Methods for treating non-small cell lung cancer (NSCLC)

Abstract

The present disclosure provides methods for improving the median progression-free lifetime (PFS) and improving the overall lifetime of a never-treated subject or a population of never-treated subjects having EGFR-positive non-small cell lung cancer (NSCLC).

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 540,742, filed September 27, 2023, and U.S. Provisional Application No. 63 / 468,375, filed May 23, 2023, the disclosure of each of which is incorporated herein by reference in its entirety.

[0002] sequence list 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 May 21, 2024, named 103693007299_SequenceListing.xml, and is 20,173 bytes in size. Technical Field

[0003] This disclosure provides a method for treating EGFR-positive non-small cell lung cancer (NSCLC) in treatment-naïve subjects. Background Technology

[0004] Lung cancer is one of the most common cancers worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% to 85% of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The most common driver mutation in NSCLC is alteration of EGFR, a receptor tyrosine kinase that controls cell growth and division. EGFR mutations are present in 10% to 15% of Western patients with NSCLC and in 40% to 50% of Asian patients. EGFR ex19del or EGFR exon 21 L858R mutations are the most common EGFR mutations.

[0005] 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 acquire resistance that prevents durable responses. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors show increased c-Met expression, 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). The five-year survival rate for all advanced NSCLC patients with EGFR mutations treated with EGFR TKIs is less than 20%. Patients with EGFR ex19del or exon 21 L858R mutations have a real-world five-year overall survival of 19%.

[0006] The progression of acquired resistance to EGFR-TKIs (such as osimertinib) in epidermal growth factor receptor mutant (EGFRm) NSCLC may be caused by the co-occurrence of complex and heterogeneous resistance patterns along with multiple resistance mechanisms, and therefore the details of these mechanisms remain elusive. Therefore, targeted therapy presents unique challenges, and new treatment paradigms are still needed for newly diagnosed NSCLC patients. Summary of the Invention

[0007] In one aspect, this article provides a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to a subject or population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of latezitinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference population harboring one or more EGFR mutations, the reference population having been administered osimertinib or latezitinib without the bispecific anti-EGFR / c-Met antibody.

[0008] On the other hand, this article provides a method for improving overall survival (OS) in a treatment-naïve subject or subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, comprising administering to the subject or 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 lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve NSCLC reference subject or reference subject population harboring one or more EGFR mutations, who has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0009] 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.

[0010] 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.

[0011] In some implementations, the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapies, including surgical resection or chemoradiotherapy.

[0012] 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.

[0013] 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 or better response in subjects according to RECIST v1.1 criteria. In some implementations, a clinical response includes a median duration of response (DOR) of at least 25 months.

[0014] In some implementations, subjects are progression-free after at least 11 months. In some implementations, subjects are progression-free after at least 23 months. In some implementations, the method achieves progression-free survival (PFS) rates of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

[0015] 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12. In some embodiments, the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing 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 a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing 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%.

[0016] 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 of about 140 mg to 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, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg. In some embodiments, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 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 1400 mg.

[0017] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. In some implementations, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0018] 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.

[0019] In some implementations, the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR m ctDNA, or no EGFR m ctDNA clearance at C3D1. Attached Figure Description

[0020] Figure 1 An exemplary schematic overview of the MARIPOSA clinical study is shown.

[0021] Figure 2 Kaplan-Meier estimates of progression-free survival (PFS) as assessed by a blinded independent central review are shown in the efficacy cohort of ervantumab-lazatinib versus osimertinib (including the lazatinib monotherapy group). PFS is presented from BICR results. Dashed lines indicate median PFS in both groups, and scale markers indicate censoring of data. The median PFS in the lazatinib group was 18.5 months (95% CI, 14.8 to 20.1).

[0022] Figure 3Kaplan-Meier estimates of progression-free survival (PFS) assessed by a blinded independent central review are shown in the efficacy cohort of ervantumab-lazaitinib versus osimertinib. Dashed lines indicate median PFS in both groups, and scale markers indicate censoring of data. Evantumab plus lazaitinib versus osimertinib prolonged PFS by 7.1 months in BICR.

[0023] Figure 4 The PFS by subgroup is shown.

[0024] Figure 5 Kaplan-Meier estimates of intermediate-term overall survival are shown. The efficacy cohort includes all patients who underwent randomization. Scale markers indicate censoring of data.

[0025] Figure 6 A diagram illustrating the CONSORT (Concerted Standards for Reporting Patient Management) is shown. 1375 patients were screened, and 1074 patients underwent randomization (429 patients received ervantumab-lazaitinib, 429 patients received osimertinib monotherapy, and 216 patients received lazaitinib monotherapy); 1062 patients received at least one dose of the trial treatment.

[0026] Figure 7 Kaplan-Meier estimates of progression-free survival, assessed by a blinded, independent central review, are shown in patients with EGFR exon 19 deletion (top) and patients with EGFR exon 21L858R (bottom). The efficacy cohort includes all patients who underwent randomization. In both figures, the hazard ratio for disease progression or death was obtained from an unstratified proportional hazards model; scale markers indicate censoring of data. The 95% confidence interval (CI) width has not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. EGFR stands for epidermal growth factor receptor.

[0027] Figure 8 Kaplan-Meier estimates of progression-free survival, assessed by a blinded independent central review, are shown in Asian patients (top) and non-Asian patients (bottom). The efficacy cohort includes all patients who underwent randomization. In both figures, the hazard ratio (HR) for disease progression or death is obtained from an unstratified proportional hazard model; the scale markers indicate censoring of the data. The 95% CI width has not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.

[0028] Figure 9Kaplan-Meier estimates of progression-free survival, assessed by a blinded independent central review, are shown in patients with a history of brain metastases (top) and in patients without a history of brain metastases (bottom). The efficacy cohort includes all patients who underwent randomization. In both figures, the hazard ratio for disease progression or death was obtained from an unstratified proportional hazards model; the scale markers indicate censoring of the data. The 95% CI width has not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.

[0029] Figure 10 Kaplan-Meier estimates of extracranial progression-free survival (EPFS) assessed by a blinded independent central review are shown in the efficacy cohort. The efficacy cohort included all patients who underwent randomization. EFS was defined as the time from randomization to disease progression (detected by extracranial scan) or death. Patients with CNS disease progression were censored if the first progression was detected only in the CNS. Dashed lines indicate median EFS in both groups; scale marks indicate censoring of data. The 95% CI width has not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. CNS represents the central nervous system. Sensitivity analysis was performed because MARIPOSA performed continuous brain imaging, and only the first CNS progression event was censored. The median EFS in the ervantumab-lazetinib group was 27.5 months (95% CI, 22.1 to inestimable) and in the osimertinib group was 18.4 months (95% CI, 16.5 to 20.2).

[0030] Figure 11 A waterfall plot showing the best percentage change in target lesions relative to baseline in the ervantumab-lazaitinib group (top) and the osimertinib group (bottom) is presented. As determined by a blinded independent central review, the number of patients with measurable disease at baseline was 421 in the ervantumab-lazaitinib group and 414 in the osimertinib group. Target lesions were measured as the sum of diameters. The objective response rate was 86% (95% CI, 83 to 89) in the ervantumab-lazaitinib group and 85% (95% CI, 81 to 88) in the osimertinib group.

[0031] Figure 12Kaplan-Meier estimates of response duration in confirmed responders within the efficacy cohort are shown. The efficacy cohort included all patients who underwent randomization. This analysis included 336 confirmed responders in the ervantumab-lazatinib group (421 patients with measurable disease at baseline via a blinded independent central review) and 314 confirmed responders in the osimertinib group (414 patients). Scale markers indicate censoring of data. The objective response rate was 86% (95% CI, 83 to 89) in the ervantumab-lazatinib group and 85% (95% CI, 81 to 88) in the osimertinib group, with median response durations of 25.8 months (95% CI, 20.1 to inestimable) and 16.8 months (95% CI, 14.8 to 18.5) in the confirmed responders, respectively.

[0032] Figure 13 The Kaplan-Meier estimate of time to treatment discontinuation is shown for the efficacy group. The efficacy group includes all patients who underwent randomization. Scale markers indicate censoring of data.

[0033] Figure 14 Kaplan-Meier estimates of time to subsequent treatment are shown for the efficacy group. The efficacy group includes all patients who underwent randomization. Scale markers indicate censoring of data.

[0034] Figure 15 Kaplan-Meier estimates of progression-free survival following initial subsequent treatment are shown, defined as the time from randomization to objective disease progression (by the investigator) or death following the initiation of subsequent systemic anticancer therapy, whichever occurs first. The efficacy cohort includes all patients who underwent randomization. Scale markers indicate censoring of data.

[0035] Figure 16 The MARIPOSA study design and methodology for the high-risk subgroup are illustrated. Detection of circulating tumor DNA (ctDNA) and co-mutations was analyzed using next-generation sequencing (NGS) of blood at baseline. Detection and clearance of Ex19del and L858R ctDNA in blood were analyzed using droplet digital PCR (ddPCR) at baseline and at C3D1. a Dosage (in a 28-day cycle): Evantuumab: 1050 mg once a week for the first 4 weeks (1400 mg if ≥80 kg), then once every 2 weeks; Lazazetinib: 240 mg daily; Osimertinib: 80 mg daily. b This includes the lazatinib monotherapy group to assess the contribution of the component. c Efficacy assessments were performed every 8 weeks (±1 week) for the first 30 months, and then every 12 weeks (±1 week) according to RECIST v1.1 analysis.d Ex19del or L858R was identified by Biodesix ddPCR.

[0036] Figure 17 The progression-free survival (PFS) determined by BICR is shown. Evantuzumab plus lazatinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months.

[0037] Figure 18 Progression-free survival (PFS) in patients with brain metastases is shown. Osimertinib demonstrated a median PFS of 13.0 months in patients with brain metastases at baseline, indicating a subgroup with poor prognosis. In patients with brain metastases at baseline, ervantumab plus lazatinib reduced the risk of progression or death by 31% compared to osimertinib. In patients without brain metastases at baseline, ervantumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 27.5 months vs. 19.9 months and HR 0.69 (95% CI, 0.53–0.89); P = 0.005.

[0038] Figure 19 Progression-free survival (PFS) in patients with liver metastases is shown. Osimertinib demonstrated a median PFS of 11.0 months in patients with liver metastases at baseline, indicating a subgroup with poor prognosis. In patients with liver metastases at baseline, ervantuzumab plus lazatinib reduced the risk of progression or death by 42% compared to osimertinib. In patients without liver metastases at baseline, ervantuzumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 24.0 months vs. 18.3 months and HR 0.74 (95% CI, 0.60–0.91); P = 0.004.

[0039] Figure 20 The pathogenic mutation patterns in circulating tumor DNA (ctDNA) at baseline are shown. Pathogenic alterations were detected in ctDNA by NGS in 85% (540 / 636 samples) at baseline. TP53 co-mutations were observed in 56% of patients from the ervantumab + lazazetinib group and 53% from the osimertinib group. MET amplification occurred in 1 patient in each group (no high-level amplification was observed). Pathogenic mutations occurring in ≥2% of patients are shown. (Used Guardant Health G360) ® Panel detection of pathogenic mutations.

[0040] Figure 21The progression-free survival (PFS) of patients with TP53 co-mutations is shown. Osimertinib demonstrated a median PFS of 12.9 months in patients with TP53 co-mutations at baseline, indicating a subgroup with poor prognosis. In patients with TP53 co-mutations at baseline, ervantumab plus lazatinib reduced the risk of progression or death by 35% compared to osimertinib. In patients with wild-type TP53 at baseline, ervantumab plus lazatinib demonstrated a consistent benefit over osimertinib: median PFS: 22.1 months vs. 19.9 months and HR 0.75 (95% CI, 0.52–1.07); P = 0.114.

[0041] Figure 22 Detectable EGFR mutant (EGFRm) ctDNA at baseline and treatment are shown. Detection and clearance of Ex19del and L858R ctDNA in the blood were analyzed by ddPCR. At baseline, analyzable ctDNA samples were provided by 336 patients in the ervantumab + lazatinib and osimertinib groups. Approximately 70% of patients in both groups had detectable EGFRm ctDNA at baseline. Matched samples were provided by 192 patients in the ervantumab + lazatinib group and 212 patients in the osimertinib group at baseline and at C3D1 (week 9). At C3D1 (week 9), detectable EGFRm ctDNA was observed in 15% of these patients in both groups.

[0042] Figure 23 Progression-free survival (PFS) is shown in patients with detectable baseline ctDNA (Ex19del or L858R as determined by Biodesix ddPCR). Osimertinib showed a median PFS of 14.8 months in patients with detectable ctDNA at baseline, indicating a subgroup with poor prognosis. In patients with detectable baseline ctDNA, ervantumab plus lazatinib reduced the risk of progression or death by 32% compared to osimertinib. In patients without detectable baseline ctDNA, ervantumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 27.7 months vs. 21.9 months and hazard ratio 0.72 (95% CI, 0.47–1.10); P = 0.132. In patients with detectable baseline ctDNA, the median PFS was 27.7 months vs. 21.9 months and the hazard ratio was 0.72 (95% CI, 0.47–1.10); P = 0.132. ® In patients with NGS-detectable baseline ctDNA, ervantuzumab plus lazatinib showed a consistent benefit over osimertinib (HR, 0.71 [95% CI, 0.57–0.89]; P = 0.003).

[0043] Figure 24Progression-free survival (PFS) in patients who did not clear ctDNA at C3D1 is shown (Ex19del or L858R as determined by Biodesix ddPCR, cycle 28 days). Osimertinib showed a median PFS of 9.1 months in patients who did not clear ctDNA at C3D1, indicating a subgroup with poor prognosis. In patients who did not clear ctDNA at C3D1, ervantumab plus lazatinib reduced the risk of progression or death by 51% compared to osimertinib. In patients who cleared ctDNA at C3D1, ervantumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 24.0 months vs. 16.5 months and HR 0.64 (95% CI, 0.48–0.87); P = 0.004.

[0044] Figure 25 Progression-free survival is shown for patients with high-risk traits. In the MARIPOSA study, 89% of patients had at least one high-risk trait detected at baseline (patients with ctDNA analyzable by NGS at baseline were included in this pooled analysis. High-risk traits included baseline-detectable ctDNA by NGS or baseline metastases to the liver or brain. For patients with detectable ctDNA, a TP53 co-mutation was presumed to be identified (if present)). Detailed Implementation

[0045] definition 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.

[0046] 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.

[0047] 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.

[0048] 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”.

[0049] As used in this specification and the appended claims, unless otherwise expressly stated, the singular forms “a,” “an,” and “described” include plural references. Thus, for example, a reference to “a cell” includes a combination of two or more cells, and so on.

[0050] 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".

[0051] 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”.

[0052] Terms such as “together with,” “together with,” “in combination with,” and “in combination with” 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.

[0053] "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).

[0054] "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.

[0055] "Prevention" of disease or symptom means preventing the development of symptoms in the test subjects.

[0056] "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 typically performed by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating a subject's likely response to a particular treatment.

[0057] "Response", "responsiveness" or "potential 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, 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 relief (whether partial or complete), whether detectable or undetectable.

[0058] "Newly diagnosed" refers to subjects who have been diagnosed with cancer (e.g., cancers that express EGFR or c-Met) but have not yet received treatment (e.g., treatment for lung cancer).

[0059] "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.

[0060] "Treatment refractory" refers to a disease that does not respond to treatment. A treatment refractory disease may be resistant to treatment before or at the start of treatment, or it may become resistant during treatment.

[0061] "Relapse" refers to the recurrence of the disease or signs and symptoms of the disease after a period of improvement following previous treatment with medication.

[0062] "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.

[0063] "Reference subjects" or "reference subject population" refers to subjects or populations of subjects with locally advanced or metastatic EGFR-mutant NCSLC carrying one or more epidermal growth factor receptor (EGFR) mutations who have never received treatment and have been given osimertinib or lazatinib without a bispecific anti-EGFR / c-Met antibody, and not with a combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lazatinib. Reference subjects or reference subject populations may have substantially the same disease progression as subjects or populations treated with a combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lazatinib. In some embodiments, the subject population and reference subject population contain at least two subjects. In some embodiments, the subject population and reference subject population contain multiple subjects to allow for statistically significant analyses of improvements in safety and efficacy.

[0064] “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.

[0065] "Cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread) to other areas of the patient's body.

[0066] "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.

[0067] "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.

[0068] 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.

[0069] "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.

[0070] "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 antigens from other species (homologous) (such as humans or monkeys, such as cynomolgus monkeys). Macaca fascicularis (cynomolgus, cyno) or chimpanzee ( Pan troglodytes(chimpanzee, chimp) antibodies exhibit cross-reactivity with the same antigen. Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0071] "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, tetramers, or multimers, single-chain antibodies, domain antibodies, and any other modified conformation of an immunoglobulin molecule containing an antigen-binding site with the 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.

[0072] 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, 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 CDRs as defined by any of the above methods (Kabat, Chothia, IMGT, or AbM).

[0073] 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 completely different types: κ and λ.

[0074] 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.

[0075] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, meaning that individual antibodies comprising this 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 have heterogeneous glycosylation within an antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0076] "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.

[0077] "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.

[0078] 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.

[0079] 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.

[0080] "PD-(L)1 axis inhibitors" are molecules that inhibit downstream signaling of PD-1. PD-(L)1 axis inhibitors can be molecules that bind to PD-1, PD-L1, or PD-L2.

[0081] "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 biosample is a blood sample. As another non-limiting example, a biosample is a plasma sample. As yet another non-limiting example, a biosample 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.

[0082] As used in this application, "low fucose" or "low fucose content" means that the fucose content of the antibody is about 1% to 15%.

[0083] 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%.

[0084] 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 for treatment-naïve subjects may also be referred to as first-line or front-line therapy.

[0085] As used in this article, RECIST v1.1 criteria refer to publicly available guidelines for response evaluation criteria in solid tumors as described in the following literature: Eisenhauer EA, Therasse P, Bogaerts J et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer2009; 45(2):228-247, which is incorporated herein by reference. Eisenhauer et al. provided the following definition of the criteria for determining objective tumor response to target lesions: - 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. - 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. - 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 the 20% relative increase, 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). - 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.

[0086] As used in this article, a partial response or better response means a partial response (PR) or a complete response (CR); and no progression means no disease progression.

[0087] The method disclosed herein New treatment options for newly diagnosed patients with EGFR mutation-positive advanced NSCLC represent a significant unmet medical need. EGFR-TKI TAGRISSO ® Osimertinib is the standard of care in the frontline patient population. Results from the FLAURA clinical trial showed that osimertinib treatment resulted in a median progression-free survival (mPFS) of 18.9 months in previously untreated patients with EGFR mutation-positive advanced NSCLC (Soria et al., N Engl J Med 2018; 378:113-125).

[0088] The inventors have developed novel methods for treating EGFR mutation-positive advanced NSCLC in treatment-naïve patients. They have also developed methods for improving median progression-free survival (PFS) and / or overall survival in treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations. Therefore, embodiments of the present invention provide methods for treating patients and / or patient populations with newly diagnosed EGFR-mutant NSCLC, methods for improving median progression-free survival in patients and / or patient populations with newly diagnosed EGFR-mutant NSCLC, and methods for improving overall survival in patients and / or patient populations with newly diagnosed EGFR-mutant NSCLC.

[0089] This article discloses a method for treating non-small cell lung cancer (NSCLC) in subjects in need of treatment, comprising administering a combination therapy to the subject comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody; and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has been diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations, and wherein the subject has never received treatment.

[0090] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of latezatitinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference population harboring one or more EGFR mutations who have received osimertinib or latezatitinib but not the bispecific anti-EGFR / c-Met antibody.

[0091] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, wherein the reference population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0092] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of NSCLC without baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0093] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, the reference population having received osimertinib or lazatinib without receiving a bispecific anti-EGFR / c-Met antibody.

[0094] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of NSCLC without baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0095] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, the reference population of whom had been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0096] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC without TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0097] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, wherein the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0098] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of locally advanced or metastatic non-small cell lung cancer (NSCLC) diagnosed with undetectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of NSCLC with undetectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0099] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

[0100] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0101] This article discloses a method for improving overall survival (OS) in treatment-naïve subjects or subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of latezatitinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve NSCLC reference subject or reference subject population harboring one or more EGFR mutations who has received osimertinib or latezatitinib but not the bispecific anti-EGFR / c-Met antibody.

[0102] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0103] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC without baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0104] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0105] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC without baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0106] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0107] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC without TP53 co-mutation, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0108] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC carrying one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0109] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve population of locally advanced or metastatic non-small cell lung cancer (NSCLC) with undetectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or population of subjects comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference population of NSCLC with undetectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or population of subjects has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0110] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0111] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) having mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method involves administering a combination therapy to the subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof. The improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC having mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0112] In some embodiments, the method is performed on subjects, and the method provides an improvement in overall survival (OS) compared to a reference subject population. In some embodiments, the method is performed on a subject population, and the method provides an improvement in OS compared to a reference subject population. In some embodiments, the method is performed on a subject population, and the method provides an improvement in OS compared to a reference subject population.

[0113] In some embodiments of the disclosed method, lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate. In some embodiments of the disclosed method, lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate monohydrate.

[0114] In some embodiments of the disclosed method, one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. In some embodiments of the disclosed method, one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments of the disclosed method, one or more EGFR mutations comprise exon 21 L858R substitutions.

[0115] In some embodiments of the disclosed method, the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapies, including surgical resection or chemoradiotherapy.

[0116] In some embodiments of the disclosed method, the method includes oral administration of lazalatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 80 mg to about 320 mg. In some embodiments of the disclosed method, the method includes oral administration of lazalatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 240 mg.

[0117] In some embodiments of the disclosed method, the method induces a clinical response in subjects according to RECIST v1.1 criteria. In some embodiments of the disclosed method, the method achieves a partial or better response in subjects according to RECIST v1.1 criteria. In some embodiments of the disclosed method, the clinical response includes a median duration of response (DOR) of at least 1 year, at least 2 years, or at least 3 years. In some embodiments of the disclosed method, the clinical response includes a median duration of response (DOR) of at least 25 months.

[0118] In some embodiments of the disclosed method, the subject is progression-free after at least 20 months. In some embodiments of the disclosed method, the subject is progression-free after at least 24 months. In some embodiments of the disclosed method, the subject is progression-free after at least 30 months. In some embodiments of the disclosed method, the subject is progression-free after at least 11 months. In some embodiments of the disclosed method, the subject is progression-free after at least 23 months. In some embodiments of the disclosed method, the method achieves a progression-free survival (PFS) rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed method, the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed method, the method achieves a PFS rate of 86% in a treatment-naïve population of subjects diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

[0119] In some embodiments of the disclosed method, 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 of the disclosed method, 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 of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed method, 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 of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0120] In some embodiments of the disclosed method, 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO: 20. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0121] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 2240 mg. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered at doses of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg. In some embodiments of the disclosed method, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose of 1050 mg. In some embodiments of the disclosed method, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose of 1400 mg.

[0122] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject. In some embodiments of the disclosed method, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 1600 mg, or if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 2240 mg. In some embodiments of the disclosed method, administration may be once every two weeks. In some embodiments of the disclosed method, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 2400 mg, or if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 3360 mg. In some embodiments of the disclosed method, administration may be once every three weeks.

[0123] In some embodiments of the disclosed method, 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.

[0124] In some embodiments of the disclosed method, the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR m ctDNA, or no EGFR m ctDNA clearance at C3D1. In some embodiments, the subject or subject population has baseline brain metastases. In some embodiments, the subject or subject population has baseline liver metastases. In some embodiments, the subject or subject population has TP53 co-mutations. In some embodiments, the subject or subject population has detectable baseline EGFR m ctDNA. In some embodiments, the subject or subject population does not have EGFR m ctDNA clearance at C3D1.

[0125] In some embodiments of the disclosed method, the subject or subject population does not have baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR m ctDNA, or no EGFR m ctDNA clearance at C3D1. In some embodiments, the subject or subject population does not have baseline brain metastases. In some embodiments, the subject or subject population does not have baseline liver metastases. In some embodiments, the subject or subject population does not have TP53 co-mutations. In some embodiments, the subject or subject population does not have detectable baseline EGFR m ctDNA. In some embodiments, the subject or subject population has EGFR m ctDNA clearance at C3D1.

[0126] In some embodiments of the disclosed method, 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 of the disclosed method, the first domain that specifically binds 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 that specifically binds to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0127] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0128] In some embodiments of the disclosed method, 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.

[0129] In some embodiments of the disclosed method, 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain that specifically binds to EGFR includes a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain that specifically binds to c-Met includes a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16.

[0130] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0131] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO: 20.

[0132] In some embodiments of the disclosed method, 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%.

[0133] In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody disclosed herein can 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 of the disclosed methods, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lazatinib.

[0134] Lazatinib is an oral, third-generation brain-penetrating EGFR TKI that targets both the T790M mutation and activates EGFR mutations without harming wild-type EGFR. Analysis of the efficacy and safety of lazatinib from the phase 3 LASER301 (NCT04248829) study demonstrated that, in all pre-specified subgroups (including Asian patients, those with exon 21 L858R mutations, and those with a history of brain metastases), lazatinib improved progression-free survival (PFS) compared to the first-generation EGFR TKI gefitinib.

[0135] 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.

[0136] Formula I In addition, WO2018 / 194356 describes its salt, hydrate and crystalline forms; and WO2019 / 022485, WO2019 / 022486 and WO2019 / 022487 disclose methods for producing lazatinib.

[0137] Lazazinib mesylate monohydrate is described below as a compound of formula Ia. Formula Ia, It can be called N -[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1 H [-pyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-(morpholin-4-yl)phenyl]acrylamide methanesulfonate hydrate.

[0138] Treatment In some embodiments, methods of the present disclosure for treating cancer in subjects for whom there is a need may include administering to the subject an effective amount of a combination therapy comprising a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).

[0139] In some embodiments, methods of this disclosure that can be used to improve median progression-free survival (PFS) in a subject population with cancer may include administering to the subject an effective amount of a combination therapy comprising a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).

[0140] In some embodiments, methods of this disclosure that can be used to improve overall survival (OS) in subjects or subject populations with cancer may include administering to the subject an effective amount of a combination therapy comprising a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody and an EGFR tyrosine kinase inhibitor (TKI).

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

[0143] application 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, edited by Troy, DB, Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing, pp. 691-1092 (see especially pp. 958-989).

[0144] 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.

[0145] In some implementations, bispecific anti-EGFR / c-Met antibodies are administered intravenously.

[0146] 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.

[0147] 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.

[0148] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously to the subject at a dose of approximately 1600 mg to approximately 3360 mg. Subcutaneous administration may be once every two weeks (Q2W) or once every three weeks (Q3W). The Q2W administration is 1600 mg (2240 ​​mg if the subject is ≥80 kg). The Q3W administration is 2400 mg (3360 mg if the subject is ≥80 kg).

[0149] 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.

[0150] 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. g, 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 8 70mg, 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.

[0151] 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, or about 1400 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 about 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.

[0152] In some implementations, if the subject weighs less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some implementations, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0153] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once weekly. In some embodiments, approximately 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once weekly. In some embodiments, approximately 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once weekly.

[0154] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, approximately 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, approximately 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein can be administered in combination with latezatitinib at any of the doses and formulations disclosed herein. As a non-limiting example, 700 mg of etanercept can be administered in combination with 240 mg of latezatitinib. As a non-limiting example, 1050 mg of etanercept can be administered in combination with 240 mg of latezatitinib. As a non-limiting example, 1050 mg of etanercept can be administered in combination with 240 mg of latezatitinib. As a non-limiting example, 1400 mg of etanercept can be administered in combination with 240 mg of latezatitinib.

[0163] 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.

[0164] In some implementations, combination therapies comprising bispecific anti-EGFR / c-Met bispecific antibodies and EGFR TKIs may further include one or more additional anticancer therapies.

[0165] 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.

[0166] Additional anticancer therapies that can be administered in the methods of this disclosure may include any one or more of chemotherapeutic agents or other anticancer therapeutic 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: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-FU; folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; and purine analogs such as fludarabine, 6-mercaptopurine, and thiodicarboxylic acid. Thiamiprids and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluorouridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergics, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as frolinic acid; and 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) ™ PALLADIA ™ ), ZACTIMA ™ ), Cisdin (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, LY 117018, 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 chemicals, 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 this invention.

[0167] Generation of bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure 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: EGFR conjugate arm >SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding arm) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding arm) WISAYNGYTNYAQKLQG >SEQ ID NO:9 (HCDR3, c-Met binding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met binding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met binding arm) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met binding arm) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO:15 (VH, c-Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO:16 (VL, c-Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 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.

[0168] 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.

[0169] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0170] 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.

[0171] 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6; and the second domain comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12.

[0172] In some embodiments, the first domain that specifically binds to EGFR includes a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14; and the second domain that specifically binds to c-Met includes a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16.

[0173] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0174] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO: 20.

[0175] In some implementations, the bispecific anti-EGFR / c-Met antibody is a biosimilar of ervantomab.

[0176] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: us.proteogenix_science / product / amivantamab-biosimilar-anti-egfr-me-rccp2-mab-research-grade / .

[0177] In some implementations, non-limiting examples of biosimilars of ervantamab can be found in publicly available online resources: thermofisher_com / antibody / product / Amivantamab-Antibody-Recombinant-Monoclonal / MA5-42260.

[0178] In some implementations, non-limiting examples of biosimilars of ervantumab can be found in publicly available online resources: genemedi_net / i / biologics-biosimilar-GMP-Bios-ab-021.

[0179] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: prosci-inc_com / product / amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966 / .

[0180] In some implementations, non-limiting examples of biosimilars of ervantomab can be found in publicly available online resources: antibodysystem_com / product / 6201.html.

[0181] In some implementations, non-limiting examples of biosimilars of amivantamab can be found in publicly available online resources: biorbyt_com / amivantamab-biosimilar-antibody-orb1140752.html.

[0182] In one implementation, the bispecific anti-EGFR / c-Met antibody contains one or more Fc silencing mutations.

[0183] In one implementation, one or more Fc silencing mutations reduce affinity for the Fcγ receptor.

[0184] In one implementation, one or more Fc silencing mutations include V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0185] 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), and using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, ). (2003) Introducing small interfering RNA specifically targeting the α-1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expressing β-1,4-N-acetylglucosamine transferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitors chifrine (Ferrara et al., J Biol 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).

[0186] 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 ervantumab, 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.

[0187] The bispecific anti-EGFR / c-Met antibody used in the methods of this disclosure can be generated, for example, through Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies, by introducing substitutions at the heavy chain CH3 interface in each half-molecule to facilitate heterodimer formation of two antibody half-molecules with different specificities in an in vitro cell-free environment or using co-expression. The Fab arm exchange reaction is the result of disulfide 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 ​​from one parent monospecific antibody forms an inter-heavy chain disulfide bond with a 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 this invention can be produced using the technique described in International Patent Publication No. 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 produce 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 ​​residues 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, the following conditions can be used: 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.

[0188] 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).

[0189] 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.

[0190] 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).

[0191] 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 Nos. WO2009 / 080254, WO2009 / 080251, WO2009 / 018386, and WO2009 / 080252.

[0192] 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.

[0193] 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.

[0194] Standard methods are typically used to mutate molecules (such as the constant result domain of antibodies) at the DNA level.

[0195] Exemplary Implementation The following is a list of exemplary implementation schemes: 1a. A method for improving median progression-free survival (PFS) in a patient population with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who have never received treatment, the method comprising administering a combination therapy to the patient population, the combination therapy comprising: (i) Therapeutic effective doses of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate, and The improvement in median PFS is relative to the median PFS of a reference group of NSCLC subjects who have never received treatment and carry one or more EGFR mutations, who have been given osimertinib or lazatinib but not the bispecific anti-EGFR / c-Met antibody.

[0196] 2a. A method for improving overall survival (OS) in a treatment-naïve subject or population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the subject or population of subjects, the combination therapy comprising: (i) Therapeutic effective doses of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate, and The improvement in OS is relative to the OS of a reference subject or reference subject population of NSCLC who has never received treatment and carries one or more EGFR mutations, who has been given osimertinib or lazatinib but not the bispecific anti-EGFR / c-Met antibody.

[0197] 3a. The method according to embodiment 1a or 2a, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate.

[0198] 4a. The method according to embodiment 1a or 2a, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate monohydrate.

[0199] 5a. The method according to any one of embodiments 1a to 4a, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0200] 6a. The method according to any one of embodiments 1a to 4a, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

[0201] 7a. The method according to any one of embodiments 1a to 4a, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

[0202] 8a. The method according to any one of embodiments 1a to 7a, wherein the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapies, said curative therapies including surgical resection or chemoradiotherapy.

[0203] 9a. The method according to embodiment 8a, wherein the curative treatment includes surgical resection or radiotherapy / chemotherapy.

[0204] 10a. The method according to any one of embodiments 1a to 9a, wherein the method comprises orally administering the lazazetinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 80 mg to about 320 mg.

[0205] 11a. The method according to any one of embodiments 1a to 10a, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 240 mg.

[0206] 12a. The method according to any one of embodiments 1a to 11a, wherein the method elicits a clinical response in the subject according to RECISTv1.1 criteria.

[0207] 13a. The method according to any one of embodiments 1a to 12a, wherein the method achieves a partial or better response in the subject according to RECISTv1.1 criteria.

[0208] 14a. The method according to any one of embodiments 1a to 13a, wherein the clinical response includes a median duration of response (DOR) of at least 25 months.

[0209] 15a. The method according to any one of embodiments 1a to 14a, wherein the subject has no progress after at least 11 months.

[0210] 16a. The method according to any one of embodiments 1a to 15a, wherein the subject has no progression after at least 23 months.

[0211] 17a. The method according to any one of embodiments 1a to 16a, wherein the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

[0212] 18a. The method according to any one of embodiments 1a to 17a, 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12.

[0213] 19a. The method according to embodiment 18a, wherein the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16.

[0214] 20a. The method according to embodiment 18a or 19a, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0215] 21a. The method according to any one of embodiments 1a to 20a, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO: 20.

[0216] 22a. The method according to any one of embodiments 1a to 21a, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0217] 23a. The method according to any one of embodiments 1a to 22a, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

[0218] 24a. The method according to embodiment 23a, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg.

[0219] 25a. The method according to embodiment 24a, 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, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg.

[0220] 26a. The method according to embodiment 25a, 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 1050 mg.

[0221] 27a. The method according to embodiment 26a, 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 1400 mg.

[0222] 28a. The method according to any one of embodiments 1a to 22a, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject.

[0223] 29a. The method according to embodiment 28a, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0224] 30a. The method according to any one of embodiments 1a to 29a, wherein 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.

[0225] 31a. The method according to any one of embodiments 1 to 30, wherein the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR mctDNA, or no EGFR mctDNA clearance at C3D1.

[0226] The following is a list of other exemplary implementations: 1b. A method of treating non-small cell lung cancer (NSCLC) in a subject in need of treatment, the method comprising administering a combination therapy to the subject, the combination therapy comprising... (i) A therapeutically effective amount of bispecific anti-EGFR / c-Met antibody; and (ii) A therapeutically effective amount of lazazetinib or its pharmaceutically acceptable salt or hydrate. The subjects mentioned above have been diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations, and The subjects mentioned above had never received any treatment.

[0227] 2b. The method according to embodiment 1b, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate.

[0228] 3b. The method according to embodiment 1b, wherein said lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate monohydrate.

[0229] 4b. The method according to any one of embodiments 1b to 3b, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0230] 5b. The method according to any one of embodiments 1b to 3b, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

[0231] 6b. The method according to any one of embodiments 1b to 3b, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

[0232] 7b. The method according to any one of embodiments 1b to 6b, wherein the subject has a newly diagnosed locally advanced or metastatic NSCLC that has never been treated and is not readily available for curative therapy, said curative therapy including surgical resection or chemoradiotherapy.

[0233] 8b. The method according to embodiment 7b, wherein the curative treatment includes surgical resection or radiotherapy / chemotherapy.

[0234] 9b. The method according to any one of embodiments 1b to 8b, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 80 mg to about 320 mg.

[0235] 10b. The method according to any one of embodiments 1b to 9b, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 240 mg.

[0236] 11b. The method according to any one of embodiments 1b to 10b, wherein the method elicits a clinical response in the subject according to RECISTv1.1 criteria.

[0237] 12b. The method according to any one of embodiments 1b to 11b, wherein the method achieves a partial or better response in the subject according to RECISTv1.1 criteria.

[0238] 13b. The method according to any one of embodiments 1b to 12b, wherein the clinical response includes a response duration (DOR) of at least 1 year, or at least 2 years, or at least 3 years.

[0239] 14b. The method according to any one of embodiments 1b to 13b, wherein the subject has no progression after at least 20 months.

[0240] 15b. The method according to any one of embodiments 1b to 13b, wherein the subject has no progression after at least 30 months.

[0241] 16b. The method according to any one of embodiments 1b to 15b, wherein the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

[0242] 17b. The method according to any one of embodiments 1b to 16b, 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 to 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.

[0243] 18b. The method according to embodiment 17b, wherein 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.

[0244] 19b. The method according to embodiment 17b or 18b, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0245] 20b. The method according to any one of embodiments 1b to 19b, wherein 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.

[0246] 21b. The method according to any one of embodiments 1b to 20b, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0247] 22b. The method according to any one of embodiments 1b to 21b, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

[0248] 23b. The method according to embodiment 22b, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg.

[0249] 24b. The method according to embodiment 23b, 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, 2100 mg, or 2240 mg.

[0250] 25b. The method according to embodiment 24b, 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 1050 mg.

[0251] 26b. The method according to embodiment 25b, 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 1400 mg.

[0252] 27b. The method according to any one of embodiments 1b to 21b, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject.

[0253] 28b. The method according to embodiment 27, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0254] 29b. The method according to any one of embodiments 1b to 28b, wherein 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. Example

[0255] 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.

[0256] Example 1. Clinical study of CHRYSALIS CHRYSALIS (NCT02609776) is a Phase 1, first-in-human, open-label dose-escalation and expansion study of ervantumab in combination with lazatinib (Study 61186372EDI1001, referred to as EDI1001). For dose escalation / expansion of ervantumab and lazatinib, enrolled subjects must have been diagnosed with an activating mutation in exon 19del or exon 21 L858R of EGFR, be treatment-naïve for metastatic disease, and have not been exposed to a third-generation TKI in the first-line setting, or have progressed after first-line treatment with a first- or second-generation TKI, or have been treated with a third-generation TKI in the first-line or second-line setting.

[0257] The initial dose cohort combined ervantumab 700 / 1050 mg (i.e., 700 mg in subjects weighing <80 kg and 1050 mg in subjects weighing ≥80 kg) with lazatinib 240 mg. Subsequent dose cohorts combined each agent from the monotherapy studies with their RP2D, namely ervantumab 1050 / 1400 mg and lazatinib 240 mg. Both dose cohorts were cleared, no dose-limiting toxicities were identified, and additional subjects were enrolled. Pharmacokinetic (PK) data indicated the absence of drug-drug interactions, as the PK profile of each drug when administered in combination was consistent with that when administered as monotherapy. Therefore, the RP2D is the recommended monotherapy for each molecule: ervantumab, 1050 mg (<80 kg) / 1400 mg (≥80 kg), intravenously, C1 once weekly, then every 2 weeks, and lazatinib 240 mg orally daily.

[0258] To further characterize the safety, resistance, and preliminary efficacy of ervantumab and lazatinib in RP2D, an additional expansion cohort (Cohort E) was initiated. Forty-five subjects were enrolled who met the following criteria: diagnosed with an activating EGFR mutation of exon 19del or exon 21 L858R, and who had progressed after first- or second-line therapy with a third-generation TKI and had never received chemotherapy. Limited prior therapy with a platinum-based chemotherapy regimen was permitted in the metastatic setting if no more than two cycles were required, administered before initiating the first EGFR TKI.

[0259] describe The aim of this study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of ervantumab as monotherapy and in combination with lazatinib, and to determine the recommended phase 2 dose (RP2D) (monotherapy), the recommended phase 2 combination dose (RP2CD) (combination therapy), and the recommended phase 2 dose (RP2Q3W) for participants with advanced non-small cell lung cancer (NSCLC) in combination chemotherapy (ervantumab in combination with standard of care carboplatin and pemetrexed) over a 21-day treatment cycle.

[0260] This open-label (all participants are known about the investigational drug), multicenter (more than one study site), first-in-human study consists of two parts. Part 1 is dose escalation of eptamab monotherapy and combination therapy, and Part 2 is dose expansion of eptamab monotherapy and combination therapy. In Part 1, participants with evaluable NSCLC will be enrolled in a RP2CD cohort for dose escalation of eptamab monotherapy, eptamab and lazatinib combination (to be administered in 28-day treatment cycles), and eptamab with standard-of-care carboplatin and pemetrexed (chemotherapy combination) (to be administered in 21-day treatment cycles). The dose will be escalated until the maximum tolerated dose (MTD, or maximum administered dose (MAD), if no MTD is found). Part 1 will follow a traditional 3+3 design. At each dose level, 3 participants will complete Cycle 1. If no dose-limiting toxicity (DLT) occurs in these 3 participants, escalation will continue in a new cohort of 3 participants. Data from Part 1 will be used to determine one or more RP2D regimens. In Part 2, participants with documented epidermal growth factor receptor (EGFR) mutations and measurable disease (whose disease has progressed after prior treatment) will be enrolled and receive ervantumab, the RP2D identified in Part 1, either as monotherapy in an RP2D regimen or in combination with lazazetinib in an RP2CD regimen. For both parts, the study will consist of the following periods: an optional pre-screening period; a screening period (up to 28 days before the first dose of the study drug); a treatment period (from the first dose of the study drug until 30 (+7) days after the last dose of the study drug or before the start of any subsequent anticancer therapy, whichever comes first); and a follow-up period (approximately 6 months). Survival of all participants will be tracked during the post-treatment follow-up period until the end of the study, and safety will be monitored throughout the study.

[0261] Research Design Research type: Intervention (clinical trial). Estimated inclusion: 780 participants. Allocation: Non-randomized. Intervention model: parallel allocation. Coverage: None (open tag). Main purpose: Treatment.

[0262] Official Name: JNJ-61186372 (human bispecific EGFR and cMet antibody) Phase 1 first-in-human open-label dose-escalation study in subjects with advanced non-small cell lung cancer.

[0263] Groups and Interventions Table 1 Outcome Indicators Preliminary results indicators 1. Part 1: Number of participants with dose-limiting toxicities (DLTs) [Time range: up to 28 days]. Dose-limiting toxicities (DLTs) are based on drug-related adverse events and include unacceptable hematologic toxicities, grade 3 or higher non-hematologic toxicities, or elevated liver enzymes suggesting drug-induced liver injury.

[0264] 2. Part 2: Number of Participants with Adverse Events (AEs) and Serious AEs [Timeframe: from screening to follow-up (30 [+7] days after the last dose)]. An adverse event (AE) is any inappropriate medical event that occurs in a participant receiving the study drug without regard to the possibility of causation. A serious adverse event (SAE) is an AE that is considered significant for any of the following outcomes or for any other reason: death; initial or long-term hospitalization; life-threatening experience (immediate risk of death); persistent or significant disability / incapacity; congenital abnormalities.

[0265] 3. Part 2: Overall Response Rate (ORR) [Timeframe: Until End of Treatment Follow-up (EOT) period (30 [+7] days after the last dose)]. Overall response rate (ORR) is defined as the percentage of participants who achieve CR or PR according to the RECIST v1.1 criteria for response to solid tumors. CR: Disappearance of all target and non-target lesions. All lymph nodes must be non-pathological in size (short axis <10 mm) and normalized in tumor marker levels; PR: Based on the persistence of the total diameter at baseline and one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits, with a reduction of at least 30% in the total diameter of target lesions.

[0266] 4. Part 2: Duration of Response (DOR) [Time range: up to the EOT follow-up period (30[+7] days after the last dose)]. DOR will be calculated as the time from the initial response of CR (all target and non-target lesions disappear. All lymph node sizes must be non-pathological (short axis less than [<] 10[mm]) and tumor marker levels must be normalized) or achieving PR for progressive disease (PD) or death due to underlying disease (based on the minimum total diameter during the study period and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits) or persistently stable disease (neither sufficient contraction to qualify for PR nor sufficient increase to qualify for progressive disease (PD), based on the minimum total diameter during the study period and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits), with a reduction of at least 30[%] in the total diameter of target lesions, whichever comes first, applicable only to participants who achieved CR or PR.

[0267] 5. Part 2: Percentage of participants with clinical benefit [Time range: up to the EOT follow-up period (30 [+7] days after the last dose)]. Clinical benefit rate is defined as the percentage of participants achieving a complete response (CR): disappearance of all target and non-target lesions. All lymph node sizes must be nonpathological (short axis less than [<] 10 mm) and normalized tumor marker levels or achieving a partial response (PR): with reference to the sum of baseline diameters and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits or persistently stable disease (neither sufficient contraction to qualify for PR nor sufficient increase to qualify for progressive disease (PD), with reference to the minimum sum of diameters during the study period and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits), and a reduction of at least 30% (%) in the total diameter of target lesions.

[0268] 6. Ctrough serum concentration of ervantumab [Time range: up to EOT (30 days after the last dose)]. Ctrough is the serum concentration observed just before the next administration.

[0269] 7. Area under the curve (AUCtau) of ervantumab from time zero to the end of the dosing interval [time range: up to EOT (30 days after the last dose)]. AUCtau is the area under the serum concentration-time curve during the dosing interval (tau).

[0270] Secondary outcome indicators 1. Maximum serum concentration (Cmax) of ervantumab [Time range: Day 1 of Cycle 1: from pre-administration to end of infusion (EOT) or follow-up (approximately 16 months) (28 days per cycle)]. Cmax is the maximum serum concentration of ervantumab observed.

[0271] 2. Time to reach the observed maximum serum concentration (Tmax) of ervaltumab [Time range: Day 1 of Cycle 1: from pre-dose to EOT or follow-up (approximately 16 months)]. Tmax is defined as the time to reach the observed maximum serum concentration of ervaltumab.

[0272] 3. Area under the serum concentration-time curve (AUC[t1-t2]) of ervantumab from time t1 to t2 [Time range: Day 1 of Cycle 1: from pre-dose to EOT or follow-up (approximately 16 months)]. AUC(t1-t2) is the area under the serum concentration-time curve of ervantumab from time t1 to t2.

[0273] 4. Area under the curve (AUCtau) of etanercept from time zero to the end of the dosing interval [Time range: Day 1 of Cycle 1: from pre-dose to EOT or follow-up (approximately 16 months)]. AUCtau is the area under the serum concentration-time curve during the dosing interval (tau).

[0274] 5. Ctrough serum concentration of ervantumab [Time range: Day 1 of Cycle 1: from pre-dose to EOT or follow-up (approximately 16 months)]. Ctrough is the serum concentration observed prior to the next administration.

[0275] 6. Maximum serum concentration (Cmax) of lazatinib [Time range: Day 1 of Cycle 1: from pre-dose to EOT (30[+7] days after the last dose [Day 15 of Cycle 4]) (28 days per cycle)]. Cmax is the maximum observed serum concentration of lazatinib.

[0276] 7. Time to reach the observed maximum serum concentration (Tmax) of lazatinib [Time range: Day 1 of Cycle 1: from before dosing to EOT (30[+7] days after the last dose [Day 15 of Cycle 4]) (28 days per cycle)]. Tmax is defined as the time to reach the observed maximum serum concentration of lazatinib.

[0277] 8. Ctrough serum concentration of lazatinib [Time range: Day 1 of Cycle 1: from pre-dose to EOT (30[+7] days after the last dose [Day 15 of Cycle 4]) (28 days per cycle)]. Ctrough is the serum concentration observed just before the next administration.

[0278] 9. Cumulative Ratio (R) of Evantuumab [Time Range: Day 1 of Cycle 1: from pre-dose to EOT or follow-up (approximately 16 months)]. R is the cumulative ratio calculated as the Cmax or AUC after multiple doses divided by the Cmax or AUC after the first dose.

[0279] 10. Number of participants with anti-drug antibodies (ADA) [Timeframe: Cycle 1, Day 1: from pre-dose to EOT or follow-up (approximately 16 months)]. Serum levels of antibodies against ervantumab used to assess potential immunogenicity.

[0280] 11. Progression-free survival (PFS) [Time range: until the end of treatment follow-up (30[+7] days after the last dose)]. PFS is defined as the time from the first infusion of the study drug to PD or death from any cause.

[0281] 12. Time to Treatment Failure (TTF) [Time range: until the end of treatment follow-up (30[+7] days after the last dose)]. TTF is defined as the time from the first infusion of the study drug to the discontinuation of treatment for any reason (including disease progression, treatment toxicity, death) and will be used to capture the clinical benefit of continued treatment beyond the disease progression defined in RECIST v1.1.

[0282] 13. Overall Survival (OS) [Timeframe: Follow-up until the end of treatment (30[+7] days after the last dose)]. OS is defined as the time from the first infusion of the study drug to death from any cause.

[0283] Qualification Standards Age eligible for the study: 18 years and older (adults and seniors). Genders meeting the study criteria: All. Accepting healthy volunteers: No.

[0284] Inclusion criteria • • Participants must have histologically or cytologically confirmed metastatic or unresectable non-small cell lung cancer (NSCLC). Participants must have experienced progression following prior standard-of-care therapy for metastatic disease (Cohort C and hepatocyte growth factor receptor gene [MET]-1: epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]; Cohort D: platinum-based chemotherapy; MET-2: according to regional standards of care; wild-type adenocarcinoma (WT-Ad) cohort and wild-type squamous cell carcinoma (WT-Sq) cohort: platinum-based chemotherapy and programmed death-1 / ligand-1 (PD-1 / L1) therapy, as a combination regimen or as a single line of treatment), or be ineligible or refuse all other currently available treatment options. In cases where a participant refuses currently available treatment options, this must be documented in the study record. For the Part 1 chemotherapy combination cohort only: Participants must have histologically or cytologically confirmed metastatic or unresectable NSCLC, be eligible for carboplatin and pemetrexed combination therapy according to standards of care, and be willing to receive additional exploratory therapy with ervantumab.

[0285] • For Part 1 only, dose escalation of the combination with lazatinib: Participants must have been diagnosed with an EGFR exon 19del or exon 21 L858R activating mutation and (a) be treatment-naïve for metastatic disease and not exposed to a third-generation TKI in the first-line setting, or (b) have progressed after first-line therapy with a first-generation (erlotinib or gefitinib) or second-generation (afatinib) TKI and are not eligible for inclusion in cohort MET-1, or (c) have been treated with a third-generation TKI (e.g., osimertinib) in the first-line or second-line setting and are not eligible for inclusion in cohort C or MET-1. For Part 1 chemotherapy combination cohort: Participants may be diagnosed with EGFR-mutant or EGFR-wild-type NSCLC. For Part 2 cohorts C, D, MET-1, and MET-2 only: Participants must also have a previously diagnosed disease with activating epidermal growth factor receptor (EGFR) mutations (including inhibitor-sensitive major mutations such as exon 19 deletion and exon 21). L858R (cohorts C, E, and MET-1), and commercially available anti-TKI mutations, such as exon 20 insertions (cohorts C, D, and MET-1) or activating cMet exon 14 skipping mutations (cohort MET-2). Documentation of primary activating EGFR or cMet mutations requires testing by a CLIA-certified laboratory (or equivalent). For cohorts WT-Ad and WT-Sq: Participants must have wild-type EGFR, anaplastic lymphoma kinase (ALK), and be free of MET exon 14 skipping mutations, as tested by an FDA-approved test or a CLIA-certified laboratory (or equivalent). Pathology reports or equivalents must be in the medical records for verification. Documentation of the absence of these mutations is not required for inclusion in the WT-Sq cohort if EGFR and ALK testing is not part of the standard of care for participants with squamous cell carcinoma histology.

[0286] • For Part 1: Participants must have an evaluable disease. For Part 2: Participants must have a measurable disease according to the Responsive Criteria for Solid Tumor Response (RECIST) v1.1.

[0287] • For Part 2: Cohorts A and B: Participants' EGFR-mutant disease must have recently progressed after treatment with a commercially available EGFR inhibitor. Exception: In participants diagnosed with a mutation associated with de novo EGFR inhibitor resistance (e.g., exon 20 insertion), only prior treatment with platinum-based combination chemotherapy is required. Cohort C: Participants with primary EGFR-mutant disease whose documented EGFR alterations (e.g., C797S) mediate resistance to prior treatment with a third-generation EGFR TKI (e.g., osimertinib), in participants with primary exon 20ins disease, the documented EGFR alteration may occur after treatment with a TKI with known activity against exon 20ins disease (e.g., poziotinib). Cohort D: Participants must have been previously diagnosed with EGFR exon 20 insertion and have not previously received treatment with a TKI with known activity against exon 20ins disease (e.g., poziotinib). Cohort MET-1: Participants with primary EGFR-mutant disease who have progressed with any EGFR TKI and have MET amplification or MET mutation. Participants with disease characterized by both MET amplification and EGFR resistance mutations to previous third-generation EGFR TKIs will be prioritized for Cohort C. Participants may have received or become intolerant of previous platinum-based chemotherapy. Cohort MET-2: Participants with primary MET exon 14 skipping mutation non-small cell lung cancer (NSCLC). Cohort E (combination of ervantumab and lazatinib): Participants must have been diagnosed with an EGFR exon 19del or exon 21 L858R activating mutation and have progressed with first- or second-line therapy with a third-generation TKI (e.g., osimertinib). Cohort WT-Ad: Participants must have been diagnosed with NSCLC histologically adenocarcinoma, with positive EGFR and / or MET expression as detected in an empirically validated immunohistochemical (IHC) assay performed by a central laboratory, and have progressed on prior platinum-based chemotherapy and PD-1 / L1 therapy (as a combination regimen or as a standalone line of treatment). Eligibility can be determined by IHC analysis of archived (pre-screening) or mandatory fresh tumor tissue collected during the screening period. Cohort WT-Sq: Participants must have been diagnosed with NSCLC histologically squamous cell carcinoma, with positive EGFR and / or MET expression as detected in an empirically validated IHC assay performed by a central laboratory, and have progressed on prior platinum-based chemotherapy and PD-1 / L1 therapy (as a combination regimen or as a standalone line of treatment). Eligibility can be determined by IHC analysis of archived (pre-screening) or mandatory fresh tumor tissue collected during the screening period.

[0288] • Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0289] Exclusion criteria : • Participants with uncontrolled intermittent illnesses, including but not limited to poorly controlled hypertension or diabetes, persistent or active infections (i.e., all antibiotics have been discontinued for at least one week prior to the first dose of the study drug), or mental illnesses / social conditions that would limit study compliance requirements. Participants with medical conditions requiring chronic continuous oxygen therapy were excluded. For the partial chemotherapy combination cohort only: additionally, participants with an active bleeding tendency.

[0290] • Prior to the first administration of the study drug, participants must have received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an exploratory anticancer agent within 2 weeks or 4 half-lives (whichever is longer). For agents with long half-lives, the maximum time required from the last dose is 4 weeks. Toxicity from prior anticancer therapy should have regressed to baseline or grade 1 or lower (except for alopecia [any grade], grade 2 or lower peripheral neuropathy, and grade 2 or lower hypothyroidism stabilized during hormone replacement). For Part 1 combination dose escalation: any prior treatment with systemic anticancer immunotherapy, including but not limited to antiPD-1 agents, antiPD-L1 agents, and antiCTLA-4 agents. For Part 1 chemotherapy combination cohort only: any prior treatment with systemic anticancer immunotherapy within the past 3 months or localized radiation therapy to the lungs within the past 6 months. For Part 2 only: Cohorts A and B: Prior chemotherapy for metastatic disease is not permitted unless the tumor mutation carries de novo resistance to EGFR TKIs (e.g., exon 20 insertion). Cohorts C and MET-1: Prior therapy with two or more lines of cytotoxic chemotherapy for metastatic disease (excluding maintenance therapy). Cohort D: Prior therapy with EGFR TKIs active against EGFR exon 20 insertions (such as poziotinib). Cohort E (combination of ervantumab and lazatinib): Any prior therapy in metastatic settings other than first-, second-, or third-generation EGFR TKIs. Cohorts WT-Ad and WT-Sq: More than three prior lines of systemic therapy in metastatic settings.

[0291] • Participants with untreated brain metastases. Participants with clearly defined, locally treated metastases who are clinically stable and asymptomatic for at least 2 weeks prior to study treatment and who have discontinued or received low-dose corticosteroid therapy (≤10 mg prednisone or equivalent) for at least 2 weeks are suitable. Exception: Participants with asymptomatic, untreated brain metastases (each less than 1 cm in diameter) may be eligible for combination therapy of ervantumab and lazatinib in Part 1 (dose escalation) or Part 2 (expansion cohort E).

[0292] • Participants must have a history of malignant tumors other than the disease under study within 3 years prior to screening (exceptions include squamous cell carcinoma and basal cell carcinoma of the skin, cervical carcinoma in situ, or malignant tumors that, according to the researcher's opinion and in agreement with the sponsor's medical monitor, are cured or have the lowest risk of recurrence within one year of screening).

[0293] • Participants who have not fully recovered from major surgery or severe traumatic injury before the first dose of the study drug, or who are expected to undergo major surgery during the study period or within 6 months after the last dose of the study drug.

[0294] • Participants have or will have any of the following: a. Invasive surgical procedures involving the body cavity within 4 weeks prior to Day 1 of Cycle 1 or before full recovery. Thoracentesis (if necessary) and percutaneous biopsy of baseline tumor tissue samples may be performed less than 4 weeks prior to Day 1 of Cycle 1, provided that the participant has adequately recovered from surgery prior to the first dose of study drug, based on the investigator's clinical judgment; b. Significant traumatic injury within 3 weeks prior to the start of Day 1 of Cycle 1 (all wounds must be fully healed before Day 1); c. Any medical condition requiring full wound healing capacity, and where a significant reduction in wound healing capacity during exploratory drug administration is anticipated to jeopardize the participant's safety; d. Major surgery is anticipated during exploratory drug administration or within 6 months after the last dose of study drug.

[0295] Results of the cohort that never received treatment (N=20) CHRYSALIS (NCT02609776) evaluated the combination of ervantumab (ami) and lazatinib (laz) in treatment-naïve patients (pt) with epidermal growth factor receptor (EGFR)-mutant NSCLC. As previously reported, 20 pts achieved partial response (100% overall response rate), but the interpretation of long-term results was limited by the length of follow-up (ChoAnn Oncol 2020; 31: suppl_4, 1258O; Cho J Thorac Oncol 2022; 17:S126, P1.16-01). In this article, long-term results from this treatment-naïve cohort are presented.

[0296] The treatment-naïve cohort included patients with advanced NSCLC suffering from EGFR exon 19 deletion (ex19del) or exon 21L858R mutation. All patients received 1050 mg of ervantumab intravenously (1400 mg if ≥80 kg) and 240 mg of lazatinib orally. Response was assessed by investigators according to RECIST v1.1. Circulating tumor DNA (ctDNA) was analyzed from plasma samples before treatment initiation, on day 1 of cycle 3, and at the end of treatment (EOT).

[0297] Of the 20 patients (median age 62.5 years, 55% female, all Asian) in the treatment-naïve cohort, 11 had EGFR ex19del NSCLC and 9 had exon 21 L858R NSCLC. The median follow-up and treatment duration were 33.6 months and 33.5 months, respectively. Ten patients (50%) were progression-free and maintained treatment, of whom 7 of the 11 (64%) had ex19del and 3 of the 9 (33%) had exon 21 L858R. The median duration of response (DOR), median progression-free survival (PFS), and median overall survival (OS) were not estimable. The estimated threshold PFS rate was 85% at 12 months, 65% at 24 months, and 51% at 36 months. Notably, 2 patients (10%) received treatment after progression. The longest duration of treatment for a patient (PT) was 37.2 months, with a DOR of 35.7 months. Treatment-related dose interruptions, reductions, and discontinuations occurred in 7 (35%), 8 (40%), and 1 (5%) PTs, respectively. The safety profile was consistent with previous reports, primarily involving adverse events related to targeted EGFR or MET.

[0298] Of the 10 patients who discontinued treatment, 4 submitted samples for ctDNA analysis at baseline and EOT. One patient developed a new [condition / condition]. PIK3CA Mutation, 1 pt showed low level HER2 Amplification, 1 pt showed a new CCNE1 and EGFR Amplification was performed, and no new mutations were detected in one pt. Updated ctDNA data at EOT will be available at the conference presentation.

[0299] At a median treatment duration of 33.5 months, median DOR, PFS, and OS were not reached in treatment-naïve patients receiving ervantumab plus lazatinib, with 50% remaining progression-free and on treatment. No new safety signals were identified.

[0300] Example 2. Clinical study of MARIPOSA MARIPOSA (NCT04487080) is an international phase 3 randomized study (Study 73841937NSC3003, also known as NSC3003 and Mariposa) in approximately 1,000 subjects with EGFR-mutant locally advanced or metastatic NSCLC comparing ervantuzumab and lazatinib as first-line treatment versus osimertinib versus lazatinib.

[0301] The study includes screening, treatment, and follow-up phases. Participants must complete the screening process within 28 days prior to randomization. For randomization, all participants must have a prior diagnosis of NSCLC, characterized by an EGFR mutation that replaces exon 19del or exon 21 L858R.

[0302] The treatment phase for participants will begin on day 1 of cycle 1 and continue in 28-day cycles until the end-of-treatment visit, approximately 30 days after discontinuation of study treatment. During the follow-up phase, the survival and symptom progression of participants who discontinue study treatment for any reason will be tracked. The follow-up phase begins after the end-of-treatment visit and continues until the end of the study, death, loss of follow-up, or withdrawal of consent, whichever occurs first.

[0303] describe The aim of this study was to evaluate the efficacy of the combination of ervantumab and lazatinib compared with osimertinib in participants with epidermal growth factor receptor (EGFR) mutations (exon 19 deletion [exon 19del] or exon 21 L858R substitution) in locally advanced or metastatic non-small cell lung cancer (NSCLC).

[0304] Lung cancer is the most frequently diagnosed cancer worldwide. In NSCLC, the most prevalent operational driver mutations lead to activation of the epidermal growth factor receptor (EGFR). Osimertinib and lazatinib are EGFR tyrosine kinase inhibitors (TKIs). Evantuumab is a novel bispecific antibody that targets the extracellular domains of both EGFR and MET, and can inhibit tumor growth driven by EGFR and mesenchymal-epithelial transition (MET) receptors. Lazatinib inhibits EGFR mutations involving primary activating exon 19del and exon 21 L858R substitution, as well as EGFR T790M+ resistance mutations. It is hypothesized that the combination of ervantuumab and lazatinib (Group A) will demonstrate superior PFS compared to osimertinib monotherapy (Group B). The study consists of three phases: screening, treatment, and follow-up. Participants will undergo assessments based on the Solid Tumor Response Evaluation Criteria (RECIST 1.1), pharmacokinetics, and safety (adverse events, laboratory tests, vital sign measurements, physical examination).

[0305] Research Design Research type: Intervention (clinical trial). Estimated inclusion: 1074 participants. Assignment: Randomized. Intervention model: parallel allocation. Masking: Triad (participant, researcher, outcome evaluator). Masking description: Only groups B and C will be completely masked (double-blind). Main purpose: Treatment.

[0306] Official title: Phase 3 randomized study of ervantuzumab and lazatinib combination therapy versus osimertinib versus lazatinib as first-line treatment in patients with EGFR-mutant locally advanced or metastatic non-small cell lung cancer.

[0307] Groups and Interventions Table 2 Outcome Indicators Preliminary results indicators 1. Progression-free survival (PFS) determined by a blinded independent central review (BICR) according to RECIST v1.1 [time range: up to approximately 42 months]. PFS was defined as the time from randomization to the date of objective disease progression or death (whichever occurred first) based on the BICR criteria for response to solid tumors (RECIST) v1.1.

[0308] Secondary outcome indicators 1. Overall Survival (OS) [Time Range: Up to approximately 60 months (from the randomization date to the date of death from any cause)]. Overall survival is defined as the time from the randomization date to the date the participant dies from any cause.

[0309] 2. Objective Response Rate (ORR) [Time range: up to approximately 42 months]. ORR is defined as the percentage of participants who achieve a complete response (CR) or a partial response (PR), as defined by BICR using the RECISTv1.1 standard.

[0310] 3. Duration of Response (DOR) [Time range: up to approximately 42 months]. DOR is defined only for participants who achieve a CR or PR as determined by researchers using RECIST v1.1 criteria, from the date of first recorded response (CR or PR) until the date of recorded progression or death (whichever occurs first).

[0311] 4. Progression-free survival (PFS2) after initial follow-up treatment [time range: up to approximately 42 months]. PFS2 is defined as the time from randomization to the date of the second objective disease progression, based on investigator assessment (after the assessment used for PFS) or death (whichever occurs first).

[0312] 5. Time to Symptom Progression (TTSP) [Time range: up to approximately 42 months]. TTSP is defined as the time from randomization to the date any of the following is recorded in the electronic case report form (eCRF) (whichever occurs first): the researcher considers the onset of a new symptom or symptom exacerbation to be associated with lung cancer and requires a change in anticancer treatment and / or clinical intervention to manage the symptoms.

[0313] 6. Intracranial PFS [Time range: up to approximately 42 months]. Intracranial PFS is defined as the time from randomization to objective intracranial disease progression or death (whichever comes first) based on the BICR using RECIST v1.1.

[0314] 7. Incidence and severity of adverse events (AEs) [Time range: up to approximately 60 months]. The incidence and severity of treatment-emergent adverse events (TEAEs) will be reported. Any adverse event occurring at or after the first administration of study treatment up to the day of the last dose plus 30 days, or until the start of subsequent anticancer therapy (if earlier), is considered to have occurred after treatment.

[0315] 8. Number of participants with clinical laboratory abnormalities [Time range: up to approximately 60 months]. The number of participants with clinical laboratory abnormalities (serum chemistry, hematology, blood coagulation, and urine samples) will be reported.

[0316] 9. Number of participants with abnormal vital signs [Time range: up to approximately 60 months]. The number of participants with abnormal vital signs (temperature, heart rate, respiratory rate, oxygen saturation, blood pressure) will be reported.

[0317] 10. Number of participants with abnormal medical examination results [Time range: up to approximately 60 months]. The number of participants with abnormal medical examination results will be reported.

[0318] 11. Serum concentrations of ervantumab [time range: up to approximately 42 months]. Serum samples will be analyzed to determine the concentrations of ervantumab.

[0319] 12. Lazazinib plasma concentrations [time range: up to approximately 42 months]. Plasma samples will be analyzed to determine lazazinib concentrations.

[0320] 13. Number of participants with anti-ervantumab antibodies [Time range: up to approximately 42 months]. The number of participants with antibodies against ervantumab will be reported.

[0321] 14. Changes from baseline in the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NCSLC-SAQ) [Time range: baseline to approximately 42 months]. The NSCLC-SAQ contains 7 items that assess cough, pain, dyspnea, fatigue, and loss of appetite during a 7-day review period. Visit counts and percentages will be used to summarize each multi-item scale and individual item.

[0322] 15. Changes from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [Time range: baseline to approximately 42 months]. The EORTC-QLQ-C30 is a core 30 questionnaire used to assess the health-related quality of life (HRQoL) of participants in cancer clinical research.

[0323] 16. Time to subsequent treatment (TTST) is defined as the time from the randomization date in the clinical trial to the start date of subsequent anticancer therapy after the study treatment is discontinued or the patient dies (whichever occurs first).

[0324] Qualification Standards Age eligible for the study: 18 years and older (adults and seniors). Genders meeting the study criteria: All. Accepting healthy volunteers: No.

[0325] Inclusion criteria : • Participants must have a newly diagnosed, histologically or cytologically confirmed, previously untreated, and untreatable locally advanced or metastatic non-small cell lung cancer (NSCLC) for which curative therapies include surgical resection or chemoradiotherapy.

[0326] • The tumor carries exon 19 deletion (exon 19del) or exon 21 L858R substitution, as detected by other validated tests according to field care standards in a U.S. Food and Drug Administration (FDA) approved or Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (sites within the United States) or accredited local laboratory (sites outside the United States).

[0327] • Mandate submission of unstained tissue from tumors (in sufficient quantities to allow for central analysis of EGFR mutation status and blood (for circulating tumor DNA [ctDNA], digital droplet polymerase chain reaction [ddPCR], and pharmacogenomics analysis).

[0328] • Any toxicity from previous anticancer therapies must have subsided to Grade 1 of the Common Terminology Criteria for Adverse Events (CTCAE) or the baseline level.

[0329] • According to the Response Evaluation Criteria for Solid Tumors (RECIST) v1.1, participants must have at least one previously untreated measurable lesion. Biopsies of measurable lesions should not be performed during screening, but if only one untreated measurable lesion is present, it is acceptable to undergo diagnostic biopsy and serve as a target lesion, provided that a baseline tumor assessment scan is performed at least 14 days after the biopsy.

[0330] Exclusion criteria : • Participants must have received any prior systemic therapy for locally advanced stage III or metastatic stage IV disease at any time (adjuvant or neoadjuvant therapy is permitted for stage I or II disease if administered more than 12 months prior to the development of locally advanced or metastatic disease).

[0331] • Participants have an active or past history of leptomeningeal disease.

[0332] • Participants had spinal cord compression that had never been treated. Eligible participants were those who had received definitive treatment via surgery or radiation therapy prior to randomization and whose neurological status had been stable for at least 2 weeks, provided that they had discontinued corticosteroid therapy or were receiving low-dose corticosteroid therapy of less than or equal to (≤) 10 mg / day of prednisone or an equivalent drug.

[0333] • Participants had an active or past history of interstitial lung disease (ILD) / pneumonia, including drug-induced or radiation-induced ILD / pneumonia.

[0334] • Participants are known to have allergies, hypersensitivity, or intolerance to the excipients used in ervantumab, lazatinib, or osimertinib formulations, or to have any contraindications to the use of osimertinib.

[0335] • Participants with symptomatic brain metastases. Participants with asymptomatic or previously treated and stable brain metastases may participate in this study.

[0336] Evantuzamab plus lazazetinib versus osimertinib for EGFR-mutant advanced non-small cell lung cancer First-line treatment for NSCLC patients: Preliminary results from MARIPOSA, a phase 3, global, randomized, controlled trial. The pivotal phase 3 MARIPOSA study met its primary endpoint, showing that RYBREVANT was superior to osimertinib. ® In addition, patients treated with lacezitinib showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS). ® The combination of latezatitinib demonstrated a safety profile consistent with previously reported data on the combination.

[0337] MARIPOSA (NCT04487080) is a study evaluating RYBREVANT as first-line treatment for patients with locally advanced or metastatic NSCLC who have EGFR exon 19 deletions (ex19del) or substitution mutations (such as exon 21 L858R). ® A randomized, open-label phase 3 study of lazatinib in combination with osimertinib and lazatinib alone enrolled 1,074 patients. The primary endpoint was progression-free survival (PFS) (using RECIST v1.1 guidelines), as assessed by a blinded independent central review (BICR). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), intracranial PFS, PFS after first subsequent treatment (PFS2), time to subsequent treatment (TTST), time to symptom progression (TTSP), and safety.

[0338] Methods: Patients with treatment-naïve EGFR-mutant (Ex19del or exon 21 L858R) locally advanced or metastatic NSCLC were randomized in a 2:2:1 ratio to ervantuzumab plus lazatinib (open-label), osimertinib (blinded), or lazatinib (blinded).

[0339] Results: In total, 1074 patients were randomized (evantuzumab + lazatinib, 429; osimertinib, 429; lazatinib, 216). Baseline characteristics were well balanced; median age was 63 years, 62% were female, 59% were Asian, and 41% had a history of brain metastases.

[0340] At a median follow-up of 22.0 months, the median PFS for ervantuzumab plus lazatinib was 23.7 months (95% CI, 19.1–27.7), while the median PFS for osimertinib was 16.6 months (95% CI, 14.8–18.5) (HR, 0.70; 95% CI, 0.58–0.85). P <0.001).

[0341] The PFS benefit of ervantumab plus lazatinib was consistent across predefined subgroups. In confirmed responders, the ORR for ervantumab plus lazatinib was 86% (95% CI, 83-89), and the ORR for osimertinib was 85% (95% CI, 81-88), with median DoRs of 25.8 months (95% CI, 20.1-NE) and 16.8 months (95% CI, 14.7-18.5), respectively. The median DoR was 9 months longer in the ervantumab plus lazatinib group compared to either osimertinib or lazatinib alone.

[0342] In the interim OS analysis, neither group reached the median; however, there was a strong trend to support ervantuzumab + lazatinib relative to osimertinib, with an HR of 0.80 (95% CI, 0.61 to 1.05). P =0.1). Evantuzumab plus lazatinib was associated with a higher rate of venous thromboembolism (VTE); mainly grade 1 to 2, occurring early, and with effective anticoagulation therapy. Compared with osimertinib, vantuzumab plus lazatinib was observed to have a higher rate of EGFR and MET-related adverse events.

[0343] Conclusion: Evantuzumab plus lazatinib provided a statistically significant and clinically meaningful improvement in PFS compared to osimertinib, with a 30% reduction in the risk of progression or death, a higher DoR value, and a strong trend toward improved OS. The safety profile of ervantuzumab plus lazatinib was consistent with previous reports. MARIPOSA has established ervantuzumab plus lazatinib as a new first-line standard of care for EGFR-mutant advanced NSCLC.

[0344] An exemplary illustrative overview of the MARIPOSA clinical study is shown in Figure 1 The PFS results are shown in the middle. Figures 2 to 4 The OS results are shown in the middle. Figure 5 middle.

[0345] Table 3: Summary of progression-free survival (PFS) determined by BICR Table 4: Summary of Overall Survival Results Table 5: Summary of Objective Responses Determined by BICR Table 6: Summary of DOR results confirmed by BICR Table 7: Summary of PFS2 Results Table 8: Summary of Time to Symptom Progression (TTSP) Results Table 9: Summary of Time to Subsequent Treatment (TTST) Results Table 10: Summary of intracranial PFS outcomes in participants with baseline brain metastases Table 11: Demographic Characteristics and Baseline Disease Characteristics* *ECOG stands for Eastern Cooperative Oncology and EGFR epidermal growth factor receptor. †Ethnicity or race is reported by the patient. Russia is considered part of Europe, and Türkiye is considered part of Asia. Other histological types include: adenocarcinoma and squamous cell carcinoma, lepidic adenocarcinoma, non-small cell lung cancer, pleomorphic carcinoma, and unknowns. ∥One patient in the ervantumab-lazetinib group had two EGFR mutation types (exon 19 deletion and exon 21 L858R).

[0346] Table 12: Efficacy endpoints* *The efficacy cohort includes all patients who underwent randomization. NE indicates that the efficacy is not estimable. †Progression-free survival (preliminary results) was assessed through a blinded, independent center review. ‡Objective response (complete or partial response) and duration of response were assessed through a blinded, independent, central review. The analysis included 421 patients with measurable disease at baseline in the ervantumab-lazatinib group and 414 patients in the osimertinib group. § Among the confirmed respondents.

[0347] In the interim survival analysis, the median overall survival for either group could not be estimated, of which 214 deaths were reported in the ervantuzumab-lazatinib and osimertinib groups out of the 390 expected deaths during the trial period. Figure 5 (and Table 12).

[0348] The median progression-free survival, as determined by a blinded, independent central review, was 23.7 months (95% CI, 19.1 to 27.7) in the ervantumab-lazatinib group and 16.6 months (95% CI, 14.8 to 18.5) in the osimertinib group. Figure 3 (and Table 12).

[0349] Table 13: Adverse Events* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the reduced incidence in the ervantumab-lazetinib group.

[0350] Most patients in the trial experienced at least one adverse event (Table 13). Infusion-related reactions occurred in 63% of patients treated with ervantumab-lazatinib (Table 13), with the majority occurring on day 1 of cycle 1. In the ervantumab-lazatinib group, adverse events leading to dosing interruption of any investigational drug were reported in 350 patients (83%), dose reductions were reported in 249 patients (59%), and discontinuation of any drug was reported in 147 patients (35%); the figures for the osimertinib group were 165 (39%), 23 (5%), and 58 (14%), respectively (Table 13).

[0351] Table 14: Representativeness of Research Participants EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer. * Obtained from a systematic review and meta-analysis of 456 NSCLC patient studies. †In NSCLC patients EGFR Co-occurrence of mutations; data were obtained from a systematic review of 87 studies. ‡In use EGFR In 74 studies of Ex19del and L858R NSCLC, logistic transformations were used from the fitted to EGFR The values ​​obtained from the linear mixed-effects model of the mutation endpoint are assumed to follow a binomial distribution.

[0352] Most patients are women, Asian or white, and have never smoked, representing the EGFR-mutant NSCLC population (Table 14).

[0353] Table 15: Initial and Subsequent Systemic Treatments* *The efficacy cohort includes all patients who underwent randomization (Evantumab-Lazatinib n=429 and Osimertinib n=429); the percentages shown are 116 patients in the ealumab-Lazatinib group and 171 patients in the osimertinib group who discontinued their randomization after their disease progression was assessed by the investigators.

[0354] At a median follow-up of 22.0 months, the median duration of treatment with ervantumab-lazaitinib was 18.5 months (range, 0.2 to 31.4), while the median duration of treatment with osimertinib was 18.0 months (range, 0.2 to 32.7). At the data cutoff, 230 patients (55%) in the ervantumab-lazaitinib group and 213 patients (50%) in the osimertinib group were still receiving their designated treatment. The most common reasons for discontinuation of treatment with the ervantumab-lazaitinib combination relative to osimertinib were progressive disease (86 [20%] vs. 154 [36%], respectively) and adverse events (86 [20%] vs. 50 [12%], respectively). Among patients with disease progression who discontinued their randomization, 67% in the ervantumab-lazaitinib group and 73% in the osimertinib group initiated their first subsequent treatment (Table 15).

[0355] Table 16: Response Endpoint* *The efficacy cohort includes all patients who underwent randomization. NE indicates that the efficacy is not estimable. †Objective response (complete or partial response) and duration of response were assessed through a blinded, independent, central review. The analysis included 421 patients with measurable disease at baseline in the ervantumab-lazatinib group and 414 patients in the osimertinib group. ‡Includes all respondents.

[0356] Table 17: Serious adverse events following treatment that occurred in at least 1% of patients* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the reduced incidence in the ervantumab-lazetinib group.

[0357] Grade 3 or higher adverse events were reported in 75% of patients treated with ervantumab-lazaitinib and in 43% of patients treated with osimertinib. The most common Grade 3 or higher adverse events (at least 10% in either group) were paronychia and rash. Serious adverse events were reported in 49% of patients treated with ervantumab-lazaitinib and in 33% of patients treated with osimertinib (Table 17).

[0358] Table 18: Incidence and median time to onset of selected adverse events of interest* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Includes the following preferred terms: rash, acneiform dermatitis, folliculitis, maculopapular rash, skin lesion, acne, erythema, pustular rash, dermatitis, pruritic rash, papular rash, erythematous rash, punctate rash, infectious dermatitis, erythema multiforme, papule, drug eruption, follicular rash, herpetic rash, epidermal exfoliation, epidermal detachment. ‡Includes the following preferred terms: pulmonary embolism, deep vein thrombosis, venous thromboembolism limb, thrombosis, venous thrombosis, superficial vein thrombosis, thrombophlebitis, embolism, venous thrombosis, jugular vein thrombosis, pulmonary infarction, axillary vein thrombosis, portal vein thrombosis, post-thrombotic syndrome, sigmoid sinus thrombosis, superior sagittal sinus thrombosis, vena cava thrombosis, pelvic vein thrombosis, pulmonary thrombosis. § Includes the following preferred terms: pneumonia and interstitial lung disease.

[0359] Table 19: Venous thromboembolic events and use of anticoagulation therapy* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the reduced incidence in the ervantumab-lazetinib group.

[0360] Venous thromboembolic (VTE) events were reported in 37% of patients in the ervantumab-lazaitinib group and 9% of patients in the osimertinib group (Table 18), the most common being pulmonary embolism and deep vein thrombosis (Table 19). Notably, 5% of patients in both groups received anticoagulation therapy at baseline. At the time of first VTE, anticoagulation therapy was rarely received (1% in the ervantumab-lazaitinib group and 0% in the osimertinib group). Of the VTE events, 62% occurred within the first 4 months of treatment in the ervantumab-lazaitinib group and 33% in the osimertinib group. Interstitial lung disease / pneumonia was reported in 3% of patients in both groups, with 1% being grade 3 or higher.

[0361] Table 20: Adverse events following treatment that led to treatment interruption, reduction, and discontinuation* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †The adverse events listed are those reported in at least 3% of patients in any group. ‡The listed adverse events are those reported in at least 1% of patients in any group.

[0362] The most common adverse events leading to any drug discontinuation were infusion-related reactions and paronychia (Table 20). The discontinuation rate due to treatment-related adverse events was 10% in the ervantumab-lazazinib group and 3% in the osimertinib group.

[0363] Table 21: Treatment-related adverse events* *The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the reduced incidence in the ervantumab-lazetinib group.

[0364] Table 22: All Level 5 Adverse Events* *The safety cohort includes all patients who underwent randomization and received at least one dose of any trial treatment. All Grade 5 adverse events correspond to treatment-related adverse events that resulted in death, and vice versa. †An event in the ervantumab-lazetinib group was considered to be related to any of the investigators’ research treatments. Two events in the ervantumab-lazetinib group were considered to be related to any of the investigators’ research treatments. § is considered relevant to any research treatment conducted by the researchers.

[0365] Adverse events resulted in the deaths of 34 (8%) patients in the ervantumab plus lazatinib group and 31 (7%) patients in the osimertinib group (Table 22).

[0366] Analysis showed that, compared with the osimertinib group, the ervantumab + lazatinib group had a statistically significant and clinically meaningful improvement in PFS, with a 30% reduction in the risk of progression or death. At a median follow-up of 22.0 months, the median PFS in the ervantumab + lazatinib group was 23.72 months, compared to 16.59 months in the osimertinib group (HR: 0.70; 95% CI: [0.58, 0.85], p=0.0002). There was a strong trend towards improved OS compared with osimertinib in the combination of ervantumab and lazatinib (HR: 0.80; 95% CI: [0.61, 1.05], p=0.1099). The safety profile of ervantumab was well-defined and tolerable, largely consistent with its intermediate-target activity against the EGFR and MET pathways. The safety profile of lazatinib is also well-defined and tolerable, and largely consistent with the safety profiles observed with other third-generation EGFR TKIs.

[0367] Example 3. First-line EGFR-mutant advanced non-small cell lung cancer with high-risk disease biomarkers Comparison of ervantuzumab galazineib and osimertinib in NSCLC: A secondary analysis from the phase 3 MARIPOSA study MARIPOSA (NCT04487080) is an international phase 3 randomized study (Study 73841937NSC3003, also known as NSC3003 and Mariposa) in approximately 1,000 subjects with EGFR-mutant locally advanced or metastatic NSCLC comparing ervantuzumab and lazatinib as first-line treatment versus osimertinib versus lazatinib.

[0368] In MARIPOSA, ervantuzumab plus lazatinib significantly improved PFS, PFS2, and DoR compared to osimertinib.

[0369] Key eligibility criteria: locally advanced or metastatic NSCLC, never treated for advanced disease, with EGFR Ex19del or L858R history, and ECOG PS of 0 or 1. The primary endpoint of progression-free survival (PFS) was determined by BICR according to RECIST v1.1c: ervantuzumab + lazazetinib versus osimertinib. High-risk subgroups analyzed: liver metastases, brain metastases, TP53 co-mutations, detectable EGFR mctDNAd at baseline, and no EGFR mctDNAd clearance at C3D1 (week 9). Figure 16 The detection of ctDNA and co-mutations was analyzed using next-generation sequencing (NGS) of blood at baseline. At baseline and at C3D1, ddPCR was used to analyze the detection and clearance of Ex19del and L858R ctDNA in the blood.

[0370] Primary endpoint: Progression-free survival (PFS) as determined by BICR. Evantuximab plus lazatinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months. Figure 17 ).

[0371] Patients with brain metastases: Osimertinib demonstrated a median PFS of 13.0 months in patients with brain metastases at baseline, indicating a subgroup with poor prognosis. In patients with brain metastases at baseline, ervantuzumab plus lazatinib, compared to osimertinib, reduced the risk of progression or death by 31%. Figure 18 In patients without brain metastases at baseline, ervantuzumab plus lazatinib demonstrated a consistent benefit over osimertinib: median PFS: 27.5 months vs. 19.9 months and HR 0.69 (95% CI, 0.53–0.89); P = 0.005. Figure 18 ).

[0372] Patients with liver metastases: Osimertinib demonstrated a median PFS of 11.0 months in patients with liver metastases at baseline, indicating a subgroup with poor prognosis. In patients with liver metastases at baseline, ervantuzumab plus lazatinib, compared to osimertinib, reduced the risk of progression or death by 42%. Figure 19 In patients without liver metastases at baseline, ervantuzumab plus lazatinib demonstrated a consistent benefit over osimertinib: median PFS: 24.0 months vs. 18.3 months and HR 0.74 (95% CI, 0.60–0.91); P = 0.004. Figure 19 ).

[0373] Next-generation sequencing (NGS) pathogenic mutation patterns in circulating tumor DNA (ctDNA) at baseline: 85% (540 / 636 samples) showed detectable pathogenic alterations in ctDNA by NGS at baseline. TP53 co-mutations were observed in 56% of patients from the ervantumab + lazatinib group and 53% from the osimertinib group. MET amplification occurred in one patient in each group (no high-level amplification was observed). Figure 20 ).

[0374] Patients with TP53 co-mutations: Osimertinib demonstrated a median PFS of 12.9 months in patients with TP53 co-mutations at baseline, indicating a subgroup with poor prognosis. In patients with TP53 co-mutations at baseline, ervantuzumab plus lazatinib, compared to osimertinib, reduced the risk of progression or death by 35%. Figure 21In patients with wild-type TP53 at baseline, ervantuzumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 22.1 months vs. 19.9 months and HR 0.75 (95% CI, 0.52–1.07); P = 0.114. Figure 21 ).

[0375] Detectable EGFR m ctDNA at baseline and treatment: Detection and clearance of Ex19del and L858R ctDNA in the blood by ddPCR analysis (Ex19del or L858R as determined by Biodesix ddPCR). At baseline, analyzable ctDNA samples were provided by 336 patients in the ervantuzumab + lazatinib and osimertinib groups. Approximately 70% of patients in both groups had detectable EGFR m ctDNA (Ex19del or L858R as determined by Biodesix ddPCR) at baseline. Figure 22 ). 192 patients in the ervantumab + lazazetinib group and 212 patients in the osimertinib group had matched samples at baseline and at C3D1 (week 9) (28-day cycle). At C3D1 (week 9) (28-day cycle), detectable EGFR mctDNAa was observed in 15% of these patients in both groups. Figure 22 ).

[0376] Patients with detectable baseline ctDNA (Ex19del or L858R as determined by Biodesix ddPCR): Osimertinib showed a median PFS of 14.8 months in patients with detectable ctDNA at baseline, indicating a subgroup with poor prognosis. In patients with detectable baseline ctDNA (Ex19del or L858R as determined by Biodesix ddPCR), ervantuzumab plus lazatinib, compared to osimertinib, reduced the risk of progression or death by 32%. Figure 23 In patients without detectable baseline ctDNA (Ex19del and L858R as determined by Biodesix ddPCR), ervantuzumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 27.7 months vs. 21.9 months and HR 0.72 (95% CI, 0.47–1.10); P = 0.132. Figure 23 ). In the presence of Guardant360 ® In patients with NGS-detectable baseline ctDNA, ervantuzumab plus lazatinib showed a consistent benefit superior to osimertinib (HR, 0.71 [95% CI, 0.57–0.89]; P = 0.003). Figure 23 ).

[0377] In patients who did not clear ctDNA at C3D1 (Ex19del or L858R as determined by Biodesix ddPCR, 28-day cycle): osimertinib showed a median PFS of 9.1 months in patients who did not clear ctDNA at C3D1 (Ex19del or L858R as determined by Biodesix ddPCR, 28-day cycle), indicating a subgroup with poor prognosis. In patients who did not clear ctDNA at C3D1 (Ex19del or L858R as determined by Biodesix ddPCR, 28-day cycle), ervantuzumab + lazazetinib was associated with a 51% reduction in the risk of progression or death compared to osimertinib. Figure 24 In patients with ctDNA clearance at C3D1a, ervantuzumab plus lazatinib demonstrated a consistent benefit superior to osimertinib: median PFS: 24.0 months vs. 16.5 months and HR 0.64 (95% CI, 0.48–0.87); P = 0.004. Figure 24 ).

[0378] PFS in patients with high-risk traits: In the MARIPOSA study, 89% of patients had at least one high-risk trait detected at baseline (patients with ctDNA analyzable by NGS at baseline were included in this pooled analysis. High-risk traits included baseline detectable ctDNA by NGS or baseline metastases to the liver or brain. For patients with detectable ctDNA, it was assumed that a TP53 co-mutation was identified (if present)).

[0379] In patients with high-risk profiles, ervatumab plus lazatinib significantly improved progression-free survival (PFS) compared to osimertinib in first-line EGFR-mutant (Ex19del / L858R) advanced NSCLC. These high-risk profiles included: a.) With baseline brain metastases (HR, 0.69; P=0.010) b.) With baseline liver metastases (HR, 0.58; P=0.017) c.) With TP53 co-mutation (HR, 0.65; P=0.003) d.) With detectable baseline EGFR m ctDNA (Ex19del and L858R as determined by Biodesix ddPCR) (HR, 0.68; P = 0.002) e.) No EGFR m ctDNA (Ex19del and L858R as determined by Biodesix ddPCR) was cleared at C3D1 (cycle 28 days) (HR, 0.49; P = 0.015). Figure 25 ).

[0380] It is estimated that 89% of patients had at least one high-risk feature at baseline (patients with ctDNA analyzable by NGS at baseline were included in this pooled analysis. High-risk features included baseline detectable ctDNA by NGS or baseline metastases to the liver or brain. For patients with detectable ctDNA, it was assumed that a TP53 co-mutation would be identified (if present)).

[0381] In the corresponding subgroup without high-risk characteristics, ervantumab plus lazatinib demonstrated a consistent PFS benefit superior to osimertinib. Evantumab plus lazatinib effectively overcomes the impact of high-risk characteristics and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

[0382] 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.

[0383] 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 patient population with locally advanced or metastatic non-small cell lung cancer (NSCLC) who has never received treatment and carries one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the patient population, the combination therapy comprising: (i) Therapeutic effective doses of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate, and The improvement in median PFS is relative to the median PFS of a reference group of NSCLC subjects who have never received treatment and carry one or more EGFR mutations, who have been given osimertinib or lazatinib but not the bispecific anti-EGFR / c-Met antibody.

2. A method for improving overall survival (OS) in a treatment-naïve subject or population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the subject or population of patients, the combination therapy comprising: (i) Therapeutic effective doses of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate, and The improvement in OS is relative to the OS of a reference subject or reference subject population of NSCLC who has never received treatment and carries one or more EGFR mutations, who has been given osimertinib or lazatinib but not the bispecific anti-EGFR / c-Met antibody.

3. The method according to claim 1 or 2, wherein the lazazetinib or a pharmaceutically acceptable salt or hydrate thereof is lazazetinib mesylate.

4. The method according to claim 1 or 2, wherein the lazazetinib or a pharmaceutically acceptable salt or hydrate thereof is lazazetinib mesylate monohydrate.

5. The method according to any one of claims 1 to 4, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

6. The method according to any one of claims 1 to 4, wherein the one or more EGFR mutations comprise one or more exon 19 deletions.

7. The method according to any one of claims 1 to 4, wherein the one or more EGFR mutations comprise exon 21 L858R substitution.

8. The method according to any one of claims 1 to 7, wherein the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapies, the curative therapies including surgical resection or chemoradiotherapy.

9. The method of claim 8, wherein the curative treatment includes surgical resection or radiotherapy / chemotherapy.

10. The method according to any one of claims 1 to 9, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 80 mg to about 320 mg.

11. The method according to any one of claims 1 to 10, wherein the method comprises orally administering the lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 240 mg.

12. The method according to any one of claims 1 to 11, wherein the method induces a clinical response in the subject according to RECIST v1.1 criteria.

13. The method according to any one of claims 1 to 12, wherein the method achieves a partial or better response in the subject according to RECIST v1.1 criteria.

14. The method according to any one of claims 1 to 13, wherein the clinical response comprises a median duration of response (DOR) of at least 25 months.

15. The method according to any one of claims 1 to 14, wherein the subject has no progress after at least 11 months.

16. The method according to any one of claims 1 to 15, wherein the subject has no progression after at least 23 months.

17. The method of any one of claims 1 to 16, wherein the method achieves a progression-free survival (PFS) rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

18. The method according to any one of claims 1 to 17, 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 a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO:

12.

19. The method of claim 18, wherein the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO:

16.

20. The method according to claim 18 or 19, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

21. The method according to any one of claims 1 to 20, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO:

20.

22. The method according to any one of claims 1 to 21, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

23. The method according to any one of claims 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

24. The method of claim 23, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg.

25. The method of claim 24, 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, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg.

26. The method of claim 25, 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 1050 mg.

27. The method of claim 26, 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 1400 mg.

28. The method according to any one of claims 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject.

29. The method of claim 28, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

30. The method according to any one of claims 1 to 29, wherein 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.

31. The method according to any one of claims 1 to 30, wherein the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR mctDNA, or no EGFR mctDNA clearance at C3D1.

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