times that of the reference population.

[0446] Example

[0447] The following examples are provided to further describe some embodiments of the implementations disclosed herein. These examples are intended to illustrate, and not limit, the disclosed implementations.

[0448] Example 1. CHRYSALIS-2 Clinical Trial

[0449] CHRYSALIS-2 (NCT04077463) is an open-label phase 1 / 1b study evaluating the safety and pharmacokinetics of latezitinib as a monotherapy or in combination with ervantumab in participants with advanced non-small cell lung cancer. The study includes multiple cohorts. Results from the LACP (latezitinib, ervantumab, carboplatin, pemetrexed) cohort of 20 patients are presented below.

[0450] method :

[0451] The CHRYSALIS-2 study's LACP cohort enrolled patients with relapsed / refractory EGFR-mutant advanced NSCLC whose disease progressed during or after treatment with EGFR TKIs as a last line of therapy (up to 3 prior lines). Patients received intravenous eleventumab 1400 mg (1750 mg, ≥80 kg) weekly for the first 4 weeks, followed by eleventumab 1750 mg (2100 mg, ≥80 kg) every 3 weeks starting from cycle 3, plus oral 240 mg lazatinib daily, and pemetrexed (500 mg / m²) on a 21-day cycle. 2 ) and carboplatin (AUC5 for the first 4 cycles). Response was assessed by the investigator according to RECIST v1.1.

[0452] result :

[0453] Of the 20 patients recruited, the median age was 61 years (range 38–76 years), 55% were female, 55% were Asian and 40% were white, and there were a median of 2 prior lines of therapy (70% prior to osimertinib, 45% prior to first- or second-generation EGFR TKIs). The objective response rate was 50%, with the median duration of response being unpredictable (median follow-up 13.1 months [range 2.4–17.5] months). Eight of the 10 responders had a response duration of ≥6 months. Eleven (55%) patients were currently receiving treatment; the median progression-free survival (PFS) was 14.0 months (95% CI, 4.3 months – unpredictable). Five patients experienced treatment beyond progression, with an incremental median treatment duration of 4.2 months (range 3.1–7.1) months. Among the 12 patients with a history of brain metastases, the median PFS was 6.7 months (95% CI, 1.4 months – unpredictable). The most common treatment-emergent adverse events (TEAEs) were rash (100%), neutropenia (90%), and infusion-related reactions (65%). The most common ≥ grade 3 TEAEs were neutropenia (70%), thrombocytopenia (25%), and fatigue (25%). For ≥ grade 3 neutropenia, febrile neutropenia, and thrombocytopenia TEAEs, all but two cases of neutropenia resolved completely by day 1 of the subsequent cycle. Fifteen of the 20 patients (75%) experienced cytopenic events during the first four cycles, while two of the 17 patients (12%) experienced cytopenic events on or after the fifth cycle. Five of the seven patients who received colony-stimulating factor for neutropenia did not experience a relapse of neutropenia. Treatment-related dose discontinuation, reduction, and interruption occurred in 18 patients (90%), 14 patients (70%), and 8 patients (40%), respectively; no patients discontinued all study agents due to TEAE.

[0454] Conclusion: In patients with EGFR-mutant advanced NSCLC who experienced disease progression while receiving EGFR TKIs, ervantuzumab, lazatinib, plus chemotherapy demonstrated a meaningful and durable response rate.

[0455] Example 2. MARIPOSA-2 Clinical Study

[0456] MARIPOSA-2 was a randomized, open-label, active-controlled, parallel, multicenter phase 3 study comparing the efficacy and safety of group A (lazatinib, ervantumab, carboplatin, and pemetrexed "LACP / ACP-L") versus group B (carboplatin and pemetrexed "CP") and group C (ervantumab, carboplatin, and pemetrexed "ACP") versus group B (CP) in participants with EGFR-mutant locally advanced or metastatic non-squamous NSCLC who had progressed during or after osimertinib treatment. Study IDs included: NCT04988295, CR109061, 2021-001825-33 (EudraCT), and 61186372NSC3002.

[0457] The aim of this study was to evaluate the efficacy of adding lazatinib to ervantumab, carboplatin, and pemetrexed (LACP / ACP-L dosing strategy) after osimertinib failure in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19del or exon 21 L858R substitution, and to compare the efficacy of ervantumab, carboplatin, and pemetrexed (ACP) with carboplatin and pemetrexed (CP). The expanded cohort aimed to further characterize the safety and efficacy of the ACP-L dosing regimen compared to ACP with additional data.

[0458] Research Design

[0459] The original study design of MARIPOSA-2 had three groups with a randomization ratio of 2:2:1 for LACP, CP, and ACP. The primary objective was to compare LACP and CP, with the ACP group used in the study to demonstrate the contribution of latezatitinib. A decision was made to modify MARIPOSA-2 to achieve the dual primary hypotheses of comparing ACP with CP and LACP with CP.

[0460] Group A was ultimately modified to discontinue latezitinib during carboplatin administration. The modified dosing regimen that initiated latezitinib after completion of carboplatin treatment is referred to as ACP-L; the previous dosing regimen (i.e., participants started latezitinib from the start of treatment) is referred to as LACP. Preliminary statistical analyses compared all participants randomly assigned between groups A and B, regardless of dosing regimen, and compared all participants randomly assigned between groups C and B based on treatment intent.

[0461] To further characterize the safety and efficacy of the modified ACP-L dosing regimen compared to ACP, a separate open-label, randomized expansion cohort was added to the study. Participant enrollment in the expansion cohort began after enrollment in the primary study was completed. The expansion cohort had the same eligibility criteria and study procedures as the primary study and operated within the same study setting. In the expansion cohort, participants were planned to be randomly assigned to the study treatment groups (A2 and C2 groups, respectively) at a 2:1 ratio.

[0462] Data from the extended cohort were not included in the preliminary analysis. The preliminary analysis of group A, as pre-specified in the Statistical Analysis Plan (SAP), pooled data from participants treated with LACP and ACP-L. Due to limited follow-up of participants receiving ACP-L in the primary study and extended cohort, a complete comparison of ACP-L with CP was not within the scope of this analysis. Figure 1 The diagrams designed for this study are provided in the document.

[0463] Inclusion / Exclusion Criteria .

[0464] Eligible patients are 18 years of age or older with locally advanced or metastatic NSCLC that has progressed during or after osimertinib monotherapy (as the most recent line of treatment) and has an EGFR Ex19del or L858R mutation. Patients with brain metastases are eligible if their intracranial disease is stable, asymptomatic, and their steroid dose remains constant. Additional information regarding the criteria is provided below.

[0465] Inclusion criteria :

[0466] • According to the Evaluation Criteria for Solid Tumor Response (RECIST) version 1.1, participants must have at least one measurable lesion that has not previously received radiotherapy;

[0467] • Participants must have histologically or cytologically confirmed locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), characterized by having an epidermal growth factor receptor (EGFR) exon 19del or exon 21 L858R mutation at the time of or after diagnosis of locally advanced or metastatic disease.

[0468] • Participants with a history of brain metastases must be treated for all lesions as clinically indicated (i.e., no current indication for further definitive local therapy). Any definitive local therapy for brain metastases must have been completed at least 14 days prior to randomization, and participants may be receiving no more than 10 mg of prednisone or its equivalent daily for the treatment of intracranial disease;

[0469] • Participants must have an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1;

[0470] • Any toxicity from previous systemic anticancer therapy must have regressed to Grade 1 or baseline level according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (except for alopecia [any grade], grade <=2 peripheral neuropathy, or grade <=2 hormone replacement-stable hypothyroidism).

[0471] • Women of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment, and must consent to further serum or urine pregnancy tests during the study period;

[0472] • Participants must have progressed on or after osimertinib monotherapy as their most recent line of treatment. Osimertinib must have been administered as first-line treatment for locally advanced or metastatic disease, or in a second-line scenario following prior treatment with a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as monotherapy. Participants receiving any type of neoadjuvant and / or adjuvant therapy are eligible if progression to locally advanced or metastatic disease occurs at least 12 months after the last dose of such therapy, and the participant then progresses in a locally advanced or metastatic scenario on or after osimertinib administration. Treatment with osimertinib must be interrupted at least 8 days (4 half-lives) prior to randomization (i.e., the last dose no later than day -8).

[0473] Exclusion criteria :

[0474] • Participants received palliative radiation therapy for NSCLC less than 14 days prior to randomization;

[0475] • Participants with symptomatic or progressive brain metastases;

[0476] • Participants have a history of or current evidence of leptomeningeal disease, or participants have spinal cord compression that has not been clearly treated with surgery or radiation.

[0477] • Participants have a known small cell transformation;

[0478] • Participants had a history of interstitial lung disease (ILD), including drug-induced ILD or radiation-induced pneumonia;

[0479] • Participants have a clinically significant cardiovascular history, including but not limited to a diagnosis of deep vein thrombosis or pulmonary embolism; myocardial infarction; unstable angina; stroke; transient ischemic attack; coronary artery / peripheral artery bypass grafting; or acute coronary syndrome within 4 weeks prior to randomization. Participants have a significant genetic predisposition to venous thromboembolic events. Participants have a history of venous thromboembolic events and have not received appropriate anticoagulation treatment as per national comprehensive cancer network or local guidelines.

[0480] Treatment duration / Trial duration :

[0481] The study comprises a screening period, a treatment period, and a follow-up period. Participants must complete the screening procedure within 28 days prior to randomization. The treatment period begins on day 1 of cycle 1 and continues in 21-day cycles until the end-of-treatment visit, which will be conducted within 30 days of treatment interruption or before initiation of subsequent systemic therapy, whichever occurs first. During the follow-up period, the survival and symptomatic progression of participants who discontinue treatment for any reason will be tracked. The follow-up period begins after the end-of-treatment visit and continues until death, loss to follow-up, or withdrawal of consent, whichever occurs first.

[0482] Main research group :

[0483] Group A

[0484] Dosing regimen 1 (LACP) :

[0485] Lazatinib 240 mg orally, once daily.

[0486] • Administer ervantumab intravenously (IV) in a 21-day cycle:

[0487] • Administer 1,400 mg (or 1,750 mg if body weight ≥80 kg) on ​​days 1 / 2 of cycle 1 (divided doses), days 8 and 15, and day 1 of cycle 2.

[0488] • Starting from cycle 3, administer 1,750 mg on day 1 of each 21-day cycle (or 2,100 mg if body weight ≥ 80 kg).

[0489] • Administer carboplatin and pemetrexed as in Group B.

[0490] Dosing regimen 2 (ACP-L) :

[0491] • Start oral lazazinib 240 mg once daily from day 1 of cycle 5, or earlier if carboplatin is discontinued earlier.

[0492] • Administer ervantumab via intravenous infusion over a 21-day cycle:

[0493] • Administer 1,400 mg (or 1,750 mg if body weight ≥80 kg) on ​​days 1 / 2 of cycle 1 (divided doses), days 8 and 15, and day 1 of cycle 2.

[0494] • Starting from cycle 3, administer 1,750 mg on day 1 of each 21-day cycle (or 2,100 mg if body weight ≥ 80 kg).

[0495] • Administer carboplatin and pemetrexed as in Group B.

[0496] Group B (CP) :

[0497] • Administer carboplatin AUC 5 on day 1 of each 21-day cycle, for up to 4 cycles.

[0498] • Administer pemetrexed 500 mg / m² with carboplatin on day 1 of each 21-day cycle. 2 This treatment lasts for up to four cycles, and then is used as a maintenance therapy until disease progression.

[0499] Group C (ACP) :

[0500] • Administer ervantumab according to the regimen in Group A.

[0501] • Administer carboplatin and pemetrexed as in Group B.

[0502] Primary endpoint and secondary endpoint :

[0503]

[0504] result :

[0505] As mentioned above, MARIPOSA-2 (NCT04988295) is a randomized, open-label phase 3 study evaluating RYBREVANT. ® Efficacy and safety of two dosing regimens: erybrivuzumab and chemotherapy. Patients with locally advanced or metastatic EGFR ex19del or L858R-replaced NSCLC who have disease progression during or after osimertinib administration will be randomized to receive rybrivuzumab. ® In addition to chemotherapy, with rybrivant ®Treatment included chemotherapy in combination with lazazetinib or chemotherapy alone. For each experimental group, dual primary endpoints were used to compare with chemotherapy alone, such as PFS assessed by blinded independent central review (BICR) (using RECIST v1.1 guidelines). Secondary endpoints included objective response, overall survival (OS), duration of response (DoR), time to follow-up therapy, PFS after the first follow-up therapy (PFS2), and intracranial PFS, as assessed by BICR. All study participants underwent continuous brain imaging to allow robust assessment of intracranial endpoints and to evaluate RYBREVANT with and without lazazetinib. ® Central nervous system (CNS) activity. Because brain metastases can lead to a significant burden and adverse outcomes for patients, this aspect of the study design provides crucial information in an area of ​​high unmet need. The study recruited 657 participants who had locally advanced or metastatic EGFR exon 19 deletion (ex19del) or L858R substitution non-small cell lung cancer (NSCLC) at or after osimertinib administration and subsequent disease progression.

[0506] Below is a summary of positive topline results from the Phase 3 MARIPOSA-2 study, which evaluated RYBREVANT in combination with and without lazatinib and chemotherapy (carboplatin and pemetrexed). ® (Ervantuzumab). This study met its dual primary endpoint, demonstrating statistically significant and clinically meaningful improvements in PFS compared to chemotherapy alone in both experimental treatment groups. Regarding the addition of RYBREVANT to chemotherapy... ® No new safety signals were detected.

[0507] A total of 657 participants were randomized in the primary study (ACP: 131; LACP / ACP-L: 263; CP: 263) and included in this primary analysis. Key efficacy results are summarized in Table 1A. At the clinical cutoff (CCO), the median study follow-up was 8.74 months, and 371 PFS events were observed via BICR.

[0508] Table 1A: Key Efficacy Results

[0509]

[0510]

[0511] Efficacy Results :

[0512] The median progression-free survival (PFS) determined through blinded independent central review was 6.3 months (95% CI, 5.55 to 8.4) for ervantumab-chemotherapy, 8.3 months (95% CI, 6.8 to 9.1) for ervantumab-lazatinib-chemotherapy, and 4.2 months (95% CI, 4.0 to 4.4) for chemotherapy alone. The hazard ratio for disease progression or death for ervantumab-chemotherapy versus chemotherapy alone was 0.48 (95% CI, 0.36 to 0.64; P < 0.001), and ervantumab-lazatinib-chemotherapy versus chemotherapy alone was similar in magnitude (0.44; 95% CI, 0.35 to 0.56; P < 0.001).

[0513] The investigator-assessed median progression-free survival was 8.2 months (95% CI, 6.8 to 10.9) for ervantumab-chemotherapy and 8.3 months (95% CI, 7.1 to 9.9) for ervantumab-lazatinib-chemotherapy, while it was 4.2 months (95% CI, 4.0 to 4.5) for chemotherapy, corresponding to similar hazard ratios of 0.41 and 0.38 for disease progression or death, respectively (compared to chemotherapy, P < 0.001).

[0514] The progression-free survival benefit was consistent across predefined subgroups of ervantumab-chemotherapy and was similar in magnitude to that of ervantumab-lazetinib-chemotherapy, including subgroups based on history of brain metastases, osimertinib therapy line, and EGFR mutation type.

[0515] The objective response rate (ORR) for ervantumab-chemotherapy was 64% (95% CI, 55 to 72), for ervantumab-lazatinib-chemotherapy it was 63% (95% CI, 57 to 69), and for chemotherapy it was 36% (95% CI, 30 to 42). Evantumab-chemotherapy (odds ratio, 3.10; 95% CI, 2.00 to 4.80; P < 0.001) and ervantumab-lazatinib-chemotherapy (odds ratio, 2.97; 95% CI, 2.08 to 4.24; P < 0.001) showed similar significant improvements compared to chemotherapy alone. In patients with confirmed responses, the median duration of response for ervantumab-chemotherapy was 6.9 months (95% CI, 5.5 to unpredictable), the median duration of response for ervantumab-lazatinib-chemotherapy was 9.4 months (95% CI, 6.9 to unpredictable), and the median duration of response for chemotherapy was 5.55 months (95% CI, 4.2 to 9.6).

[0516] The study observed 161 deaths, and a trend favoring ervantumab-chemotherapy versus chemotherapy for improved overall survival was observed (hazard ratio, 0.77; 95% CI, 0.49 to 1.21). For ervantumab-lazatinib-chemotherapy versus chemotherapy, a harmless effect was observed (hazard ratio, 0.96; 95% CI, 0.67 to 1.35).

[0517] The median intracranial progression-free survival (PFS) for ervantumab-chemotherapy was 12.45 months (95% CI, 10.8 to inestimable), for ervantumab-lazatinib-chemotherapy it was 12.8 months (95% CI, 11.1 to 14.3), and for chemotherapy alone it was 8.3 months (95% CI, 7.3 to 11.3). The improvement from ervantumab-chemotherapy compared to chemotherapy was significant (hazard ratio for disease progression or death, 0.55; 95% CI, 0.38 to 0.79; P = 0.001) and similar in magnitude to that from ervantumab-lazatinib-chemotherapy compared to chemotherapy alone (hazard ratio for disease progression or death, 0.58; 95% CI, 0.44 to 0.78; P < 0.001).

[0518] Due to limited follow-up of participants who received ACP-L in the primary study and extended cohort to date, a comparison of ACP-L with CP is not within the scope of this analysis and will be further evaluated when additional data become available.

[0519] discuss

[0520] Compared with chemotherapy, eptamab-chemotherapy and eptamab-lazatinib-chemotherapy significantly prolonged progression-free survival, reducing the risk of disease progression or death by 52% and 56%, respectively. Early separation of the curves was observed between eptamab-chemotherapy and eptamab-lazatinib-chemotherapy versus chemotherapy. The progression-free survival benefit was consistent across predefined subgroups. The orders of magnitude of improvement between eptamab-chemotherapy and eptamab-lazatinib-chemotherapy compared with chemotherapy were similar.

[0521] Evantumab is a large molecule and is not expected to cross the blood-brain barrier easily. This is one of the key driving factors for including lazatinib (a known CNS-active TKI) in the vantumab-lazatinib-chemotherapy group. Therefore, it is noteworthy that vantumab-chemotherapy has demonstrated similar advantages over chemotherapy in terms of intracranial progression-free survival. These findings suggest that vantumab exerts an antitumor effect intracranially, whether through direct binding to intracranial metastases or indirectly through immune-based mechanisms remains unclear. Despite the continued frequent use of TKIs for CNS progression considerations, previous prospective trials have not shown improved clinical outcomes with this approach.

[0522] Resistance to osimertinib is diverse, polyclonal, and difficult to treat. Currently, there are no approved targeted therapies in the post-osimertinib scenario. Recently, two studies of immunotherapy-chemotherapy regimens failed to demonstrate efficacy in the TKI-resistant scenario. Currently, six other phase 3 studies (NCT05261399, NCT04765059, NCT05089734, NCT05338970, NCT04656652, NCT05184712) are investigating targeted therapy combinations versus chemotherapy as second-line (or later) treatment for EGFR-mutant advanced NSCLC, highlighting unmet needs in this patient population.

[0523] Overall, in patients with EGFR-mutant advanced NSCLC whose disease progressed during or after osimertinib monotherapy, ervantumab-chemotherapy and ervantumab-lazetinib-chemotherapy had significantly longer progression-free survival compared to chemotherapy.

[0524] Updated data: Post-progression outcomes and additional safety data from MARIPOSA-2

[0525] As described below, post-progression outcomes and additional safety data from MARIPOSA-2 are evaluated.

[0526] Methods: The following analysis focuses on 131 patients randomized to ervantumab-chemotherapy (safety pool: n=130) and 263 patients randomized to chemotherapy (safety pool: n=243). A third group (ervantumab-lazatinib-chemotherapy) was modified during the study and will be reported in the future. Post-progression endpoints were time to treatment interruption (TTD), time to follow-up therapy (TTST), and progression-free survival (PFS) after the first follow-up therapy (PFS2).

[0527] Results: At a median follow-up of 8.7 months (mo), 55 / 130 patients (42%) in the ervantumab-chemotherapy group and 173 / 243 patients (71%) in the chemotherapy group had progressive disease (PD). Among those with PD, 19 / 55 patients (35%) in the ervantumab-chemotherapy group and 28 / 173 patients (16%) in the chemotherapy group received treatment for >4 weeks after progression, with median (95% CI) treatment duration after progression of 18.3 (9.0–NE) and 9.0 (6.0–16.4) weeks, respectively. Compared with chemotherapy, ervantumab-chemotherapy significantly prolonged TTD (median, 11.0 months vs. 4.5 months with chemotherapy; HR, 0.37 [95% CI, 0.28–0.50]; P<0.0001), TTST (median, 12.1 months vs. 6.6 months with chemotherapy; HR, 0.42 [95% CI, 0.30–0.59]; P<0.0001), and PFS2 (median, 13.9 months vs. 11.3 months with chemotherapy; HR, 0.60 [95% CI, 0.40–0.92]; P=0.017). Among patients with PD, 75% (41 / 55) in the ervantumab-chemotherapy group discontinued treatment after progression, compared to 93% (161 / 173) in the chemotherapy group. In patients who underwent eptamab-chemotherapy, 63% (26 / 41) and 63% (101 / 161) of patients who underwent chemotherapy initiated their first subsequent systemic therapy. The most common subsequent therapies were osimertinib and docetaxel in both groups. In patients who underwent eptamab-chemotherapy, the first onset of adverse events such as cytopenia, skin conditions, and fatigue was highest in the first 4 months and decreased over time.

[0528] in conclusion Evantuximab-chemotherapy significantly prolonged TTD, TTST, and PFS2 compared to chemotherapy alone. Evantuximab-chemotherapy represents a new standard of care for patients with EGFR-mutant advanced NSCLC whose disease has progressed after osimertinib administration.

[0529] Updated data: Secondary analysis of patient-related endpoints from MARIPOSA-2

[0530] The following provides an evaluation of the time to symptomatic progression (TTSP) and patient-reported outcomes (PRO) for MARIPOSA-2.

[0531] methodThe following analysis included 131 patients randomized to ervantumab-chemotherapy and 263 patients randomized to chemotherapy (intent-to-treat group [ITT]). TTSP was defined as the time from randomization to the onset of new / worsening lung cancer symptoms requiring a change in cancer therapy or death (whichever occurred first). Patient-reported outcomes (PROs) were measured using the EORTC-QLQ-C30, NSCLC-SAQ, and PROMIS-PF 8c instruments.

[0532] result At a median follow-up of 8.7 months, a trend toward improvement in median TTSP was observed between ervantumab-chemotherapy and chemotherapy (14.9 months vs. 13.0 months; HR, 0.74 [95% CI, 0.51–1.07]; P = 0.10).

[0533] The median duration of treatment with ervantumab-chemotherapy was 6.3 months, compared to 3.7 months with chemotherapy. At 6 months (189 days), the percentage of ITT patients maintaining treatment and having improved or stable physical function relative to baseline was 37% for ervantumab-chemotherapy and 21% for chemotherapy. For ervantumab-chemotherapy versus chemotherapy, the percentages of patients with improved or stable emotional function (38% vs. 21%), cognitive function (38% vs. 20%), role function (30% vs. 19%), and overall health status (40% vs. 19%) were significantly higher.

[0534] Based on data from the EORTC-QLQ-C30, in the ervantumab-chemotherapy group versus chemotherapy group, at 6 months, 28% and 13% of patients reported no dyspnea, 23% and 15% reported no pain, and 10% and 5% reported no fatigue, respectively. According to the EORTC-QLQ-C30, compared to chemotherapy alone, more patients in the ervantumab-chemotherapy group reported improved / stabilized function or absence of key symptoms.

[0535] According to the NSCLC-SAQ, ervantuzumab-chemotherapy significantly prolonged the time to persistent worsening of lung cancer symptoms compared to chemotherapy alone (11.6 months vs. 8.5 months).

[0536] According to PROMIS-PF 8c, ervantuzumab versus chemotherapy numerically prolonged the time to persistent deterioration of bodily function (11.6 months vs. 9.4 months).

[0537] Conclusion: Compared with chemotherapy, ervantumab-chemotherapy numerically prolonged the time to symptomatic progression. In the ITT population, more patients reported improved or stable function and were symptom-free in ervantumab-chemotherapy compared to chemotherapy alone. In patients with EGFR-mutant advanced NSCLC who progressed after osimertinib administration, the PFS benefit of ervantumab-chemotherapy was achieved while maintaining a low disease burden and high levels of function.

[0538] Example 3. Evans in EGFR-mutant advanced non-small cell lung cancer after disease progression following osimertinib administration. Toxomab plus chemotherapy vs. chemotherapy: MARIPOSA-2's second-stage overall survival

[0539] background In the phase 3 MARIPOSA-2 study (NCT04988295), ervantumab (ami)-chemotherapy (chemo; carboplatin / pemetrexed) demonstrated superior progression-free survival (PFS) compared to chemotherapy in patients (pt) with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who progressed after osimertinib administration (osi; HR, 0.48; 95% CI, 0.36–0.64; P<0.001). A favorable trend of ervantumab-chemotherapy versus chemotherapy was observed in the first interim analysis (IA) of overall survival (OS; median follow-up: 8.7 months) (HR, 0.77; 95% CI, 0.49–1.21). The second IA (IA2) of OS and post-progression outcomes are reported.

[0540] method MARIPOSA-2 recruits patients with EGFR-mutant (Ex19del / L858R) advanced NSCLC who have received osimertinib treatment. The primary endpoint is progression-free survival (PFS). An IA2 assessment of OS is pre-specified when approximately 75% of all OS events are observed. OS will be evaluated using a two-sided alpha value of 0.0142 (O'Brien-Fleming alpha depletion method, as performed via the Lan-DeMets method). Other endpoints include time to treatment interruption (TTD), time to follow-up therapy (TTST), and PFS following the first follow-up therapy (PFS2).

[0541] resultAt IA2, 208 OS events were observed in both groups. After a median follow-up of 18.1 months, ervantumab-chemotherapy showed a numerical improvement in OS compared to chemotherapy (median, 17.7 months vs. 15.3 months; HR, 0.73; 95% CI, 0.54–0.99; P=0.039), but did not reach the pre-specified significance threshold. At 18 months, 50% of patients were alive compared to chemotherapy, and 40% were alive compared to chemotherapy alone. The OS benefit of ervantumab-chemotherapy compared to chemotherapy was generally consistent across predefined subgroups. A significant prolongation of PFS2 in ervantumab-chemotherapy compared to chemotherapy (median, 16.0 months vs. 11.6 months; HR, 0.64; 95% CI, 0.48–0.85; P=0.002) and improvement over time supported the OS findings. Significantly prolonged TTD and TTST are favorable for ervantumab-chemotherapy (Table 2).

[0542] Table 2. Efficacy Results

[0543]

[0544] Figure 2 The MARIPOSA-2 study design is shown. Secondary / exploratory efficacy endpoints reported include: overall survival (OS); time to symptomatic progression (TTSP); time to treatment interruption (TTD); time to follow-up therapy (TTST); and progression-free survival (PFS) after the first follow-up therapy (PFS2). A second interim analysis of OS was pre-specified when approximately 75% of planned OS events were observed. The significance level of the second interim analysis of OS was determined based on the O'Brien-Fleming α exhaustion method (two-sided α: 0.0142) implemented using the Lan-DeMets method.

[0545] Figure 3 Overall survival is shown. Evantuximab-chemotherapy versus chemotherapy showed a clear and improving trend in OS. P-values ​​were calculated using a log-rank test stratified by osimertinib line of therapy (first-line vs. second-line), history of brain metastases (yes or no), and Asian ethnicity (yes or no). OS was assessed with a two-sided alpha value of 0.0142.

[0546] Figure 4The time to symptomatic progression (TTSP) is shown as the time from randomization to the onset of a new symptom or worsening of symptoms that researchers consider relevant to lung cancer and requires modification of anticancer treatment and / or clinical intervention to manage the symptoms. Evantumab-chemotherapy significantly improved TTSP compared to chemotherapy alone. b- In previous analyses, vantumab-chemotherapy numerically improved TTSP compared to chemotherapy (HR, 0.74; 95% CI, 0.51–1.07; P = 0.10). P-values ​​were calculated using a log-rank test stratified by osimertinib line of therapy (first-line vs. second-line), history of brain metastases (yes or no), and Asian ethnicity (yes or no).

[0547] Figure 5 The treatment interruption time (TTD, the time from randomization to the interruption of all study treatments for any reason, including disease progression, treatment toxicity, or death, is shown.) In previous analyses, ervantuzumab-chemotherapy significantly prolonged the TTD compared to chemotherapy alone (HR, 0.37; 95% CI, 0.28–0.50; P < 0.0001). The 1 cP values ​​were derived from a log-rank test stratified by osimertinib therapy line (first-line vs. second-line), history of brain metastases (yes or no), and Asian ethnicity (yes or no).

[0548] Figure 6 The time to follow-up therapy is shown (from the date of randomization to the date of initiation of follow-up anticancer therapy after study treatment interruption or death, whichever occurs first). Evantumab-chemotherapy significantly prolonged TTST compared to chemotherapy alone. b- In previous analyses, vantumab-chemotherapy significantly prolonged TTST compared to chemotherapy alone (HR, 0.42; 95% CI, 0.30–0.59; P<0.0001). 1 P- values ​​were determined using a log-rank test stratified by osimertinib therapy line (first-line vs. second-line), history of brain metastases (yes or no), and Asian ethnicity (yes or no).

[0549] Figure 7 PFS (PFS2, the time from randomization to the date of the second objective disease progression or death following the initiation of subsequent anticancer therapy based on investigator assessment (after the assessment used for PFS) is shown). Evantumab-chemotherapy significantly prolonged PFS2 compared to chemotherapy alone. b- In previous analyses, vantumab-chemotherapy significantly prolonged PFS2 compared to chemotherapy alone (HR, 0.60; 95% CI, 0.40–0.92; P=0.017). P-values ​​were calculated using a log-rank test stratified by osimertinib therapy line (first-line vs. second-line), history of brain metastases (yes or no), and Asian ethnicity (yes or no). No single therapy category was identified as the most prominent subsequent therapy, highlighting the limited options in the three-line scenario.

[0550] Conclusion: In EGFR-mutant advanced NSCLC, ervantuximab-chemotherapy numerically improved overall survival (OS) and significantly prolonged post-progression outcomes compared to chemotherapy after osimertinib administration. At a median follow-up of 18.1 months, the data continued to favor ervantuximab-chemotherapy over chemotherapy, with a promising trend toward OS improvement in the osimertinib-administered scenario (median, 17.7 months vs. 15.3 months; HR, 0.73; P = 0.039).

[0551] Post-progression endpoints showed significant and sustained improvement with ervantuximab-chemotherapy compared to chemotherapy:

[0552] -Time to symptomatic progression (HR, 0.73; P = 0.026)

[0553] - Treatment interruption time (HR, 0.42; P < 0.0001)

[0554] -Time to administer follow-up therapy (HR, 0.51; P < 0.0001)

[0555] - Progression-free survival after the first follow-up therapy (HR, 0.64; P=0.002).

[0556] The combination of ervantomab's multi-target MoA and immune cell-directed activity with the anti-tumor effects of chemotherapy may contribute to the observed durability.

[0557] These MARIPOSA-2 follow-up results confirm the superior results of ervantuzumab-chemotherapy versus chemotherapy in EGFR-mutant advanced NSCLC after disease progression following osimertinib administration.

[0558] * * *

[0559] This invention is not limited to the specific embodiments described herein. In fact, various modifications of the invention will become apparent to those skilled in the art from the foregoing description, in addition to those described herein. Such modifications are intended to fall within the scope of the appended claims.

[0560] All patents, applications, publications, test methods, documents and other materials cited herein are incorporated herein by reference in their entirety as if they were physically present in this specification.

Claims

1. A method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising: (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody (ii) Treatment with an effective dose of carboplatin, and (iii) Treat with an effective dose of pemetrexed. The improvement in median PFS is relative to the median PFS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, and who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

2. The method according to claim 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO:

12.

3. The method of claim 1 or claim 2, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

4. The method of claim 3, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

5. The method of claim 3, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

6. The method according to any one of claims 1 to 5, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

7. The method according to any one of claims 1 to 5, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

8. The method according to any one of claims 1 to 5, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

9. The method according to any one of claims 1 to 5, wherein the at least one prior TKI comprises osimertinib.

10. The method according to any one of claims 1 to 9, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

11. The method according to any one of claims 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

12. The method according to any one of claims 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

13. The method according to claims 1 to 12, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

14. The method of claim 13, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

15. The method of claim 14, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

16. The method of claim 15, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

17. The method of claim 14, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

18. The method of claim 14, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

19. The method of claim 18, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

20. The method of claim 14, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

21. The method according to any one of claims 1 to 20, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

22. The method according to any one of claims 1 to 21, wherein the method comprises administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

23. The method of claim 22, wherein the method comprises: a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3. as well as b) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles; as well as c) On day 1 of each 21-day cycle, use carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

24. The method of claim 23, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

25. The method of any one of claims 1 to 24, wherein the combination therapy achieves the median PFS improvement for at least two weeks.

26. The method of claim 25, wherein the combination therapy achieves at least one month of improvement in median PFS.

27. The method of claim 26, wherein the combination therapy achieves at least 1.5 months of improvement in median PFS.

28. The method of claim 27, wherein the combination therapy achieves at least a 2-month improvement in median PFS.

29. The method of claim 28, wherein the subject exhibits at least 4.5 months of progression-free survival.

30. The method of claim 29, wherein the subject exhibits at least 5 months of progression-free survival.

31. The method of claim 30, wherein the subject exhibits at least 5.5 months of progression-free survival.

32. The method of claim 31, wherein the subject exhibits at least 6 months of progression-free survival.

33. The method of claim 32, wherein the subject exhibits at least 10 months of progression-free survival.

34. The method of claim 33, wherein the subject exhibits at least 12 months of progression-free survival.

35. The method of claim 34, wherein the subject exhibits at least 14 months of progression-free survival.

36. The method according to any one of claims 1 to 35, wherein the combination therapy further improves the objective response relative to the reference population.

37. The method according to any one of claims 1 to 36, wherein the combination therapy further improves overall survival (OS) relative to the reference population.

38. The method according to any one of claims 1 to 37, wherein the combination therapy further improves the duration of response (DoR) relative to the reference population.

39. The method according to any one of claims 1 to 38, wherein the combination therapy further improves the time required for subsequent therapies relative to the reference population.

40. The method according to any one of claims 1 to 39, wherein the combination therapy further improves PFS (PFS2) after the first follow-up therapy relative to the reference population.

41. The method according to any one of claims 1 to 40, wherein the combination therapy further improves median intracranial PFS relative to the reference population.

42. A method for improving median progression-free survival (PFS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising: (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate. (iii) Treatment with an effective dose of carboplatin, and (iv) Treat with an effective dose of pemetrexed. The improvement in median PFS is relative to the median PFS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody, nor lazatinib or its pharmaceutically acceptable salts or hydrates.

43. The method of claim 41, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO:

12.

44. The method of claim 42 or claim 43, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

45. The method of claim 44, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

46. ​​The method of claim 44, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

47. The method according to any one of claims 42 to 46, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

48. The method according to any one of claims 42 to 46, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

49. The method according to any one of claims 42 to 46, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

50. The method according to any one of claims 42 to 46, wherein the at least one prior TKI comprises osimertinib.

51. The method according to any one of claims 42 to 50, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

52. The method according to any one of claims 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

53. The method according to any one of claims 42 to 51, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

54. The method according to any one of claims 42 to 53, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

55. The method of claim 54, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

56. The method of claim 55, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

57. The method of claim 56, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

58. The method of claim 55, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

59. The method of claim 55, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

60. The method of claim 59, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

61. The method of claim 55, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

62. The method according to any one of claims 42 to 61, wherein the lazazetinib or a pharmaceutically acceptable salt or hydrate thereof is lazazetinib mesylate.

63. The method according to any one of claims 42 to 61, wherein the lazazetinib or a pharmaceutically acceptable salt or hydrate thereof is lazazetinib mesylate monohydrate.

64. The method according to any one of claims 42 to 63, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily at a dose of about 240 mg.

65. The method of claim 64, wherein the method comprises orally administering lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily at a dose of about 240 mg, starting from day 1 of cycle 5 or earlier if carboplatin is discontinued earlier.

66. The method according to any one of claims 42 to 65, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

67. The method according to any one of claims 42 to 66, wherein the method comprises administering carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

68. The method of claim 67, wherein the method comprises: a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3. as well as b)(i) Administer the lazazetinib or its pharmaceutically acceptable salt or hydrate orally once daily at a dose of approximately 240 mg; or (ii) Begin oral administration of lazatinib or its pharmaceutically acceptable salt or hydrate once daily at a dose of approximately 240 mg, starting on day 1 of cycle 5 or earlier if carboplatin is discontinued earlier. as well as c) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles; as well as d) On day 1 of each 21-day cycle, administer carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

69. The method of claim 68, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

70. The method of any one of claims 42 to 69, wherein the combination therapy achieves the median PFS improvement for at least two weeks.

71. The method of claim 70, wherein the combination therapy achieves at least one month of improvement in median PFS.

72. The method of claim 71, wherein the combination therapy achieves at least 1.5 months of improvement in median PFS.

73. The method of claim 72, wherein the combination therapy achieves at least a 2-month improvement in median PFS.

74. The method of claim 73, wherein the subject exhibits at least 4.5 months of progression-free survival.

75. The method of claim 74, wherein the subject exhibits at least 5 months of progression-free survival.

76. The method of claim 75, wherein the subject exhibits at least 5.5 months of progression-free survival.

77. The method of claim 76, wherein the subject exhibits at least 6 months of progression-free survival.

78. The method of claim 77, wherein the subject exhibits at least 10 months of progression-free survival.

79. The method of claim 78, wherein the subject exhibits at least 12 months of progression-free survival.

80. The method of claim 79, wherein the subject exhibits at least 14 months of progression-free survival.

81. The method according to any one of claims 42 to 80, wherein the combination therapy further improves the objective response relative to the reference population.

82. The method according to any one of claims 42 to 81, wherein the combination therapy further improves overall survival (OS) relative to the reference population.

83. The method according to any one of claims 42 to 82, wherein the combination therapy further improves the duration of response (DoR) relative to the reference population.

84. The method according to any one of claims 42 to 83, wherein the combination therapy further improves the time required for subsequent therapies relative to the reference population.

85. The method according to any one of claims 42 to 84, wherein the combination therapy further improves PFS (PFS2) after the first follow-up therapy relative to the reference population.

86. The method according to any one of claims 42 to 85, wherein the combination therapy further improves median intracranial PFS relative to the reference population.

87. A method for improving median overall survival (OS) in a subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, said subject population whose NSCLC progresses during or after treatment with at least one prior tyrosine kinase inhibitor (TKI), said method comprising administering a combination therapy to said subject population, said combination therapy comprising: (i) Therapeutic effective dose of bispecific anti-EGFR / c-Met antibody (ii) Treatment with an effective dose of carboplatin, and (iii) Treat with an effective dose of pemetrexed. The improvement in median OS is relative to the median OS of a reference group of subjects with NSCLC carrying one or more EGFR mutations who had progressed during or after treatment with the at least one prior TKI, and who had been given carboplatin and pemetrexed but not the bispecific anti-EGFR / c-Met antibody.

88. The method of claim 87, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO:

12.

89. The method of claim 87 or claim 88, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

90. The method of claim 89, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

91. The method of claim 89, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

92. The method according to any one of claims 87 to 91, wherein the at least one prior TKI comprises a first-generation EGFR TKI.

93. The method according to any one of claims 87 to 91, wherein the at least one prior TKI comprises a second-generation EGFR TKI.

94. The method according to any one of claims 87 to 91, wherein the at least one prior TKI comprises a third-generation EGFR TKI.

95. The method according to any one of claims 87 to 91, wherein the at least one prior TKI comprises osimertinib.

96. The method according to any one of claims 87 to 95, wherein the administration of the combination therapy begins on day 1 of the first cycle of the first 21-day cycle and continues in subsequent 21-day cycles.

97. The method according to any one of claims 87 to 96, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

98. The method according to any one of claims 87 to 96, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

99. The method according to any one of claims 87 to 98, wherein the method comprises administering the bispecific anti-EGFR / c-Met antibody in an amount between about 140 mg and about 2240 mg.

100. The method of claim 99, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 1750 mg, 2100 mg, or 2240 mg.

101. The method of claim 100, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

102. The method of claim 101, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

103. The method of claim 100, wherein if the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3.

104. The method of claim 100, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2.

105. The method of claim 104, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

106. The method of claim 100, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3.

107. The method according to any one of claims 87 to 106, wherein the method comprises administering the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles.

108. The method according to any one of claims 87 to 107, wherein the method comprises administering the carboplatin at approximately 500 mg / m² on day 1 of each 21-day cycle. 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

109. The method of claim 108, wherein the method comprises: a)(i) If the subject has a weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1400 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (ii) If the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on day 1 of each 21-day cycle, starting from cycle 3; or (iii) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 1750 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2; or (iv) If the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody shall be administered at a dose of approximately 2100 mg on day 1 of each 21-day cycle, starting from cycle 3. as well as b) Administer the carboplatin at a dose of AUC 5 on day 1 of each 21-day cycle for up to 4 cycles; as well as c) On day 1 of each 21-day cycle, use carboplatin at approximately 500 mg / m². 2 The prescribed dose of pemetrexed was administered for up to four cycles, followed by maintenance until disease progression.

110. The method of claim 109, wherein the dose of the bispecific anti-EGFR / c-Met antibody on day 1 of cycle 1 is administered as a fractionated dose on day 1 and day 2.

111. The method according to any one of claims 87 to 110, wherein the subject population receiving the combination therapy achieves at least two months of median OS improvement relative to the reference population.

112. The method of claim 111, wherein the subject population receiving the combination therapy achieves the median OS improvement for at least 2.4 months relative to the reference population.

113. The method of claim 111, wherein the subject population receiving the combination therapy achieved the median OS improvement of approximately 2.4 months relative to the reference population.

114. The method of claim 111, wherein the subject receiving the combination therapy exhibits an overall survival of at least 17 months.

115. The method of claim 114, wherein the subject receiving the combination therapy exhibits an overall survival of at least about 17.7 months.

116. The method of claim 114, wherein the subject receiving the combination therapy exhibits an overall survival of approximately 17.7 months.

117. The method according to any one of claims 87 to 116, wherein the combination therapy further achieves an improvement in the time to symptomatic progression (TTSP) relative to the reference population.

118. The method according to any one of claims 87 to 116, wherein the combination therapy further improves the time to follow-up therapy (TTST) relative to the reference population.

119. The method according to any one of claims 87 to 116, wherein the combination therapy further improves PFS (PFS2) after the first follow-up therapy relative to the reference population.

120. The method according to any one of claims 87 to 116, wherein the combination therapy further improves treatment interruption time (TTD) relative to the reference population.

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