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

Abstract

This disclosure provides a method for improving median progression-free survival (PFS) and overall survival in treatment-naive subjects or a treatment-naive population with EGFR-positive non-small cell lung cancer (NSCLC).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 540,742, filed on 27 September 2023, and U.S. Provisional Patent Application No. 63 / 468,375, filed on 23 May 2023, the disclosures of each of these applications being incorporated herein by reference in their entirety.

[0002] (Sequence Listing) This application includes a sequence listing submitted electronically in XML format, the entire listing of which is incorporated herein by reference. The XML copy was created on 21 May 2024, named 103693007299_SequenceListing.xml, and has a size of 20,173 bytes.

[0003] (Field of invention) This disclosure provides a method for treating EGFR-positive non-small cell lung cancer (NSCLC) in patients who have not previously received treatment. [Background technology]

[0004] Lung cancer is one of the most common cancers worldwide, with NSCLC accounting for 80–85 percent of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, a receptor tyrosine kinase that controls cell growth and division. EGFR mutations are present in 10–15 percent of Western patients with NSCLC that have adenocarcinoma tissue and occur in 40–50 percent 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 a high response rate to EGFR tyrosine kinase inhibitors (EGFR TKIs). While the majority of NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, virtually all acquire resistance that prevents a sustained response. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors exhibit increased c-Met expression, amplification of the c-Met gene, or increased levels of hepatocyte growth factor, its only known ligand (Turke et al., Cancer Cell, 17:77-88, 2010). The 5-year survival rate for all individuals with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent. Patients with EGFR ex19del or exon 21 L858R mutations have a 19 percent real-world 5-year overall survival rate.

[0006] The progression of acquired resistance to EGFR-TKIs such as osimertinib in epidermal growth factor receptor variant (EGFRm) NSCLC is likely to arise from a complex and heterogeneous pattern of resistance, along with the simultaneous development of multiple resistance mechanisms, and therefore the details of such mechanisms remain unclear. Consequently, targeted therapy presents unique challenges, and a new treatment paradigm for newly diagnosed NSCLC patients is still needed. [Overview of the project]

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

[0008] In another embodiment, the foregoing provides a method for improving overall survival (OS) in a subject or target population having treatment-naive locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, comprising administering to the subject or target population a combination therapy comprising (i) a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and (ii) a therapeutically effective dose of razertinib or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a reference subject or reference population having treatment-naive NSCLC with one or more EGFR mutations, the reference subject or reference population having been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0009] In some embodiments, lasertinib, or a pharmaceutically acceptable salt or hydrate thereof, is lasertinib mesylate. In some embodiments, lasertinib, or a pharmaceutically acceptable salt or hydrate thereof, is lasertinib mesylate monohydrate.

[0010] In some embodiments, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. In some embodiments, one or more EGFR mutations include one or more exon 19 deletions. In some embodiments, one or more EGFR mutations include exon 21 L858R substitutions.

[0011] In some embodiments, the subjects have newly diagnosed locally advanced NSCLC or metastatic NSCLC that are unsuitable for curative therapy including surgical resection or chemoradiation. In some embodiments, curative therapy includes surgical resection or chemoradiation.

[0012] In some embodiments, the method involves orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg once daily. In some embodiments, the method involves orally administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg once daily.

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

[0014] In some embodiments, subjects are progression-free after at least 11 months. In some embodiments, subjects are progression-free after at least 23 months. In some embodiments, the method achieves 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-naive population of subjects diagnosed with locally progressive or metastatic NSCLC with one or more epidermal growth factor receptor (EGFR) mutations.

[0015] In some embodiments, a 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 determination region 1 (HCDR1) containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, a light chain complementarity determination region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 containing SEQ ID NO: 7, HCDR2 containing SEQ ID NO: 8, HCDR3 containing SEQ ID NO: 9, LCDR1 containing SEQ ID NO: 10, LCDR2 containing SEQ ID NO: 11, and LCDR3 containing SEQ ID NO: 12. In some embodiments, the first domain that specifically binds 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 that specifically binds to c-Met comprises VH containing SEQ ID NO: 15 and VL containing SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the 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 branched glycan structure having a fucose content of about 1% to about 15%.

[0016] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously to a 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 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. In some embodiments, when 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. In some embodiments, when the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0017] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to a subject. In some embodiments, 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 embodiments, 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 embodiments, the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFRm ctDNA, or no EGFRm ctDNA clearance at C3D1. Brief Description of the Drawings

[0020] [Figure 1] An exemplary schematic diagram of the MARIPOSA clinical trial is shown. [Figure 2]Shows the Kaplan-Meier estimated values of progression-free survival (PFS) evaluated by the blinded independent review committee in the efficacy population including the group receiving single-agent lazertinib. PFS is indicated by the results of BICR. The dashed line indicates the median PFS in the two groups, and the check mark indicates the data cutoff. The median PFS (mPFS) in the lazertinib group was 18.5 months (95% CI, 14.8–20.1). [Figure 3] Shows the Kaplan-Meier estimated values of progression-free survival (PFS) evaluated by the blinded independent review committee in the efficacy population of amivantamab-lazertinib vs osimertinib. The dashed line indicates the median PFS in the two groups, and the check mark indicates the data cutoff. PFS by BICR was prolonged by 7.1 months for amivantamab + lazertinib vs osimertinib. [Figure 4] Shows PFS for each subgroup. [Figure 5] Shows the Kaplan-Meier estimated values of provisional overall survival. The efficacy population included all randomized patients. The check mark indicates the data cutoff. [Figure 6] Shows the Consolidated Standards of Reporting Trials (CONSORT) diagram for the clinical trial of patient treatment. 1375 patients were screened and 1074 were randomized (429 to amivantamab-lazertinib, 429 to single-agent osimertinib, and 216 to single-agent lazertinib); 1062 patients received at least one dose of the study treatment. [Figure 7]The Kaplan-Meier estimates of progression-free survival, assessed by a blinded independent review committee, are shown for patients with EGFR exon 19 deletion (top) and patients with EGFR exon 21 L858R (bottom). The efficacy population included all patients who were randomized. In both panels, hazard ratios for disease progression or death were obtained from an unstratified proportional hazards model; checkmarks indicate censored data. 95% confidence intervals (CI) widths are not adjusted for multiplicity and cannot be used to predict definitive treatment effects. EGFR represents the epidermal growth factor receptor. [Figure 8] Kaplan-Meier estimates of progression-free survival, assessed by a blinded independent review committee, are shown for Asian (top) and non-Asian (bottom) patients. The efficacy population included all patients who underwent randomization. In both panels, hazard ratios (HRs) for disease progression or death were obtained from an unstratified proportional hazards model; checkmarks indicate censored data. 95% confidence intervals are not adjusted for multiplicity and cannot be used to infer definitive treatment effects. [Figure 9] The Kaplan-Meier estimates of progression-free survival, assessed by a blinded independent review committee, are shown for patients with a history of brain metastases (top) and patients without a history of brain metastases (bottom). The efficacy population included all patients who underwent randomization. In both panels, hazard ratios for disease progression or death were obtained from an unstratified proportional hazards model; checkmarks indicate censored data. The 95% CI width is not adjusted for multiplicity and cannot be used to infer definitive treatment effects. [Figure 10]This shows Kaplan-Meier estimates of extracranial progression-free survival (CNS) as assessed by a blinded, independent review committee in the efficacy population. The efficacy population included all patients who underwent randomization. CNS was defined as the time from randomization to disease progression (detected by extracranial scan) or death. If the first progression was detected only in the CNS, these patients were censored at the time of CNS disease progression. The dashed line shows the median CNS in the two groups; the checkmark indicates data censoring. The 95% CI width is not adjusted for multiplicity and cannot be used to infer definitive treatment effects. CNS represents the central nervous system. Because MARIPOSA performed serial brain imaging, the first progression event in the CNS only was censored for sensitivity analysis. The median extracranial progression-free survival was 27.5 months (95% CI, 22.1–not estimable) in the amivantamab-lazertinib group and 18.4 months (95% CI, 16.5–20.2) in the osimertinib group. [Figure 11] Waterfall plots of the best percentage change from baseline in target lesions in the amivantamaib-lazertinib group (top) and the osimertinib group (bottom) are shown. The number of patients with measurable disease at baseline, as determined by a blinded independent review committee, was 421 in the amivantamaib-lazertinib group and 414 in the osimertinib group. Target lesions were measured as the sum of their diameters. The objective response rates were 86% (95% CI, 83–89) in the amivantamaib-lazertinib group and 85% (95% CI, 81–88) in the osimertinib group. [Figure 12]The Kaplan-Meier estimates of duration of response among confirmed responders in the efficacy population are shown. The efficacy population included all patients who were randomized. This analysis included 336 confirmed responders in the amivantamaib-lazertinib group (out of 421 patients with measurable disease at baseline as determined by a blinded independent review committee) and 314 confirmed responders in the osimertinib group (out of 414 patients). Check marks indicate censored data. The objective response rates were 86% (95% CI, 83–89) in the amivantamaib-lazertinib group and 85% (95% CI, 81–88) in the osimertinib group, with median duration of response among confirmed responders being 25.8 months (95% CI, 20.1–not estimable) and 16.8 months (95% CI, 14.8–18.5), respectively. [Figure 13] This shows the Kaplan-Meier estimate of time to treatment discontinuation in the efficacy population. The efficacy population included all patients who were randomized. Check marks indicate censored data. [Figure 14] This shows the Kaplan-Meier estimate of the time to subsequent treatment in the efficacy population. The efficacy population included all patients who were randomized. Check marks indicate censored data. [Figure 15] The Kaplan-Meier estimate of progression-free survival after the first subsequent therapy is shown, defined as the time from randomization to the earlier of objective disease progression (as determined by the principal investigator) or death after the initiation of subsequent systemic anticancer therapy. The efficacy population included all patients who were randomized. A checkmark indicates censored data. [Figure 16]The MARIPOSA trial design and methods for high-risk subgroups are presented. Circulating tumor (ctDNA) and co-mutation detection were analyzed by 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 C3D1. a. Dosage (in 28-day cycles): Amivantamab: 1050 mg weekly for the first 4 weeks (1400 mg for ≥80 kg), then every 2 weeks; Lazertinib: 240 mg daily; Osimertinib: 80 mg daily. b. The contribution of each component was evaluated, including the lasertinib monotherapy group. c. Efficacy evaluation was analyzed according to RECIST v1.1, every 8 weeks (±1 week) for the first 30 months, then every 12 weeks (±1 week). Ex19del or L858R by dBiodesix ddPCR. [Figure 17] Progression-free survival is indicated by BICR. Amivantamab plus lazertinib reduced the risk of progression or death by 30% and improved the median PFS by 7.1 months. [Figure 18] This report shows progression-free survival in patients with brain metastases. Osimertinib demonstrated a median PFS of 13.0 months in patients with brain metastases at baseline, which represented a poor prognosis subgroup. In patients with brain metastases at baseline, amivantamab plus lazertinib reduced the risk of progression or death by 31% compared to osimertinib. In patients without brain metastases at baseline, amivantamab plus lazertinib showed a consistent benefit compared to osimertinib: median PFS: 27.5 vs. 19.9 months and HR 0.69 (95% CI, 0.53–0.89); P=0.005. [Figure 19]This report shows progression-free survival in patients with liver metastases. Osimertinib demonstrated a median PFS of 11.0 months in patients with liver metastases at baseline, indicating a poor prognosis subgroup. In patients with liver metastases at baseline, amivantamab plus lazertinib reduced the risk of progression or death by 42% compared to osimertinib. In patients without liver metastases at baseline, amivantamab plus lazertinib showed a consistent benefit compared to osimertinib: median PFS: 24.0 vs. 18.3 months and HR 0.74 (95% CI, 0.60-0.91); P=0.004. [Figure 20] This shows baseline next-generation sequencing circulating tumor DNA (ctDNA) pathogenicity mutation patterns. 85% (540 / 636 samples) had pathogenic changes detected in ctDNA at baseline by NGS. TP53 comutas were observed in 56% of the amivantamab + lazertinib group and 53% of the osimertinib group. MET amplification occurred in one patient in each group (none of which were high-level amplifications). Only pathogenic mutations occurring in ≥2% of patients are shown. Pathogenic mutations were detected using the Guardant Health G360® panel. [Figure 21] This report shows progression-free survival in patients with TP53 comutas. Osimertinib demonstrated a median PFS of 12.9 months in patients with TP53 comutas at baseline, which represented a poor prognosis subgroup. In patients with TP53 comutas at baseline, amivantamab plus lasertinib reduced the risk of progression or death by 35% compared to osimertinib. In patients with wild-type TP53 at baseline, amivantamab plus lasertinib demonstrated a consistent benefit over osimertinib: median PFS: 22.1 vs. 19.9 months and HR 0.75 (95% CI, 0.52–1.07); P=0.114. [Figure 22]This report shows detectable EGFR variant (EGFRm) ctDNA at baseline and during treatment. Ex19del and L858R ctDNA in blood were detected and cleared by ddPCR. At baseline, 336 patients in both the amivantamab + lazertinib and osimertinib groups provided analyzable ctDNA samples. Approximately 70% of patients in both groups had detectable EGFRm ctDNA at baseline. 192 patients in the amivantamab + lazertinib group and 212 patients in the osimertinib group had matched samples at baseline and C3D1 (week 9). At C3D1 (week 9), detectable EGFRm ctDNA was observed in 15% of these patients in both groups. [Figure 23] This shows progression-free survival in patients with detectable baseline ctDNA (Ex19del or L858R by Biodesix ddPCR). Osimertinib showed a median PFS of 14.8 months in patients with detectable baseline ctDNA, which represented a poor prognosis subgroup. In patients with detectable baseline ctDNAa, amivantamab + lasertinib reduced the risk of progression or death by 32% compared to osimertinib. In patients without detectable baseline ctDNA, amivantamab + lasertinib showed a consistent benefit compared to osimertinib: median PFS: 27.7 vs. 21.9 months and hazard ratio 0.72 (95% CI, 0.47–1.10); P=0.132. In patients with baseline ctDNA detectable by Guardant360® NGS, amivantamab plus lasertinib demonstrated consistent benefit over osimertinib (HR, 0.71 [95% CI, 0.57~0.89]; P=0.003). [Figure 24]This shows progression-free survival in patients whose ctDNA was not cleared on C3D1 (Ex19del or L858R by Biodesix ddPCR; cycle was 28 days). Osimertinib showed a median PFS of 9.1 months in patients whose ctDNA was not cleared on C3D1, which indicated a poor prognosis subgroup. In patients whose ctDNA was not cleared on C3D1, amivantamab + lasertinib reduced the risk of progression or death by 51% compared to osimertinib. In patients whose ctDNA was cleared on C3D1, amivantamab + lasertinib showed a consistent benefit compared to osimertinib: median PFS: 24.0 vs. 16.5 months and HR 0.64 (95% CI, 0.48~0.87); P=0.004. [Figure 25] This shows progression-free survival in patients with high-risk features. In the MARIPOSA trial, 89% of patients had at least one high-risk feature detected at baseline (patients with NGS-analyzable ctDNA at baseline were included in this pooled analysis. High-risk features included NGS-detectable ctDNA at baseline, or baseline metastases in the liver or brain. For patients with detectable ctDNA, it was assumed that the TP53 comutase would be identified if present). [Modes for carrying out the invention]

[0021] definition All publications cited herein, including but not limited to patents and patent applications, are incorporated herein by reference as if they were fully described.

[0022] The terms used herein should be understood to be used solely to describe specific embodiments and not to limit them. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains.

[0023] Any methods and materials similar to or equivalent to those described herein may be used to carry out the tests of the present invention, and exemplary materials and methods are described herein. The following terms are used in describing and claiming the present invention.

[0024] Where a list is presented, please understand that, unless otherwise stated, each individual element of that list and all combinations of that list are distinct embodiments. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0025] As used herein and in the attached Claims, the singular forms "a," "an," and "the" refer to multiple subjects unless otherwise explicitly indicated. For example, a reference to "a cell" includes a combination of two or more cells.

[0026] The connecting term "and / or" between multiple enumerated elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements together. Any one of these options is understood to be included in the meaning and therefore satisfies the requirements of the term "and / or" when used herein. The simultaneous applicability of two or more of the options is also understood to be included in the meaning and therefore satisfies the requirements of the term "and / or."

[0027] The transitional phrases “comprising,” “consisting essentially of,” and “consisting” are intended to imply meanings generally accepted in patent terminology, namely, (i) “comprising” is synonymous with “containing,” “containing,” or “characterizing,” and is comprehensive or non-restrictive, not excluding additional unlisted elements or process steps; (ii) “consisting of” excludes any elements, processes, or components not specified in the claims; and (iii) “consisting essentially of” limits the scope of the claims to specified materials or processes and those that “do not substantially affect the basic and novel features” of the claimed invention. Embodiments described with the phrase “comprising” (or its synonyms) also provide embodiments described independently with “consisting” and “consisting essentially of.”

[0028] Terms such as "co-administration," "administered together," "administered in combination," and "in combination" encompass the administration of the selected therapeutic agent or drug to a single patient and are intended to include treatment regimens in which the therapeutic agent or drug is administered by the same or different routes of administration or at the same or different times.

[0029] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides, polypeptides, vectors, or viruses) that has been substantially separated and / or purified from other components of a system in which molecules are produced, such as recombinant cells, in addition to proteins subjected to at least one purification or isolation step. "Isolated" means a molecule that is substantially free of other cellular material and / or chemicals, and includes molecules isolated to a higher purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0030] "To treat," "to be treating," or "to treat" a disease or disability such as cancer means achieving one or more of the following: reducing the severity and / or duration of the disability; inhibiting the worsening of symptoms characteristic of the disability being treated; limiting or preventing recurrence of the disability in a person who previously had the disability; or limiting or preventing recurrence of symptoms in a person who previously had the disability.

[0031] To "prevent," "prevent," "prevention," or "prophylaxis" a disease or disability means to prevent the occurrence of the disability in the subject.

[0032] "To diagnose" or "diagnose" refers to determining whether a subject has a given disease or condition, or is likely to develop it in the future, or is likely to respond to treatment for a previously diagnosed disease or condition; in other words, it refers to a method of stratifying a patient population based on their likelihood of responding to treatment. Diagnosis is typically made by a physician based on general guidelines for the disease being diagnosed, or other criteria indicating that the subject is likely to respond to a particular treatment.

[0033] "Responsive," "responsive," or "likely responsive" means any kind of improvement or positive response, whether detectable or undetectable, such as reduction or recovery of one or more symptoms, a decrease in the severity of the disease, a stabilized (i.e., non-worsening) disease state, prevention of disease spread, delay or slowing of disease progression, recovery or mitigation of a disease state, and remission (whether partial or total).

[0034] "Newly diagnosed" refers to individuals who have been diagnosed with cancer (e.g., EGFR or c-Met-expressing cancer) but have not yet received treatment (e.g., treatment for lung cancer).

[0035] The "therapeutic dose" refers to the amount effective in achieving the desired therapeutic outcome at the required dosage and duration. The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or combination of drugs to induce the desired response in the individual. An example of an effective drug or combination of drugs is, for example, the patient's improved health status.

[0036] "Refractory" refers to a disease that does not respond to treatment. Refractory diseases may be resistant to treatment before or at the start of treatment, or they may become resistant during treatment.

[0037] "Recurrent" refers to the recurrence of a disease or its signs and symptoms after a period of improvement following previous treatment with medication.

[0038] "Subject" includes any human or non-human animal. "Human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. The terms "subject" and "patient" are used interchangeably in this specification.

[0039] The “reference subjects” or “reference population” refers to subjects or subjects who are treatment-naive and have one or more epidermal growth factor receptor (EGFR) mutations and are locally progressive EGFR mutant NCSLC or metastatic EGFR mutant NCSLC, and who have been administered osimertinib or lasertinib without the bispecific anti-EGFR / c-Met antibody, instead of the combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lasertinib. The reference subjects or reference population may have substantially the same disease progression as the subjects or subjects treated with the combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lasertinib. In some embodiments, the subjects and reference populations include at least two subjects. In some embodiments, the subjects and reference populations include several subjects that enable a statistically significant analysis of improvements in safety and efficacy.

[0040] "Approximately" means that a particular value is within the acceptable margin of error as determined by those skilled in the art, and this depends to some extent on the method by which the value is measured or determined, i.e., on the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless otherwise expressly stated in the example or elsewhere in this specification, "approximately" means within one standard deviation or up to 5%, whichever is greater, according to the practice of the art.

[0041] Cancer refers to the abnormal proliferation of cells that grow uncontrollably and, in some cases, tend to metastasize (spread) to other parts of the patient's body.

[0042] "EGFR or c-Met expressing cancer" refers to cancer that has detectable expression of EGFR or c-Met, or has mutations or amplifications of EGFR or c-Met. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemical analysis, flow cytometry, or Western blotting.

[0043] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, as well as its naturally occurring variants.

[0044] As used herein, “hepatocyte growth factor receptor” or “c-Met” refers to human c-Met and its native variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0045] A "bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody having 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 typically a VH / VL pair, and the bispecific anti-EGFR / c-Met antibody is monovalent with respect to binding to EGFR and c-Met.

[0046] "Specific binding," or "specific binding," or "specific binding," refers to the binding of an antibody to an antigen or an epitope within an antigen with a higher affinity than to other antigens. Typically, an antibody has a typical equilibrium dissociation constant (K). D ) has a K factor regarding binding to nonspecific antigens (e.g., BSA, casein). D At least 100 times smaller than, approximately 5 × 10 -8 Less than M, for example, about 1 × 10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or approximately 1 × 10 -12 K below M D Antibodies bind to an antigen or an epitope within an antigen. The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may cross-react to other related antigens, such as the same antigen (homolog) from other species, e.g., humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno) or Pan troglodytes (chimpanzee, chimp). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0047] The term "antibody" has a broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies such as bispecific, triplicate, and quadruplicate antibodies; dimers, tetramers, or multimers; single-chain antibodies; domain antibodies; and immunoglobulin molecules, including any other modified forms of immunoglobulin molecules containing antigen-binding sites of the required specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds, and a multimer thereof (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 are interspersed with framework regions (FRs) and can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs). Each VH and VL consists of three CDRs and four FR segments arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminus to the carboxyl terminus.

[0048] 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 those by 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). Correspondence between various descriptions and variable region numbering is documented (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). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise specified herein.

[0049] Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of their heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0050] An "antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments may be synthetic polypeptides, enzyme-available polypeptides, or genetically modified polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelid VH domains, FR3-CDR3-FR4 moieties, and other smallest recognition units consisting of amino acid residues that reproduce the CDR of an antibody, such as HCDR1, HCDR2, and / or HCDR3, as well as LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single-chain antibody designs. When the VH and VL domains are expressed in separate single-chain antibody constructs, the VH / VL domains can form intramolecular or intermolecular pairs to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or diabodies, which are described, for example, in International Publications 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047.

[0051] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules that is identical except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain, isomerization or deamidementation of amino acids, oxidation of methionine, or post-translational modifications such as deamidementation of asparagine or glutamine; in other words, an individual antibody that constitutes a population. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or polyvalent.

[0052] "Recombinant" refers to DNA, antibodies, and other proteins prepared, expressed, created, or isolated by recombinant means when segments from different sources join together to produce recombinant DNA, antibodies, or proteins.

[0053] "Bispecificity" refers to an antibody that specifically binds to two different antigens, or to two different epitopes within the same antigen. Bispecific antibodies may cross-react to other related antigens, such as human or monkey antigens, or to the same antigen (homolog) from other species, such as Macaca cynomolgus (e.g., cynomolgus, cyno) or Pan troglodytes, or they may bind to epitopes shared between two or more different antigens.

[0054] A “biosimilar” (of an approved reference product / biological drug, i.e., a reference-listed drug) refers to a biological drug that is very similar to a reference drug, based on data from analytical studies demonstrating that the biological product is very similar to the reference drug, with no clinically significant difference between the biosimilar and the reference drug in terms of safety, purity, and potency; (b) animal studies (including toxicity assessments); and / or (c) clinical trials (multiple) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use, such as the conditions under which the standard formulation is approved and the conditions under which the standard formulation is intended to be used, as well as the conditions for granting approval to the biosimilar (including immunogenicity and pharmacokinetic or pharmacodynamic assessments). A biosimilar may be an interchangeable product that can be used as a substitute for the standard formulation in a pharmacy without the intervention of a prescribing healthcare professional. To comply with further standards of "interoperability," biosimilars are required to produce the same clinical outcomes as the standard formulation in any given patient, and if the biosimilar is administered to an individual multiple times, the risk of reduced safety or efficacy from alternating or switching between the biosimilar and the standard formulation shall not exceed the risk of using the standard formulation without such alternation or switching. To the extent that the mechanism of action of the standard formulation is known, the biosimilar shall utilize the same mechanism of action for the proposed conditions of use. The proposed conditions of use, recommended or presented in the labeling for the biosimilar shall be those already approved for the standard formulation. The route of administration, dosage form, and / or potency of the biosimilar shall be the same as that of the standard formulation, and the biosimilar shall be manufactured, processed, packaged or stored in facilities that meet standards designed to ensure that the biosimilar maintains safety, purity, and potency. Biosimilars may include slight modifications to the amino acid sequence (e.g., N-terminal or C-terminal shortening) that are not expected to alter the performance of the biosimilar compared to the standard formulation.

[0055] An "antagonist" or "inhibitor" is a molecule that, when bound to a cellular protein, inhibits at least one reaction or activity induced by that protein's native ligand. A molecule is an antagonist if at least one reaction 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 at least one reaction or activity inhibited in the absence of the antagonist (e.g., a negative control), or if the inhibition is statistically significant compared to the inhibition in the absence of the antagonist.

[0056] A "PD-(L)1 axis inhibitor" refers to a molecule that inhibits PD-1 downstream signaling. A PD-(L)1 axis inhibitor may be a molecule that binds to PD-1, PD-L1, or PD-L2.

[0057] A “biological sample” refers to a collection of fluids, cells, or tissues present within a subject, in addition to similar fluids, cells, or tissues isolated from the subject. Exemplary samples include biological fluids such as blood, serum, and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tears, feces, sputum, mucosal secretions from secretory tissues and organs, vaginal secretions, ascites, fluids from the pleural cavity, pericardial cavity, peritoneal cavity, abdominal cavity, and other body cavities, fluids recovered by bronchial lavage, synovial fluid, the subject or biological origin, such as cell and organ culture media including conditioned media for cells or organs, liquid solutions in contact with lavage solutions, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine-needle aspirations, surgically excised tissues, organ cultures, or cell cultures. In a non-limiting example, a biological sample is a blood sample. In another non-limiting example, a biological sample is a plasma sample. In yet another non-limiting example, a biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA) that can be isolated from various 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.

[0058] As used in this application, "low fucose" or "low fucose content" refers to an antibody having a fucose content of approximately 1% to 15%.

[0059] As used herein, “normal fucose” or “normal fucose content” means that the antibody has a fucose content greater than approximately 50%, typically greater than approximately 80%, or greater than 85%.

[0060] As used herein, “treatment-naive” refers to a subject diagnosed with locally advanced NSCLC or metastatic NSCLC who has not yet received anti-cancer treatment for NSCLC; therefore, the subject is chemotherapy-naive and TKI-naive, meaning they have not received, for example, chemotherapy or tyrosine kinase inhibitors (including first-generation, second-generation, or third-generation TKIs), or other anti-NSCLC treatments. The method of treating a treatment-naive subject may also be called first-line treatment or front-line treatment.

[0061] As used herein, RECIST v1.1 criteria refer to the publicly available guidelines for response evaluation criteria in solid tumors described in Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247 (incorporated herein by reference). Eisenhauer et al. provide definitions of the following criteria used to determine the objective tumor response to a target lesion: - Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must be reduced to less than 10 mm in their short axis. - Partial response (PR): A reduction of at least 30% in the sum of the diameters of target lesions, relative to the sum of the diameters at baseline. - Progressive disease (PD): An increase of at least 20% in the sum of the diameters of target lesions, based on the minimum sum in the trial (including the baseline sum if it is the minimum in the trial). In addition to a 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). -Stable disease (SD): Based on the minimum sum of diameters during the trial, there is neither sufficient contraction to qualify for partial reduction (PR) nor sufficient increase to qualify for progressive reduction (PD).

[0062] As used herein, partial response or better means partial response (PR) or complete response (CR); progression-free means the absence of disease progression.

[0063] Method of Disclosure New treatment options for newly diagnosed patients with EGFR mutation-positive advanced NSCLC represent a significant unmet medical need. The 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 patients with previously untreated EGFR mutation-positive advanced NSCLC (Soria et al., N Engl J Med 2018;378:113-125).

[0064] The inventors have developed a novel method for treating EGFR mutation-positive advanced NSCLC in patients who have not received prior treatment. The inventors have further developed a method for improving median progression-free survival and / or overall survival in patients with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer who have one or more epidermal growth factor receptor (EGFR) mutations and who have not received prior treatment. Therefore, embodiments of the present invention provide a method for treating patients and / or patient populations with newly diagnosed EGFR-mutated non-small cell lung cancer (NSCLC), a method for improving median progression-free survival, and a method for improving overall survival.

[0065] Disclosed herein is a method for treating non-small cell lung cancer (NSCLC) in a patient in need of treatment, comprising administering to the patient a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has been diagnosed with locally advanced or metastatic NSCLC having one or more epidermal growth factor receptor (EGFR) mutations, and the patient is treatment-naive.

[0066] Disclosed herein is a method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, comprising administering to the target population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a reference population having NSCLC with one or more EGFR mutations, the reference population having been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0067] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC with baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0068] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC without baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0069] Also disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC with baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0070] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC without baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0071] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer having a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population having NSCLC with a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0072] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC without a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0073] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer having detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population having NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0074] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0075] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without mutational EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprising administering to the control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC without mutational EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC has one or more exon 19 deletions or exon 21 This method involves the presence of the L858R substitution and a reference population that has been administered osimertinib or razeltinib without the use of bispecific anti-EGFR / c-Met antibodies.

[0076] Disclosed herein is a method for improving the median progression-free survival (PFS) in a treatment-naive control population diagnosed with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with mutational EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprising administering to the control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in median PFS is compared to the median PFS of a treatment-naive reference control population with NSCLC having mutational EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC has one or more exon 19 deletions or exon 21 This method involves the presence of the L858R substitution and a reference population that has been administered osimertinib or razeltinib without the use of bispecific anti-EGFR / c-Met antibodies.

[0077] Disclosed herein are methods for improving overall survival (OS) in subjects or a target population having treatment-naive locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, comprising administering to the subjects or target population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a reference subject or a reference population having treatment-naive NSCLC with one or more EGFR mutations, wherein the reference subject or reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0078] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population with NSCLC with baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0079] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population with NSCLC without baseline brain metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0080] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population with baseline NSCLC with liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0081] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population with NSCLC without baseline liver metastases, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0082] Disclosed herein is a method for improving overall survival (OS) in a treatment-naive target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or target population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population having NSCLC with a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0083] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population having NSCLC without a TP53 comutase, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0084] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the control subject or control population is administered a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population having NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0085] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population having NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0086] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer that is C3D1 and lacks mutant EGFR circulating tumor DNA clearance, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population with NSCLC that is C3D1 and lacks mutant EGFR circulating tumor DNA clearance, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0087] Also disclosed herein is a method for improving overall survival (OS) in a treatment-naive control population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with C3D1 mutant EGFR circulating tumor DNA clearance, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and comprises administering to the subject or control population a combination therapy comprising a therapeutically effective dose of a bispecific anti-EGFR / c-Met antibody and a therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in OS is compared to the OS of a treatment-naive reference subject or reference population having NSCLC with C3D1 mutant EGFR circulating tumor DNA clearance, wherein the NSCLC has one or more exon 19 deletions or exon 21 L858R substitutions, and the reference population has been administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

[0088] In some embodiments, the method is performed on a subject and provides an improvement in OS compared to a reference subject. In some embodiments, the method is performed on a subject and results in an improvement in OS compared to a reference subject population. In some embodiments, the method is performed on a subject population and results in an improvement in OS compared to a reference subject population.

[0089] In some embodiments of the disclosed method, razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate. In some embodiments of the disclosed method, razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate monohydrate.

[0090] In some embodiments of the disclosed method, one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof.

[0091] In some embodiments of the disclosed method, the subject has newly diagnosed locally advanced NSCLC or metastatic NSCLC that is unsuitable for curative therapy including surgical resection or chemoradiation. In some embodiments of the disclosed method, the curative therapy includes surgical resection or chemoradiation.

[0092] In some embodiments of the disclosed method, the method comprises administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 80 mg to about 320 mg. In some embodiments of the disclosed method, the method comprises administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 240 mg.

[0093] In some embodiments of the disclosed method, the method induces a clinical response in a subject according to the RECIST v1.1 criteria. In some embodiments of the disclosed method, the method achieves a partial response or a better response in a subject according to the 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.

[0094] In some embodiments of the disclosed method, subjects are progression-free after at least 20 months. In some embodiments of the disclosed method, subjects are progression-free after at least 24 months. In some embodiments of the disclosed method, subjects are progression-free after at least 30 months. In some embodiments of the disclosed method, subjects are progression-free after at least 11 months. In some embodiments of the disclosed method, subjects are progression-free after at least 23 months. In some embodiments of the disclosed method, the method achieves PFS rates of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a treatment-naive population of subjects diagnosed with locally progressive NSCLC or metastatic NSCLC having one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed method, the method achieves 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-naive population diagnosed with locally advanced NSCLC or metastatic NSCLC having 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-naive population diagnosed with locally advanced NSCLC or metastatic NSCLC having one or more epidermal growth factor receptor (EGFR) mutations.

[0095] In some embodiments of the disclosed method, a 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, 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 the second domain that binds to c-Met comprises the 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. 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. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the 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 branched glycan structure having a fucose content of about 1% to about 15%.

[0096] In some embodiments of the disclosed method, a 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, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 containing SEQ ID NO: 7, HCDR2 containing SEQ ID NO: 8, HCDR3 containing SEQ ID NO: 9, LCDR1 containing SEQ ID NO: 10, LCDR2 containing SEQ ID NO: 11, and LCDR3 containing SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain that specifically binds 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 that specifically binds to c-Met comprises VH containing SEQ ID NO: 15 and VL containing SEQ ID NO: 16. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the 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 branched glycan structure having a fucose content of about 1% to about 15%.

[0097] 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 in doses ranging from approximately 140 mg to approximately 2240 mg. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered in doses ranging from approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1575 mg, approximately 1600 mg, approximately 2100 mg, or approximately 2240 mg. In some embodiments of the disclosed method, if the subject has a body weight of 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 has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose of 1400 mg.

[0098] 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 in a dose sufficient to achieve a therapeutic effect in the subject. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 1600 mg if the subject weighs less than 80 kg, or at a dose of 2240 mg if the subject weighs 80 kg or more. In some embodiments of the disclosed method, administration may be once every two weeks. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of 2400 mg if the subject weighs less than 80 kg, or at a dose of 3360 mg if the subject weighs 80 kg or more. In some embodiments of the disclosed method, administration may be once every three weeks.

[0099] 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.

[0100] In some embodiments of the disclosed method, the subject or target population has baseline brain metastases, baseline liver metastases, TP53 comutas, detectable baseline EGFRm ctDNA, or does not have EGFRm ctDNA clearance at C3D1. In some embodiments, the subject or target population has baseline brain metastases. In some embodiments, the subject or target population has baseline liver metastases. In some embodiments, the subject or target population has TP53 comutas. In some embodiments, the subject or target population has detectable baseline EGFRm ctDNA. In some embodiments, the subject or target population does not have EGFRm ctDNA clearance at C3D1.

[0101] In some embodiments of the disclosed method, the subjects or target population do not have baseline brain metastases, baseline liver metastases, TP53 comutas, detectable baseline EGFRm ctDNA, or EGFRm ctDNA clearance at C3D1. In some embodiments, the subjects or target population do not have baseline brain metastases. In some embodiments, the subjects or target population do not have baseline liver metastases. In some embodiments, the subjects or target population do not have TP53 comutas. In some embodiments, the subjects or target population do not have detectable baseline EGFRm ctDNA. In some embodiments, the subjects or target population have EGFRm ctDNA clearance at C3D1.

[0102] In some embodiments of the disclosed method, a 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, 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 the second domain that binds to c-Met comprises the 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. In some embodiments of the disclosed method, a 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 a second domain that specifically binds to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0103] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0104] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0105] In some embodiments of the disclosed method, a 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, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 containing SEQ ID NO: 7, HCDR2 containing SEQ ID NO: 8, HCDR3 containing SEQ ID NO: 9, LCDR1 containing SEQ ID NO: 10, LCDR2 containing SEQ ID NO: 11, and LCDR3 containing SEQ ID NO: 12. In some embodiments of the disclosed method, a first domain that specifically binds 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 a second domain that specifically binds to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16.

[0106] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0107] 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.

[0108] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1% to about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 2% to about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 3% to about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 4% to about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 11%.In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure having a fucose content of about 15%.

[0109] In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI), for example, an epidermal growth factor receptor (EGFR TKI), but not limited to the following. Non-limiting examples of TKIs include erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, razertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib.

[0110] Lazertinib is an oral, third-generation brain-penetrating EGFR TKI that targets both T790M mutations and activated EGFR mutations while preserving wild-type EGFR. An analysis of the efficacy and safety of lazertinib from the Phase 3 LASER301 (NCT04248829) trial demonstrated that lazertinib improved PFS compared to the first-generation EGFR TKI gefitinib in all pre-identified subgroups, including Asian patients, patients with the exon 21 L858R mutation, and patients with a history of brain metastases.

[0111] Lazertinib is described in International Publication No. 2016 / 060443 as N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazole-1-yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, shown below as the compound of formula I.

[0112] [ka]

[0113] Furthermore, International Publication No. 2018 / 194356 describes its salt, hydrate and crystalline forms; International Publication Nos. 2019 / 022485, 2019 / 022486, and 2019 / 022487 disclose methods for producing razertinib.

[0114] Lazertinib mesylate monohydrate is shown below as the compound of formula Ia,

[0115] [ka] This may be referred to as N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazole-1-yl]pyrimidine-2-yl]amino]-4-methoxy-2-(morpholine-4-yl)phenyl]acrylamide methanesulfonate hydrate.

[0116] therapeutic method In some embodiments, a method of the present disclosure useful for treating cancer in subjects requiring cancer treatment may involve administering an effective dose 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) to the subject.

[0117] In some embodiments, methods of the present disclosure useful for improving median progression-free survival (PFS) in a target population with cancer may include administering to subjects an effective dose of 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).

[0118] In some embodiments, methods of the present disclosure useful for improving overall survival (OS) in subjects or a target population with cancer may include administering to subjects an effective dose of 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).

[0119] In some embodiments of the disclosed method, a 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, 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 the second domain that binds to c-Met comprises the 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. 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. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the 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 branched glycan structure having a fucose content of about 1% to about 15%.

[0120] In some embodiments of the disclosed method, a 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, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 containing SEQ ID NO: 7, HCDR2 containing SEQ ID NO: 8, HCDR3 containing SEQ ID NO: 9, LCDR1 containing SEQ ID NO: 10, LCDR2 containing SEQ ID NO: 11, and LCDR3 containing SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain that specifically binds 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 that specifically binds to c-Met comprises VH containing SEQ ID NO: 15 and VL containing SEQ ID NO: 16. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is of the 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 branched glycan structure having a fucose content of about 1% to about 15%.

[0121] Administration Bispecific anti-EGFR / c-Met antibodies can be administered in a pharmaceutically acceptable carrier. “Carrier” refers to a diluent, adjuvant, excipient, or vehicle in which the antibody of the present invention is administered together. Such a vehicle may be water and a liquid oil, including oils derived from petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, or sesame oil. For example, a bispecific anti-EGFR / c-Met antibody may be formulated using 0.4% physiological saline and 0.3% glycine. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may contain sterile water, and other excipients may be added for increased solubility or preservation. Suspensions or solutions for injection may also be prepared using an aqueous carrier with appropriate additives. Suitable vehicles and formulations (including other human proteins, such as human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing, pp. 691-1092, and in particular, see pp. 958-989.

[0122] The mode of administration may be any preferred route for delivering the bispecific anti-EGFR-c-Met antibody to the host using formulations of tablets, capsules, liquids, powders, gels, or particles, for example, parenteral administration such as intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, or pulmonary, or transmucosal (oral, intranasal, intravaginal, or intrarectal), and the formulations may be contained in syringes, implantable devices, osmotic pumps, cartridges, micropumps, or other means well known in the art and recognized by those skilled in the art. Site-specific administration can be achieved, for example, by intratumor, intraarticular, intrabronchial, intraabdominal, intraarticular capsule, intracartilage, intrasinus, intracavitary, intracerebellar, intraventricular, intracolon, intracervical, intrastomical, intrahepatic, intramyocardium, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostate, intrapulmonary, intrarectum, intranephrium, intraretinal, intraspinal cord, synovial sac, intrathoracic, intrauterine, intravascular, intrabladder, intrafocal, intravaginal, rectal, oral cavity, sublingual, intranasal, or percutaneous delivery.

[0123] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0124] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. The bispecific anti-EGFR / c-Met antibody may be administered subcutaneously or intradermally in a dose sufficient to achieve a therapeutic effect in the subject.

[0125] In some embodiments, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous formulation, as disclosed in PCT International Publication No. 2022 / 224187(A1).

[0126] In some embodiments, 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 dose is 1600 mg (2240 ​​mg if the subject weighs 80 kg or more). The Q3W dose is 2400 mg (3360 mg if the subject weighs 80 kg or more).

[0127] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 1400 mg to approximately 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 1400 mg to approximately 1750 mg.

[0128] In some embodiments, the bispecific anti-EGFR / c-Met antibody is about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 又800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 10(10 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg,Approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, 1575mg, approximately 1580mg, approximately 1590mg, approximately 1600mg, about 1610mg, 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1 700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, about 1780mg, about 1790mg, about 1 800mg, about 1810mg, about 1820mg, about 1830mg, about 1840mg, about 1850mg, about 1860mg, about 1870mg, about 1880mg, 1890mg, about 19 00mg, about 1910mg, about 1920mg, about 1930mg, about 1940mg, about 1950mg, about 1960mg, about 1970mg, about 1980mg, about 1990mg, about 20 00mg, 2100mg, 2110mg, 2120mg, 2130mg, 2140mg, 2150mg, 2160mg, 2170mg, 2180mg, 2190mg, 2200m It is administered in doses of g, 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.

[0129] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 350 mg, approximately 700 mg, approximately 1050 mg, or approximately 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 1400 mg.

[0130] 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 embodiments, if the subject weighs 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

[0131] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, approximately 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, approximately 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week.

[0132] 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.

[0133] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. 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.

[0134] In some embodiments, 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.

[0135] In some embodiments, a suitable mode of administration for delivering razertinib to a target may be oral administration, for example, oral administration of tablets. Lazertinib tablet formulations suitable for oral administration according to the present invention are described, for example, in International Publication No. 2021 / 209893 and International Publication No. 2020 / 079637, which are incorporated herein by reference.

[0136] In some embodiments, lasertinib is administered in doses of approximately 10 mg to approximately 400 mg. In some embodiments, lasertinib is administered in doses of approximately 20 mg to approximately 320 mg. In some embodiments, lasertinib is administered in doses of approximately 50 mg to approximately 300 mg. In some embodiments, lasertinib is administered in doses of approximately 100 mg to approximately 300 mg. In some embodiments, lasertinib is administered in doses of approximately 150 mg to approximately 280 mg. In some embodiments, lasertinib is administered in doses of approximately 200 mg to approximately 250 mg. In some embodiments, lasertinib is administered in doses of approximately 220 mg to approximately 250 mg.

[0137] In some embodiments, lasertinib is administered in doses of approximately 20 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 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, or 400 mg. In some embodiments, lasertinib is administered in doses of approximately 240 mg.

[0138] In some embodiments, lasertinib is administered daily. In some embodiments, lasertinib is administered twice a week. In some embodiments, lasertinib is administered once a week. In some embodiments, lasertinib is administered once every two weeks. In some embodiments, lasertinib is administered once every three weeks. In some embodiments, lasertinib is administered once every four weeks.

[0139] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which may be administered using any of the doses and dosages disclosed herein. In some embodiments, razertinib is administered in doses ranging from about 10 mg to about 400 mg. In some embodiments, razertinib is administered in doses ranging from about 20 mg to about 320 mg. In some embodiments, lasertinib is administered in doses of approximately 20 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 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, or 400 mg. In some embodiments, lasertinib is administered in doses of approximately 240 mg.

[0140] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which may be administered in any of the doses and dosages disclosed herein. As an unspecified example, 700 mg of amivantamab may be administered in combination with 240 mg of razertinib. As an unspecified example, 1050 mg of amivantamab may be administered in combination with 240 mg of razertinib. As an unspecified example, 1050 mg of amivantamab may be administered in combination with 240 mg of razertinib. As an unspecified example, 1400 mg of amivantamab may be administered in combination with 240 mg of razertinib.

[0141] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which is administered daily, every other day, twice a week, or once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which is administered daily. In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with razertinib, which is administered orally.

[0142] In some embodiments, the combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI may further comprise one or more additional anticancer therapies.

[0143] In some embodiments, the methods of the present disclosure involve administering a cancer therapy that does not include a combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI as disclosed herein. In some embodiments, the cancer therapy may include any one of those described herein. As a non-limiting example, the cancer therapy that may be administered in the methods of the present disclosure may include any number of different platinum-based chemotherapy regimens or combinations thereof. As a non-limiting example, the platinum-based chemotherapy regimens may include carboplatin, cisplatin, or combinations thereof.

[0144] The anticancer therapies that can be administered in the method of this disclosure include any one or more chemotherapeutic agents or other anticancer therapeutic agents known to those skilled in the art. Chemotherapy agents are chemical compounds useful for treating cancer and include growth inhibitors or other cytotoxic agents, such as alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, and angiogenesis inhibitors. Examples of chemotherapeutic agents include alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and piposulfan; aziridines, e.g., benzodopa, carbocon, metsuredopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards, e.g., chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, fotemustine, lomustine, nimustine Ranimustine; antibiotics such as aclasinomysin, actinomycin, autramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin;Antimetabolites, e.g., methotrexate and 5-FU; folate analogs, e.g., denopterin, methotrexate, pteropterin, trimethrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, phloxuridine, etc.; androgens, e.g., carsterone, dromostanolone propionate, Epiciostanol, mepitiostane, testolactone; anti-adrenal agents, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., folic acid; acegraton; aldofamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisantren; edatraxate; defofamine; demecolsin; diazicone; elfornithine; elliptinium acetate acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; ronidamin; mitoglucon; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK(registered trademark); razoxane; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobromane; gacytosine ine); Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Members of the taxoid or taxane family, e.g., paclitaxel (TAXOL®, docetaxel (TAXOTERE®)) and their analogues; Chlorambucil; Gemcitabine; 6-Thiogunine; Mercaptopurine; Methotrexate; Platinum analogues, e.g., cisplatin and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin;Aminopterin; Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; Sorafenib (NEXAVAR®), Sunitinib (SUTENT®), Pazopanib (VOTRIENT®), Toceranib (PALLADIA®), Vandetanib (ZACTIMA®), Cediranib (RECENTIN®), Regorafenib (BAY73-4506), Axitinib (AG013736), Restaurtinib (CEP-701), Erlotinib (TARCEVA®), Gefitinib (IRESSA®), Afatinib (BIBW Examples include receptor tyrosine kinase and / or angiogenesis inhibitors, such as lapatinib (TYKERB®), neratinib (HKI-272), and any pharmaceutically acceptable salts, acids, or derivatives of any of the above. Antihormone agents that act to control or inhibit the hormonal effects on tumors, such as anti-estrogen agents including tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifen, LY 117018, onapristone, and toremifene (FARESTON®); and anti-androgen agents, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and any pharmaceutically acceptable salts, acids, or derivatives of any of the above. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al., eds.), Chapter 10, McMillan Publishing, are also applicable to the method of the present invention.

[0145] Generation of bispecific anti-EGFR / c-Met antibodies used in the methods disclosed herein An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of this disclosure is amivantamab. Amivantamab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164, which is incorporated herein by reference in its entirety. Amivantamab is characterized by the following amino acid sequence:

[0146] EGFR binding group >Sequence ID 1 (HCDR1, EGFR binding group) TYGMH >Sequence ID 2 (HCDR2, EGFR binding group) VIWDDGSYKYYGDSVKG >Sequence ID 3 (HCDR3, EGFR binding group) DGITMVRGVMKDYFDY >Sequence ID 4 (LCDR1, EGFR binding group) RASQDISSALV >Sequence ID 5 (LCDR2, EGFR binding group) DASSLES >Sequence ID 6 (LCDR3, EGFR binding group) QQFNSYPLT >Sequence ID 7 (HCDR1, c-Met binding group) SYGIS >Sequence ID 8 (HCDR2, c-Met binding group) WISAYNGYTNYAQKLQG >Sequence ID 9 (HCDR3, c-Met binding group) DLRGTNYFDY >Sequence ID 10 (LCDR1, c-Met binding group) RASQGISNWLA >Sequence ID 11 (LCDR2, c-Met binding group) AASSLLS >Sequence ID 12 (LCDR3, c-Met binding group) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding group) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >Sequence ID 14 (VL, EGFR binding group) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >Sequence ID 15 (VH, c-Met binding group) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >Sequence ID 16 (VL, c-Met binding group) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >Sequence ID 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >Sequence ID 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >Sequence ID 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >Sequence ID 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0147] In some embodiments, a 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 includes the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the 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 the second domain includes the 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.

[0148] 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.

[0149] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0150] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0151] In some embodiments, a 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, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and 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.

[0152] 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.

[0153] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0154] 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.

[0155] In some embodiments, a bispecific anti-EGFR / c-Met antibody is a biosimilar of amivantamab.

[0156] In some embodiments, non-limiting examples of amivantamab biosimilars can be found in the publicly available web resource:us.proteogenix_science / product / amivantamab-biosimilar-anti-egfr-me-rccp2-mab-research-grade / .

[0157] In some embodiments, non-limiting examples of biosimilars of amibantamab can be found in the publicly available web resource: thermofisher_com / antibody / product / amibantamab-Antibody-Recombinant-Monoclonal / MA5-42260.

[0158] In some embodiments, non-limiting examples of biosimilars of amibantamab can be found in the publicly available web resource:genemedi_net / i / biologics-biosimilar-GMP-Bios-ab-021.

[0159] In some embodiments, non-limiting examples of amivantamab biosimilars can be found in the publicly available web resource:prosci-inc_com / product / amivantamab-egfr-me-rccp2-research-grade-biosimilar-10-966 / .

[0160] In some embodiments, non-limiting examples of amibantamab biosimilars can be found in the publicly available web resource: antibodysystem_com / product / 6201.html.

[0161] In some embodiments, non-limiting examples of amivantamab biosimilars can be found in the publicly available web resource:biorbyt_com / amivantamab-biosimilar-antibody-orb1140752.html.

[0162] In one embodiment, the bispecific anti-EGFR / c-Met antibody contains one or more Fc silencing mutations.

[0163] In one embodiment, one or more Fc silencing mutations reduce affinity for the Fcγ receptor.

[0164] In one embodiment, one or more Fc silencing mutations include V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0165] In one embodiment, the bispecific anti-EGFR / c-Met antibody contains a branched glycan structure with a fucose content between approximately 1% and 15%. Antibodies with low fucose content can be produced using various methods that have been reported to successfully express relatively highly defucosylated antibodies containing branched complex-type Fc oligosaccharides, such as: control of culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012), application of variant CHO strain Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of variant CHO strain EB66 as the host cell line (Olivier et al., MAbs;2(4), 2010; electronically published before print; PMID:20562582), and application of rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473,2003), introduction of specific small interfering RNA to the α-1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908,2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or kifunensin, a potent α-mannosidase I inhibitor (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 antibody glycans enhances antibody-mediated cellular cytotoxicity (ADCC).

[0166] Other publicly available bispecific anti-EGFR / c-Met antibodies may be used in the method of this disclosure, provided they exhibit similar characteristics to amivantamab, as described in U.S. Patent No. 9,593,164. Bispecific anti-EGFR / c-Met antibodies that can be used in the method of this disclosure may also be produced by combining a publicly available EGFR-binding VH / VL domain with a c-Met-binding VH / VL domain and testing the resulting bispecific antibody for its characteristics as described in U.S. Patent No. 9,593,164.

[0167] The bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure can be generated by Fab group exchange (or half-body exchange) between two monospecific bivalent antibodies, for example, by introducing substitutions at the heavy chain CH3 interface in each half to facilitate the formation of heterodimers of two antibody halves with different specificities, either in vitro or using co-expression in a cell-free environment. The Fab group exchange reaction is the result of a disulfide bond isomerization reaction and dissociation-association of the CH3 domain. The heavy chain disulfide bond in the hinge region of the parent monospecific antibody is reduced. The resulting free cysteine ​​from one of the parent monospecific antibodies forms an intra-heavy chain disulfide bond with a cysteine ​​residue of the second parent monospecific antibody molecule, while simultaneously, the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domains of the Fab group can be manipulated to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab groups or halves, each binding to a different epitope, namely, the epitope at EGFR and the epitope at c-Met. For example, the bispecific antibody of the present invention can be produced using the technique described in International Publication No. 2011 / 131746. For IgG1 antibodies, the mutation F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild-type IgG2 and IgG2 antibodies having the F405L and R409K substitutions may be used. For IgG4 antibodies, wild-type IgG4 and IgG4 antibodies having the F405L and R409K substitutions may be used. To produce a bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are manipulated to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under sufficiently reducing conditions that allow cysteine ​​to undergo disulfide bond isomerization in the hinge region, thereby producing a bispecific antibody by Fab group exchange. The incubation conditions can, ideally, be returned to non-reducing conditions.Exemplary reducing agents that can be used include 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation can be performed at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol at a pH of 5 to 8, for example, pH 7.0 or pH 7.4, for at least 90 minutes.

[0168] 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), electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0169] In the "knob-in-hole" technique (see, for example, International Publication No. 2006 / 028936), the select amino acid forming the interface of the human IgG CH3 domain can be mutated at a position that affects CH3 domain interaction to promote heterodimer formation. An amino acid with a small side chain (the hole) is introduced into the heavy chain of an antibody that specifically binds to a first antigen, and an amino acid with a large side chain (the knob) is introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of preferential interaction between the heavy chain containing the "hole" and the heavy chain containing the "knob". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (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).

[0170] In addition to using a "knob-in-hole" technique for promoting Fab group exchange, CrossMAb technology utilizes CH1 / CL domain exchange in one of the semigroups to ensure correct light chain pairing of the resulting bispecific antibody (see, for example, U.S. Patents 8,242,247).

[0171] The full-length bispecific antibodies of the present invention may be generated by using other cross-referencing techniques to exchange variable, constant, or both domains between or within the heavy chain of the bispecific antibody, in one or both groups. Examples of such exchanges include VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1 as described in International Publications 2009 / 080254, 2009 / 080251, 2009 / 018386, and 2009 / 080252.

[0172] Other methods, such as promoting heavy chain heterodimerization by using electrostatic interactions through the substitution of a positively charged residue on one CH3 surface with a negatively charged residue on a second CH3 surface, may be used as described in U.S. Patent Application Publication 2010 / 0015133, U.S. Patent Application Publication 2009 / 0182127, U.S. Patent Application Publication 2010 / 028637, or U.S. Patent Application Publication 2011 / 0123532. In other methods, heterodimerization is performed by the following substitutions, as described in U.S. Patent Application Publication 2012 / 0149876 or U.S. Patent Application Publication 2013 / 0195849: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / This can be enhanced by T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (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).

[0173] The bispecific antibodies of the present invention may be generated using SEEDbody technology. SEEDbody has a selective IgG residue in its constant domain that is substituted with an IgA residue to promote heterodimerization, as described in U.S. Patent Application Publication No. 2007 / 0287170.

[0174] Mutations are typically performed at the DNA level on molecules such as the constant domain of an antibody, using standard methods.

[0175] Exemplary Embodiments A list of exemplary embodiments is provided below: 1a. A method to improve the median progression-free survival (PFS) in a target population with locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer that is treatment-naive and has one or more epidermal growth factor receptor (EGFR) mutations, wherein the target population (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof. This includes administering combination therapy that includes, The method involves comparing the improvement in median PFS with the median PFS of a reference population with treatment-naive NSCLC containing one or more EGFR mutations, where the reference population was administered osimertinib or razertinib without bispecific anti-EGFR / c-Met antibody. 2a. A method for improving overall survival (OS) in subjects or a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, wherein the subjects or target population (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof. This includes administering combination therapy that includes, The improvement in overall survival (OS) is compared to the OS of a reference subject or reference population with NSCLC having one or more EGFR mutations and who has not received prior treatment, and the reference subject or reference population is administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody. 3a. The method according to Embodiment 1a or 2a, wherein razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate. 4a. The method according to Embodiment 1a or 2a, wherein razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate monohydrate. 5a. The method according to any one of Embodiments 1a to 4a, wherein one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 6a. The method according to any one of Embodiments 1a to 4a, wherein one or more EGFR mutations include one or more exon 19 deletions. 7a. The method according to any one of Embodiments 1a to 4a, wherein one or more EGFR mutations include an exon 21 L858R substitution. 8a. The method according to any one of Embodiments 1a to 7a, wherein the subject has newly diagnosed locally advanced NSCLC or metastatic NSCLC that is not suitable for curative therapy including surgical resection or chemoradiotherapy. 9a. The method according to embodiment 8a, wherein the curative therapy includes surgical excision or chemoradiation. 10a. The method according to any one of Embodiments 1a to 9a, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 80 mg to about 320 mg. 11a. The method according to any one of Embodiments 1a to 10a, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 240 mg. 12a. The method according to any one of Embodiments 1a to 11a, which induces a clinical response in a subject according to the RECIST v1.1 criteria. 13a. The method according to any one of Embodiments 1a to 12a, which achieves a partial response or a better response in a subject according to the RECIST v1.1 criteria. 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. 15a. The method according to any one of Embodiments 1a to 14a, wherein the subject is progression-free after at least 11 months. 16a. The method according to any one of Embodiments 1a to 15a, wherein the subject is progression-free after at least 23 months. 17a. The method according to any one of Embodiments 1a to 16a, achieving 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-naive population of patients diagnosed with locally progressive NSCLC or metastatic NSCLC having one or more epidermal growth factor receptor (EGFR) mutations. 18a. The method according to any one of Embodiments 1a to 17a, wherein 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, the first domain comprising a heavy chain complementarity determining region 1 (HCDR1) containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the second domain that binds to c-Met comprises HCDR1 containing SEQ ID NO: 7, HCDR2 containing SEQ ID NO: 8, HCDR3 containing SEQ ID NO: 9, LCDR1 containing SEQ ID NO: 10, LCDR2 containing SEQ ID NO: 11, and LCDR3 containing SEQ ID NO: 12. 19a. The method according to Embodiment 18a, wherein the first domain that specifically binds 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 that specifically binds to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16. 20a. The method according to Embodiment 18a or 19a, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 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. 22a. The method according to any one of Embodiments 1a to 21a, wherein the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of approximately 1% to approximately 15%. 23a. The method according to any one of Embodiments 1a to 22a, wherein a bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. 24a. The method according to Embodiment 23a, wherein a bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 140 mg to approximately 2240 mg. 25a. The method according to Embodiment 24a, wherein a bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, 750 mg, 800 mg, 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. 26a. The method according to Embodiment 25a, wherein if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 27a. The method according to Embodiment 26a, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. 28a. The method according to any one of Embodiments 1a to 22a, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. 29a. The method according to Embodiment 28a, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally in a dose sufficient to achieve a therapeutic effect in the subject. 30a. The method according to any one of Embodiments 1a to 29a, wherein a 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. 31a. The method according to any one of Embodiments 1 to 30, wherein the subject or target population has baseline brain metastases, baseline liver metastases, TP53 comutation, detectable baseline EGFRm ctDNA, or does not have EGFRm ctDNA clearance at C3D1.

[0176] The following is a list of further exemplary embodiments: 1b. A method for treating non-small cell lung cancer (NSCLC) in a patient requiring treatment for NSCLC, wherein the patient (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody; and (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof. This includes administering combination therapy that includes, The subjects are diagnosed with locally progressive NSCLC or metastatic NSCLC with one or more epidermal growth factor receptor (EGFR) mutations. The target group is those who have never received treatment before, and the method is one of them. 2b. The method according to Embodiment 1b, wherein razertinib, or a pharmaceutically acceptable salt or hydrate thereof, is razertinib mesylate. 3b. The method according to Embodiment 1b, wherein lasertinib, or a pharmaceutically acceptable salt or hydrate thereof, is lasertinib mesylate monohydrate. 4b. The method according to any one of Embodiments 1b to 3b, wherein one or more EGFR mutations include one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 5b. The method according to any one of embodiments 1b to 3b, wherein one or more EGFR mutations include one or more exon 19 deletions. 6b. The method according to any one of embodiments 1b to 3b, wherein one or more EGFR mutations include an exon 21 L858R substitution. 7b. The method according to any one of Embodiments 1b to 6b, wherein the subject is treatment-naive and unsuitable for curative therapy including surgical resection or chemoradiotherapy, and has newly diagnosed locally advanced NSCLC or metastatic NSCLC. 8b. The method according to embodiment 7b, wherein the curative therapy includes surgical excision or chemoradiation. 9b. The method according to any one of Embodiments 1b to 8b, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 80 mg to about 320 mg. 10b. The method according to any one of Embodiments 1b to 9b, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 240 mg. 11b. The method according to any one of Embodiments 1b to 10b, which induces a clinical response in a subject according to the RECIST v1.1 criteria. 12b. The method according to any one of Embodiments 1b to 11b, which achieves a partial response or a better response in a subject according to the RECIST v1.1 criteria. 13b. The method according to any one of Embodiments 1b to 12b, wherein the clinical response includes a duration of response (DOR) of at least one year, at least two years, or at least three years. 14b. The method according to any one of Embodiments 1b to 13b, wherein the subject is progression-free after at least 20 months. 15b. The method according to any one of Embodiments 1b to 13b, wherein the subject is progression-free after at least 30 months. 16b. The method according to any one of Embodiments 1b to 15b, achieving a PFS rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a treatment-naive population of subjects diagnosed with locally advanced NSCLC or metastatic NSCLC having one or more epidermal growth factor receptor (EGFR) mutations. 17b. The method according to any one of Embodiments 1b to 16b, wherein 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, the first domain comprising the 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 the second domain that binds to c-Met comprising 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. 18b. The method according to Embodiment 17b, wherein 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. 19b. The method according to Embodiment 17b or 18b, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 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. 21b. The method according to any one of Embodiments 1b to 20b, wherein the bispecific anti-EGFR / c-Met antibody comprises a branched glycan structure having a fucose content of approximately 1% to approximately 15%. 22b. The method according to any one of Embodiments 1b to 21b, wherein a bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. 23b. The method according to Embodiment 22b, wherein a bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 140 mg to approximately 2240 mg. 24b. The method according to Embodiment 23b, wherein a bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, 750 mg, 800 mg, 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. 25b. The method according to Embodiment 24b, wherein if the subject has a body weight of less than 80 kg, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 26b. The method according to Embodiment 25b, wherein if the subject has a body weight of 80 kg or more, a bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg. 27b. The method according to any one of Embodiments 1b to 21b, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. 28b. The method according to Embodiment 27, wherein a bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally in a dose sufficient to achieve a therapeutic effect in the subject. 29b. The method according to any one of Embodiments 1b to 28b, wherein a 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. [Examples]

[0177] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are illustrative and not intended to limit the embodiments of the present disclosure.

[0178] Example 1. CHRYSALIS Clinical Trial CHRYSALIS (NCT02609776) is a Phase 1 human, first-line, open-label dose-escalation and expansion study of amivantamab in combination with razertinib (known as trial 61186372EDI1001, EDI1001). To be eligible for amivantamab and razertinib dose-escalation / expansion, enrolled patients must have been diagnosed with an EGFR Exon 19del or Exon 21 L858R activating mutation and be either treatment-naïve for metastatic disease without access to a third-generation TKI in the front-line setting, or have progressed after first- or second-generation front-line treatment, or have been treated with a third-generation TKI in either the front-line or second-line setting.

[0179] The initial dose cohort was a combination of amivantamab 700 / 1050 mg (i.e., 700 mg for subjects weighing less than 80 kg and 1050 mg for subjects weighing 80 kg or more) and razertinib 240 mg. The subsequent dose cohort was a combination of each drug from the monotherapy trial's RP2D, namely amivantamab 1050 / 1400 mg and razertinib 240 mg. Both dose cohorts were removed without identifying dose-limiting toxicities, and further subjects were enrolled. Pharmacokinetic (PK) data demonstrated the absence of drug-drug interactions, as the PK profiles of each drug when administered in combination were consistent with those of each drug when administered as monotherapy. Therefore, RP2D was the recommended monotherapy for each component: amivantamab, 1050 mg (less than 80 kg) / 1400 mg (80 kg or more), administered intravenously, C1 once weekly, then every two weeks, and 240 mg of razertinib orally daily.

[0180] To further characterize the safety, tolerability, and preliminary efficacy of amivantamab and razertinib in RP2D, an additional expanded cohort (Cohort E) was initiated. Forty-five subjects meeting the following criteria were enrolled: diagnosed with exon 19 del or exon 21 L858R activated EGFR mutation, and disease progression after first-line or second-line treatment prior to third-generation TKI and chemotherapy. Limited prior treatment with platinum-based chemotherapy regimens in a metastatic setting was permitted if it did not exceed two cycles and was administered prior to the initiation of the first EGFR TKI.

[0181] explanation The objectives of this study are to evaluate the safety, pharmacokinetics, and preliminary efficacy of amivantamab as monotherapy and in combination with razertinib; to determine the recommended phase 2 dose (RP2D) (monotherapy) and recommended phase 2 combination dose (RP2CD) (combination therapy); and to determine the recommended phase 2 dose (RP2Q3W) of combination chemotherapy (amivantamab in combination with standard treatment carboplatin and pemetrexed) in a 21-day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).

[0182] This open-label (all participants know the identity of the investigational drug), multicenter (two or more study sites), first-in-human trial consists of two parts. Part 1 is amivantamab monotherapy and combination dose escalation, and Part 2 is amivantamab monotherapy and combination dose expansion. In Part 1, participants with evaluable NSCLC are enrolled in cohorts at escalating dose levels of amivantamab monotherapy, RP2CD (amivantamab and lazertinib combination administered in a 28-day treatment cycle), and RP2Q3W (combination chemotherapy) (amivantamab in combination with standard treatment carboplatin and pemetrexed administered in a 21-day treatment cycle). Doses are escalated until the maximum tolerated dose (MTD, or maximum administered dose (MAD) if no MTD is found). Part 1 follows the conventional 3+3 design. Three participants complete Cycle 1 at each dose level. If no dose-limiting toxicity (DLT) occurs in these three participants, dose escalation will be continued in a new cohort of the three participants. One or more RP2D regimens will be determined using data from Part 1. In Part 2, participants with recorded epidermal growth factor receptor (EGFR) mutations and measurable disease whose disease has progressed after prior treatment will be enrolled and will receive amivantamab as monotherapy in the RP2D regimen determined in Part 1, or in combination with razertinib in the RP2CD regimen. Both parts of the study will consist of the following periods: any pre-screening period; screening period (up to 28 days before the first dose of the study drug); treatment period (from the first dose of the study drug to 30 (±7) days after the last dose of the study drug, or before the initiation of any subsequent anticancer treatment, whichever comes first); and follow-up period (approximately 6 months). All participants will be followed for survival during the post-treatment follow-up period until the end of the study, and safety will be monitored throughout the study.

[0183] Test design Study type: Intervention (clinical trial).

[0184] Estimated registrations: 780 participants.

[0185] Assignment: Non-randomized.

[0186] Intervention model: Parallel allocation.

[0187] Masking: None (open label).

[0188] Primary purpose: treatment.

[0189] Official title: Phase 1 human first-line open-label dose-escalation study of JNJ-61186372, a human bispecific EGFR and c-Met antibody, in patients with advanced non-small cell lung cancer.

[0190] Group and intervention

[0191] [Table 1]

[0192] Evaluation items Primary evaluation items 1. Part 1: Number of participants with dose-limiting toxicity (DLT) [Time frame: up to day 28]. Dose-limiting toxicity (DLT) is defined as a drug-related adverse event and includes unacceptable hematological toxicity, grade 3 or higher non-hematological toxicity, or elevated liver enzymes suggestive of drug-induced liver injury.

[0193] 2. Part 2: Number of participants with adverse events (AEs) and serious AEs [Timeframe: Screening up to follow-up (30 [+7] days after the last dose)]. An adverse event (AE) is any unfavorable medical event in a participant who received the study drug, regardless of the possibility of causal relationship. A serious adverse event (SAE) is an AE that results in any of the following outcomes or is considered serious for any other reason: death; early or prolonged hospitalization; life-threatening experience (immediate risk of death); persistent or significant disability / inability; birth defects.

[0194] 3. Part 2: Overall Response Rate (ORR) [Timeframe: End of Treatment (EOT) follow-up period (30 [+7] days after the last dose)]. Overall response rate (ORR) is defined as the percentage of participants who achieve either a complete response (CR) or a partial response (PR) according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). CR: Clearance of all target and non-target lesions. All lymph nodes must be non-pathological in terms of size (short axis less than 10 mm) and normalization of tumor marker levels; PR: Reduction of at least 30% of the sum of the diameters of target lesions, with reference to the sum of the diameters and persistence of one or more non-target lesions, and / or maintenance above the normal limit of tumor marker levels.

[0195] 4. Part 2: Duration of Response (DOR) [Timeframe: End of End-of-Treatment (EOT) follow-up period (30 [+7] days after the last dose)]. DOR is calculated as the time from the initial response of CR (clearance of all target and non-target lesions). All lymph nodes must be non-pathological only for participants who achieve CR or PR, from size (short axis < 10 [mm]) and normalized tumor marker levels, or PR (at least 30 [%] reduction in the sum of target lesion diameters, 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 limit), to progressive disease (PD) or death due to underlying disease, whichever comes first.

[0196] 5. Part 2: Percentage of participants with clinical benefit [Timeframe: End of Occupational Therapy (EOT) follow-up period (30 [+7] days after the last dose)]. The clinical benefit rate is defined as complete response (CR): the percentage of participants who achieve clearance of all target and non-target lesions. All lymph nodes must be non-pathological in size (<10 mm short axis) and normalized tumor marker levels or partial response (PR): a reduction of at least 30 percent (%) of the total diameter of target lesions, 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 limit, or permanent stable disease (no reduction sufficient to qualify for PR and no increase sufficient to qualify for progressive disease (PD), with reference to the minimum sum of diameters during the study and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limit).

[0197] 6. Trough serum concentration of amivantamab [Time frame: up to EOT (30 days after the last dose)]. The trough is the observed serum concentration immediately before the next dose.

[0198] 7. Area under the curve (AUCtau) of amivantamab from time zero to the end of the dosing interval [time frame: up to EOT (30 days after the last dose)]. AUCtau is the area under the serum concentration-time curve during the dosing interval period (tau).

[0199] Secondary evaluation items 1. Maximum serum concentration (Cmax) of amivantamab [Time frame: Day 1 of Cycle 1: From before administration to end of infusion (EOT) or follow-up (approximately 16 months) (each cycle is 28 days)]. Cmax is the maximum serum concentration of amivantamab observed.

[0200] 2. Time to reach the observed maximum serum concentration (Tmax) of amivantamab [Time frame: Day 1 of Cycle 1: From administration to EOT or observation (approximately 16 months)]. Tmax is defined as the time to reach the observed maximum serum concentration of amivantamab.

[0201] 3. Area under the serum concentration-time curve (AUC[t1-t2]) for amivantamab from time t1 to t2 [Time frame: Day 1 of Cycle 1: From pre-administration to EOT or follow-up (approximately 16 months)]. AUC(t1-t2) is the area under the serum amivantamab concentration-time curve from time t1 to t2.

[0202] 4. Area under the curve (AUCtau) of amivantamab from time 0 to the end of the dosing interval [Time frame: Day 1 of Cycle 1: From pre-administration to EOT or follow-up (approximately 16 months)]. AUCtau is the area under the serum concentration-time curve during the dosing interval period (tau).

[0203] 5. Trough serum concentration of amivantamab [Time frame: Day 1 of Cycle 1: From before administration to EOT or follow-up (approximately 16 months)]. The trough is the serum concentration observed immediately before the next administration.

[0204] 6. Maximum serum concentration (Cmax) of razertinib [Time frame: Day 1 of Cycle 1: From administration to EOT (30 [+7] days after the last dose [Day 15 of Cycle 4]) (each cycle is 28 days)]. Cmax is the maximum serum concentration of razertinib observed.

[0205] 7. Time to reach the observed maximum serum concentration (Tmax) of razertinib [Time frame: Day 1 of Cycle 1: From administration to EOT (30 [+7] days after the last dose [Day 15 of Cycle 4]) (each cycle is 28 days)]. Tmax is defined as the time to reach the observed maximum serum concentration of razertinib.

[0206] 8. Trough serum concentration of razertinib [Time frame: Day 1 of Cycle 1: From before administration to EOT (30 [+7] days after the last dose [Day 15 of Cycle 4]) (Each cycle is 28 days)]. The trough is the serum concentration observed immediately before the next dose.

[0207] 9. Amivantamab accumulation rate (R) [Time frame: Day 1 of Cycle 1: From pre-administration to EOT or follow-up (approximately 16 months)]. R is the accumulation ratio calculated by dividing the Cmax or AUC after multiple doses by the Cmax or AUC after the first dose, respectively.

[0208] 10. Number of participants with anti-drug antibodies (ADA) [Time frame: Day 1 of Cycle 1: From pre-administration to EOT or follow-up (approximately 16 months)]. Serum levels of antibodies against amivantamab for assessment of potential immunogenicity.

[0209] 11. Progression-free survival (PFS) [Time frame: up to the end of treatment follow-up period (30 [+7] days after the last dose)]. PFS is defined as the period from the first infusion of the investigational drug to PD or death from any cause.

[0210] 12. Time to Treatment Failure (TTF) [Timeframe: up to the end of treatment follow-up period (30 [+7] days after the last dose)]. TTF is defined as the period from the first infusion of the investigational drug until treatment is discontinued for any reason, such as disease progression, treatment toxicity, or death, and is used to capture the clinical benefit for patients who continue treatment beyond disease progression as defined in RECIST v1.1.

[0211] 13. Overall Survival (OS) [Timeframe: up to the end of treatment follow-up period (30 [+7] days after the final dose)]. OS is defined as the period from the first infusion of the investigational drug to death from any cause.

[0212] Eligibility criteria. Eligible age for the exam: 18 years or older (adults, seniors).

[0213] Eligible gender for the exam: All.

[0214] Acceptance of healthy volunteers: number.

[0215] Inclusion criteria: Participants must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is metastatic or unresectable. Participants must have progressed after previous standard treatment (Cohort C and hepatocyte growth factor receptor [MET]-1: epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]; Cohort D: platinum-based chemotherapy; MET-2: regional standard treatment; Cohort wild-type adenocarcinoma (WT-Ad) and wild-type squamous cell carcinoma (WT-Sq): platinum-containing chemotherapy for metastatic disease and programmed death-1 / ligand-1 (PD-1 / L1) therapy (either as a combination regimen or separate treatment line), or be ineligible for or have refused all other currently available treatment options. If a participant refuses any currently available treatment options, this must be recorded in the study record. For Part 1 combination chemotherapy cohorts only: Participants must have histologically or cytologically confirmed metastatic or unresectable NSCLC, be eligible for treatment with carboplatin and pemetrexed combination according to standard treatment, and be willing to receive additional investigational treatment with amivantamab. Regarding the Part 1 combination dose escalation using razertinib alone: ​​Participants must be diagnosed with an EGFR exon 19 del or exon 21 L858R activating mutation and must either (a) be treatment-naïve for metastatic disease without access to a third-generation TKI in a front-line setting, or (b) have progressed after front-line treatment with a first-generation (erlotinib or gefitinib) or second-generation (afatinib) TKI and be ineligible for Cohort MET-1, or (c) have been treated with a third-generation TKI (e.g., osimertinib) in either a front-line or second-line setting and be ineligible for enrollment in either Cohort C or MET-1. Regarding the Part 1 combination chemotherapy cohort: Participants may be diagnosed with EGFR-mutated NSCLC or EGFR wild-type NSCLC. For Part 2 cohorts C, D, MET-1, and MET-2 only: Participants must also have a disease with a previously diagnosed activated epidermal growth factor receptor (EGFR) mutation (including both inhibitor-sensitive primary mutations such as exon 19 deletion and exon 21 L858R (cohorts C, E, and MET-1)), as well as a commercially available TKI-resistant mutation such as exon 20 insertion (cohorts C, D, and MET-1) or activated cMet exon 14 skipping mutation (cohort MET-2). Documentation of primary activated EGFR or cMet mutation eligibility by testing at a CLIA-accredited laboratory (or equivalent) is required. For Part 2 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 a Food and Drug Administration (FDA)-approved laboratory or CLIA-accredited laboratory (or equivalent). Pathology reports or equivalents must be in the medical record for verification. If testing for EGFR and ALK is not part of the standard treatment for participants with squamous cell carcinoma histology, documentation of the absence of these mutations is not required for enrollment in the WT-Sq cohort. Regarding Part 1: Participants must have a measurable disease. Regarding Part 2: Participants must have a measurable disease according to the Response Criteria in Solid Tumors (RECIST) v1.1. • Regarding Part 2: Cohorts A and B: Participants' EGFR mutation-type disease must have progressed most recently after treatment with a commercially available EGFR inhibitor. Exception: Participants diagnosed with a mutation associated with de novo EGFR inhibitor resistance (e.g., exon 20 insertion) are only required to have received prior treatment with combination platinum-based chemotherapy. Cohort C: Participants with primary exon 20 ins disease who have a recorded EGFR alteration (e.g., C797S) that mediates resistance to prior treatment with a third-generation EGFR TKI (e.g., osimertinib), and whose recorded EGFR alteration may occur after treatment with a TKI with known activity against exon 20 ins disease (e.g., poziotinib). Cohort D: Participants must have been previously diagnosed with an EGFR exon 20 insertion and must not have been previously treated with a TKI with known activity against exon 20 ins disease (e.g., poziotinib). Cohort MET-1: Participants with a recorded primary EGFR mutation and who have progressed with any EGFR TKI and subsequently developed MET amplification or a recorded MET mutation. Participants with disease characterized by both MET amplification and EGFR resistance mutations to previous third-generation EGFR TKIs will be preferentially enrolled in Cohort C. Participants have previously received or been intolerant to platinum-based chemotherapy. Cohort MET-2: Participants with a recorded primary MET exon 14 skipping mutation in non-small cell lung cancer (NSCLC). Cohort E (amivantamab and lazertinib combination): Participants must have been diagnosed with an EGFR exon 19 del or exon 21 L858R activating mutation and have progressed after first-line or second-line treatment with a third-generation TKI (e.g., osimertinib). Cohort WT-Ad: Participants must be diagnosed with NSCLC of adenocarcinoma histology, have positive EGFR and / or MET expression detected by validated immunohistochemistry (IHC) assays performed by a central laboratory, and have progressed with prior platinum-containing chemotherapy and PD-1 / L1 therapy, either as a combination regimen or separate lines of treatment.Eligibility may be determined through IHC analysis of either archived (pre-screening) or mandatory fresh tumor tissue collected during the screening period. Cohort WT-Sq: Participants must be diagnosed with NSCLC in squamous cell carcinoma tissue, have positive EGFR and / or MET expression detected by a validated IHC assay performed by a central laboratory, and have progressed with prior platinum-containing chemotherapy and PD-1 / L1 therapy, either as a combination regimen or separate lines of treatment. Eligibility may be determined through IHC analysis of either archived (pre-screening) or mandatory fresh tumor tissue collected during screening. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0216] Exclusion criteria: Participants have uncontrolled interventional illnesses, including but not limited to poorly controlled hypertension or diabetes, ongoing or active infections (i.e., all antibiotics discontinued for at least one week prior to the first dose of the study drug), or psychotic / social conditions that limit compliance with study requirements. Participants with conditions requiring long-term continuous oxygen therapy are excluded. For the Part 1 combination chemotherapy cohort only: Additionally, participants with active bleeding tendencies. • Participants had received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with the investigational anticancer drug within two weeks prior to the first dose of the investigational drug or within four half-lives, whichever is longer. For drugs with long half-lives, the maximum required time from the last dose is four weeks. Toxicity from previous anticancer therapy should have subsided to baseline levels or grade 1 or less (excluding alopecia [any grade], peripheral neuropathy of grade 2 or less [<=], and hormone replacement-stable hypothyroidism of grade < 2 [<]). Part 1 combination dose escalation: Prior treatment with systemic anticancer immunotherapy, including but not limited to anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents. Part 1 chemotherapy combination cohort only: Prior treatment with systemic anticancer immunotherapy in the past three months or local radiotherapy to the lungs within the past six months. Part 2 only: Prior chemotherapy for metastatic disease is not permitted unless the tumor mutation possesses de novo resistance to EGFR TKIs (e.g., exon 20 insertion). Cohort C and MET-1: Prior treatment with two or more lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy not included). Cohort D: Prior treatment with an EGFR TKI (such as poziotinib) that has activity against EGFR exon 20 insertion. Cohort E (amivantamab and lazertinib combination): Any prior treatment in a metastatic situation using something other than a first, second, or third-generation EGFR TKI. Cohorts WT-Ad and WT-Sq: Three or more lines of systemic prior treatment in a metastatic setting. • Participants with untreated brain metastases. Participants must have definitively locally treated metastases that have been clinically stable and asymptomatic for at least two weeks and have not received or have not received low-dose corticosteroid treatment (prednisone or equivalent at ≤10 mg) at least two weeks prior to the study treatment. Exception: Participants with asymptomatic, untreated brain metastases less than 1 cm in diameter may be eligible for amivantamab and lasertinib combination therapy in Part 1 combination dose escalation or Part 2 combination expansion cohort E. • Participants must have a history of malignant tumors other than the disease being investigated within three years prior to screening (with the exception of squamous cell carcinoma and basal cell carcinoma of the skin, and carcinoma in situ of the cervix, or malignant tumors that are considered cured or have a minimal risk of recurrence within one year of screening, in the opinion of the principal investigator in coordination with the sponsor's medical monitor). Participants must not have fully recovered from major surgery or significant trauma prior to the first dose of the study drug, or must be scheduled to undergo major surgery during the study period or within six months after the last dose of the study drug. a. Participants have or are scheduled to have any of the following: an invasive surgical procedure involving entry into a body cavity within four weeks prior to day 1 of cycle 1, or that will not fully recover. a. Thoracentesis (if necessary) and percutaneous biopsy for baseline tumor tissue samples may be performed less than four weeks prior to day 1 of cycle 1, if the participant has adequately recovered from surgery before the first dose of the investigational drug, in the clinical judgment of the principal investigator; b. a major traumatic injury within three weeks prior to the start of day 1 of cycle 1 (all wounds must be fully healed prior to day 1); c. any medical condition requiring full wound healing capacity that is expected to jeopardize the participant's safety if wound healing capacity is significantly impaired during administration of the investigational drug; d. a planned major surgery during or within six months after the last dose of the investigational drug.

[0217] Results from the treatment-naive cohort (N=20) CHRYSALIS (NCT02609776) evaluated the combination of amivantamab (ami) and lazertinib (laz) in treatment-naive patients (pts) with epidermal growth factor receptor (EGFR) mutant NSCLC. As previously reported, 20 patients achieved partial response (100% overall response rate), but the interpretation of long-term outcomes was limited by the length of follow-up (Cho Ann Oncol 2020;31:suppl_4, 1258O;Cho J Thorac Oncol 2022;17:S126,P1.16-01). This specification presents the long-term results from this treatment-naive cohort.

[0218] The treatment-naive cohort enrolled patients with EGFR exon 19 deletion (ex19del) or exon 21 L858R mutation-type progressive NSCLC. All patients received 1050 mg of IV ami (1400 mg if ≥80 kg) and 240 mg of oral laz. Responses were assessed by the principal investigator 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 end of treatment (EOT).

[0219] Of the 20 patients enrolled in the treatment-naive cohort (median age 62.5 years, 55% female, all Asian), 11 had EGFR ex19del and 9 had exon 21 L858R NSCLC. The median follow-up and treatment durations were 33.6 months and 33.5 months, respectively. Ten patients (50%) were progression-free and remained in treatment, including 7 (64%) of the 11 with ex19del and 3 (33%) of the 9 with exon 21 L858R. Median duration of response (DOR), median progression-free survival (PFS), and median overall survival (OS) were not estimable. Estimated landmark PFS rates were 85% at 12 months, 65% at 24 months, and 51% at 36 months. Notably, 2 (10%) patients were treated beyond progression. The patient with the longest treatment duration had a treatment period of 37.2 months and a duration of treatment (DOR) of 35.7 months. Interruption, reduction, and discontinuation of treatment-related administration of either ami or laz occurred in 7 patients (35%), 8 patients (40%), and 1 patient (5%), respectively. The safety profile was consistent with previous reports, mainly involving on-target EGFR or MET-related adverse events.

[0220] Of the 10 patients who discontinued treatment, 4 submitted samples for ctDNA analysis at both baseline and EOT. There was 1 pt with a new PIK3CA mutation, 1 pt with low-level HER2 amplification, 1 pt with new CCNE1 and EGFR amplifications, and 1 pt with no new mutations detected. Updated data on ctDNA at EOT may be available at the time of conference presentation.

[0221] At the median treatment duration of 3 months, median DOR, PFS, and OS were not reached in treatment-naive patients receiving ami + laz, and 50% remained progression-free and on treatment. No new safety signals were reported.

[0222] Example 2. MARIPOSA Clinical Trial MARIPOSA (NCT04487080) is an international, phase 3, randomized trial of amivantamab and lazertinib combination therapy vs osimertinib vs lazertinib as first-line treatment in approximately 1,000 subjects with EGFR-mutated, locally advanced NSCLC or metastatic NSCLC (Study 73841937NSC3003, NSC3003, and also known as Mariposa).

[0223] This trial includes a screening phase, a treatment phase, and a follow-up phase. Participants must complete screening procedures within 28 days prior to randomization. For randomization, all participants must have been previously diagnosed with NSCLC characterized by exon 19 del or exon 21 L858R substitution EGFR mutations.

[0224] The treatment phase for participants starts on day 1 of cycle 1 and continues as 28-day cycles up to the end-of-treatment visit, approximately 30 days after discontinuation of study treatment. Participants who discontinue study treatment for any reason are followed for survival and symptom progression during the follow-up phase. The follow-up phase starts after the end-of-treatment visit and continues until either the end of the study, death, loss to follow-up, or early withdrawal of consent, whichever comes first.

[0225] explanation The purpose of this study is to evaluate the efficacy of the combination of amivantamab and lazertinib compared to osimertinib in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for epidermal growth factor receptor (EGFR) mutations (exon 19 deletion [exon 19 del] or exon 21 L858R substitution).

[0226] Lung cancer is the most commonly diagnosed cancer worldwide. In NSCLC, the most common actionable driver mutations result in activation of the epidermal growth factor receptor (EGFR). Osimertinib and razertinib are EGFR tyrosine kinase inhibitors (TKIs). Amivantamab 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. Razertinib inhibits primary activating exon 19 del and exon 21 L858R substitution EGFR mutations, as well as EGFR T790M+ resistance mutations. The hypothesis is that the combination of amivantamab and razertinib (Group A) will show superior PFS compared to osimertinib monotherapy (Group B). This trial consists of three phases: a screening phase, a treatment phase, and a follow-up phase. Participants will undergo evaluations of response criteria for solid tumors (RECIST 1.1), pharmacokinetics, and safety (adverse events, clinical laboratory tests, vital signs measurement, and physical examinations).

[0227] Test design Study type: Intervention (clinical trial).

[0228] Estimated registrations: 1074 participants.

[0229] Assignment: Randomized.

[0230] Intervention model: Parallel allocation.

[0231] Masking: Triple (participants, principal investigators, outcome assessors).

[0232] Masking explanation: Only groups B and C are masked for all (double-blind).

[0233] Primary purpose: treatment.

[0234] Official title: A Phase 3 Randomized Trial of Amivantamab and Lazertinib vs. Osimertinib vs. Lazertinib as First-Line Treatment in Patients with EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

[0235] Group and intervention

[0236] [Table 2]

[0237] Evaluation items Primary evaluation items 1. Progression-free survival (PFS) will be assessed by a blinded independent review committee (BICR) according to RECIST v1.1 [timeframe: up to approximately 42 months]. PFS will be defined as the time from randomization to the first occurrence of objective disease progression or death, based on the BICR using the Response Assessment Criteria (RECIST) v1.1 in solid tumors.

[0238] Secondary evaluation items 1. Overall Survival (OS) [Timeframe: up to approximately 60 months (time from the date of randomization to the date of death from any cause)]. Overall survival is defined as the time from the date of randomization to the date of death of the participant from any cause.

[0239] 2. Objective Response Rate (ORR) [Timeframe: up to approximately 42 months]. ORR is defined as the percentage of participants who achieve either a complete response (CR) or a partial response (PR), as defined by BICR using the RECIST v1.1 criteria.

[0240] 3. Duration of Response (DOR) [Timeframe: up to approximately 42 months]. DOR is defined as the time from the date of the first documented response (CR or PR), for participants who achieved CR or PR as determined by the Investigator using RECIST v1.1 criteria, to the earlier of the date of documented progression or death.

[0241] 4. Progression-Free Survival After the First Subsequent Therapy (PFS2) [Timeframe: up to approximately 42 months]. PFS2 is defined as the time from randomization to the date of the second objective disease progression after the initiation of subsequent anti-cancer therapy, based on either the Investigator's assessment (after PFS has been used) or death, whichever comes first.

[0242] 5. Time to Symptomatic Progression (TTSP) [Timeframe: up to approximately 42 months]. TTSP is defined as the time from randomization to documentation in the electronic case report form (eCRF) of either (whichever comes first): the onset of new symptoms or worsening of symptoms that are considered by the Investigator to be related to lung cancer and require either a change in anti-cancer therapy and / or clinical intervention to manage the symptoms.

[0243] 6. Intracranial PFS [Timeframe: up to approximately 42 months]. Intracranial PFS is defined as the time from randomization to the earlier of the date of objective progression of intracranial disease or death, based on BICR using RECIST v1.1.

[0244] 7. Incidence and Severity of Adverse Events (AE) [Timeframe: up to approximately 60 months]. Report the incidence and severity of treatment-emergent adverse events (TEAE). Any adverse event that occurs at the first administration of the study treatment or thereafter, up to 30 days after the last dose or until the initiation of subsequent anti-cancer therapy (whichever is earlier) is considered to be treatment-emergent.

[0245] 8. Number of Participants with Clinical Laboratory Abnormalities [Timeframe: up to approximately 60 months]. Report the number of participants with clinical laboratory abnormalities (serum chemistry, hematology, blood coagulation, and urine samples).

[0246] 9. Number of participants with abnormal vital signs [Time frame: up to approximately 60 months]. Report the number of participants with abnormal vital signs (body temperature, heart rate, respiratory rate, oxygen saturation, blood pressure).

[0247] 10. Number of participants with abnormal physical examination findings [Time frame: up to approximately 60 months]. Report the number of participants with abnormal physical examination findings.

[0248] 11. Serum concentration of amivantamab [Time frame: up to approximately 42 months]. The concentration of amivantamab is determined by analyzing serum samples.

[0249] 12. Plasma concentration of lasertinib [Time frame: up to approximately 42 months]. The concentration of lasertinib is determined by analyzing the plasma sample.

[0250] 13. Number of participants with anti-amibantamab antibodies [Time frame: up to approximately 42 months]. The number of participants with antibodies against amibantamab is reported.

[0251] 14. Changes from baseline in the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NCSLC-SAQ) [Time frame: from baseline to approximately 42 months]. The NSCLC-SAQ consists of seven items that assess cough, pain, dyspnea, fatigue, and loss of appetite over a 7-day recall period. Each multi-item scale and individual item is summarized using counts and percentages per visit.

[0252] 15. Change from baseline in the European Organisation for Cancer Research and Treatment (EORTC) Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [Time frame: from baseline to approximately 42 months]. The EORTC-QLQ-C30 is a 30-item core questionnaire used to assess health-related quality of life (HRQoL) in participants in cancer clinical trials.

[0253] 16. The time to follow-up therapy (TTST) is defined as the time from the date of randomization in a clinical trial to the start of follow-up anticancer therapy after discontinuation of the study treatment or death, whichever comes first.

[0254] Eligibility criteria. Eligible age for the exam: 18 years or older (adults, seniors).

[0255] Eligible gender for the exam: All.

[0256] Acceptance of healthy volunteers: number.

[0257] Inclusion criteria: Participants must be treatment-naïve and have newly diagnosed histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) that is unsuitable for curative therapy, including surgical resection or chemoradiotherapy. The tumor harbors an exon 19 deletion (exon 19 del) or exon 21 L858R substitution, as detectable by FDA-approved or other validated testing in a Clinical Laboratory Improvement and Correction (CLIA) accredited laboratory (in the United States) or an accredited local laboratory (outside the US), in accordance with institutional standard treatment. • Mandatory submission of unstained tissue from tumors (sufficient in volume to enable central analysis of EGFR mutation status and blood for circulating tumor deoxyribonucleic acid [ctDNA], digital droplet polymerase chain reaction [ddPCR], and pharmacological genomic analysis). • Any toxicity from previous anticancer therapy must have subsided to Grade 1 or baseline level according to the Common Terminology Criteria for Adverse Events (CTCAE). Participants must have at least one measurable lesion according to the Response Assessment Criteria (RECIST) v1.1 for previously unirradiated solid tumors. Measurable lesions should not have been biopsied during screening, but if only one unirradiated measurable lesion is present, it may be accepted as a target lesion if a baseline tumor assessment scan is performed at least 14 days after the biopsy.

[0258] Exclusion criteria: Participants have received any prior systemic treatment at any time for locally advanced stage III or metastatic stage IV disease (adjuvant or neoadjuvant therapy for stage I or II disease is permitted if administered more than 12 months prior to the onset of locally advanced or metastatic disease). Participants have an active or past history of piatric disease. Participants whose spinal cord compression has not been treated are eligible if they have been definitively treated with surgery or radiation and have had a stable neurological condition for at least two weeks prior to randomization, and have not received corticosteroid treatment or have received low-dose corticosteroid treatment of 10 milligrams (mg / day) or less (<=) of prednisone or its equivalent. Participants have an active or past history of interstitial lung disease (ILD) / pneumonia, including drug-induced or radiation-induced ILD / pneumonia. • Participants are known to have allergies, hypersensitivity, or intolerance to excipients used in formulations of amivantamab, lazertinib, or osimertinib, or to have any contraindications to the use of osimertinib. • Participants with signs of brain metastasis. Participants with asymptomatic or previously treated stable brain metastases may participate in this study.

[0259] Primary results from the MARIPOSA Phase 3, global, randomized, controlled trial: Amivantamab plus razertinib vs. osimertinib as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC): The critically important Phase 3 MARIPOSA trial met its primary endpoint, demonstrating statistically and clinically significant improvement in progression-free survival (PFS) in patients treated with RYBREVANT® plus razertinib compared to osimertinib. The RYBREVANT® and razertinib combination exhibited a safety profile consistent with previously reported data for the combination.

[0260] MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomized, open-label phase 3 trial evaluating RYBREVANT® in combination with razertinib, compared to osimertinib and razertinib monotherapy, as first-line treatment for patients with locally advanced or metastatic NSCLC with substitutional mutations such as EGFR exon 19 deletion (ex19del) or exon 21 L858R. The primary endpoint of the trial is progression-free survival (PFS) (using RECIST v1.1 guidelines) as assessed by a blinded independent review committee (BICR). Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DoR), intracranial PFS, PFS after first subsequent therapy (PFS2), time to subsequent therapy (TTST), time to progression (TTSP), and safety.

[0261] Methods: Patients who were previously untreated and had locally advanced or metastatic NSCLC with EGFR mutations (Ex19del or exon 21 L858R) were randomized in a 2:2:1 ratio to receive amivantamab plus razertinib (open-label), osimertinib (blinded), or razertinib (blinded).

[0262] Results: A total of 1074 patients were randomized (amivantamab + lasertinib, 429; osimertinib, 429; lasertinib, 216). Baseline characteristics were well-balanced. The median age was 63 years, 62% were female, 59% were Asian, and 41% had a history of brain metastases.

[0263] At a median follow-up period of 22.0 months, the median PFS was 23.7 months (95% CI, 19.1–27.7) for amivantamab plus lazertinib and 16.6 months (95% CI, 14.8–18.5) for osimertinib (HR, 0.70; 95% CI, 0.58–0.85; P<0.001).

[0264] The PFS benefit of amivantamab plus lasertinib was consistent across specified subgroups. The ORR was 86% (95% CI, 83–89) for amivantamab plus lasertinib, compared to 85% (95% CI, 81–88) for osimertinib, with a median DoR of 25.8 months (95% CI, 20.1–NE) versus 16.8 months (95% CI, 14.7–18.5), respectively, among confirmed responders. The median DoR was 9 months longer in the amivantamab plus lasertinib group compared to the osimertinib group or the lasertinib group.

[0265] In the preliminary OS analysis, the median was not reached in either group; however, a strong trend favored amivantamab plus lasertinib over osimertinib with an HR of 0.80 (95% CI, 0.61–1.05; P=0.1). Amivantamab plus lasertinib was associated with a higher rate of venous thromboembolism (VTE), most of which were grade 1–2, occurred early, and were effectively managed with anticoagulation. A higher rate of EGFR and MET-related adverse events was observed with amivantamab plus lasertinib over osimertinib.

[0266] Conclusion: Amivantamab plus lasertinib 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 numerically higher DoR, and a strong trend toward improved OS. The safety profile of amivantamab plus lasertinib was consistent with previous reports. MARIPOSA has established amivantamab plus lasertinib as a new first-line standard of treatment for EGFR-mutated progressive NSCLC.

[0267] A schematic diagram illustrating the MARIPOSA clinical trial is shown in Figure 1. The PFS results are shown in Figures 2-4. The OS results are shown in Figure 5.

[0268] [Table 3]

[0269]

Table 4

[0270]

Table 5

[0271]

Table 6

[0272]

Table 7

Table 8

Table 9

Table 10

Table 11

[0277] [Table 12] * The efficacy population included all patients who underwent randomization. NE indicates inability to estimate. †Progression-free survival (primary outcome) was evaluated by a blinded, independent review committee. Objective response (complete or partial response) and duration of response were evaluated by a blinded independent review committee. The analysis included 421 patients with measurable disease at baseline in the amivantamab-lazertinib group and 414 patients in the osimertinib group. §Among the confirmed responders.

[0278] At the time of the interim survival analysis, the median overall survival could not be estimated in any group, and 214 deaths were reported in the amivantamab-lazertinib and osimertinib groups out of 390 deaths expected during the study period (Figure 5 and Table 12).

[0279] The median progression-free survival, as determined by a blinded independent review committee, was 23.7 months (95% CI, 19.1–27.7) in the amivantamab-lazertinib group and 16.6 months (95% CI, 14.8–18.5) in the osimertinib group (Figure 3 and Table 12).

[0280] [Table 13] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Events in this category are listed in order of the decrease in incidence in the amivantamab-lazertinib group.

[0281] Most patients in the trial experienced at least one adverse event (Table 13). Infusion-related reactions occurred in 63% of patients treated with amivantamagb-lazertinib (Table 13), with the majority occurring on day 1 of cycle 1. In the amivantamagb-lazertinib group, adverse events resulting in discontinuation of any study drug were reported in 350 patients (83%), reduction of any drug was reported in 249 patients (59%), and discontinuation of any drug was reported in 147 patients (35%); the numbers in the osimertinib group were 165 (39%), 23 (5%), and 58 (14%), respectively (Table 13).

[0282] [Table 14] EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer. * This was obtained from a systematic review and meta-analysis of 456 trials in patients with NSCLC. †Pooled prevalence of EGFR mutations in patients with NSCLC; data were obtained from periodic reviews of 87 trials. ‡Values ​​obtained from a linear mixed-effects model fitted to the EGFR mutation endpoint using a logistic transformation assuming a binomial distribution, from 74 trials using EGFREx19del and L858R NSCLC.

[0283] Most patients are female, Asian, or Caucasian, and have never smoked, which is representative of the EGFR variant NSCLC population (Table 14).

[0284] [Table 15-1]

[0285] [Table 15-2] *The efficacy population includes all patients who were randomized (n=429 for amivantamai-lazertinib and n=429 for osimertinib); the percentages shown here are those among the 116 patients in the amivantamai-lazertinib group and the 171 patients in the osimertinib group who were assessed by the investigator for disease progression and discontinued treatment during the randomized treatment period.

[0286] At a median follow-up period of 22.0 months, the median duration of treatment was 18.5 months (range, 0.2–31.4) for amivantamaib-lazertinib and 18.0 months (range, 0.2–32.7) for osimertinib. At the data cutoff, the assigned treatment was still being administered to 230 patients (55%) in the amivantamaib-lazertinib group and 213 patients (50%) in the osimertinib group. The most common reasons for discontinuation of the amivantamaib-lazertinib combination over 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 randomized treatment, 67% in the amivantamaib-lazertinib group and 73% in the osimertinib group initiated their first subsequent therapy (Table 15).

[0287] [Table 16] * The efficacy population included all patients who underwent randomization. NE indicates inability to estimate. †Objective response (complete or partial response) and duration of response were evaluated by a blinded independent review committee. The analysis included 421 patients with measurable disease at baseline in the amivantamab-lazertinib group and 414 patients in the osimertinib group. ‡Includes all respondents.

[0288] [Table 17] *The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Events in this category are listed in order of the decrease in incidence in the amivantamab-lazertinib group.

[0289] Grade 3 or higher adverse events were reported in 75% of patients treated with amivantamab-lasertinib and 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 amivantamab-lasertinib and 33% of patients treated with osimertinib (Table 17).

[0290] [Table 18] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Includes the following preferred terms: rash, acneiform dermatitis, folliculitis, maculopapular rash, skin lesion, acne, erythema, pustular rash, dermatitis, pruritic rash, papular rash, erythematous rash, macular rash, infectious dermatitis, erythema multiforme, papule, drug eruption, follicular rash, vesicular rash, skin peeling, epidermal peeling. ‡Include the following preferred terms: pulmonary embolism, deep vein thrombosis, venous thrombosis of the limb, thrombosis, venous thrombosis, superficial venous thrombosis, thrombophlebitis, embolism, embolic vein, 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 artery thrombosis. §Include the following preferred terms: pneumonia and interstitial lung disease.

[0291] [Table 19] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Events in this category are listed in order of the decrease in incidence in the amivantamab-lazertinib group.

[0292] Venous thromboembolic (VTE) events were reported in 37% of patients in the amivantamaib-lasertinib group and 9% in the osimertinib group (Table 18), with pulmonary embolism and deep vein thrombosis being the most common (Table 19). Notably, 5% of patients in both groups received anticoagulation at baseline. Very few patients were receiving anticoagulation at the time of their first VTE (1% for amivantamaib-lasertinib and 0% for osimertinib). Of the VTE events, 62% occurred in the first four months of treatment in the amivantamaib-lasertinib group, compared to 33% in the osimertinib group. Interstitial pneumonia / pneumonia was reported by 3% of patients in both groups, with 1% being grade 3 or higher.

[0293] [Table 20-1]

[0294] [Table 20-2] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Adverse events reported in at least 3% of patients in either group are listed. †Adverse events reported in at least 1% of patients in either group are listed.

[0295] The most common adverse events resulting from discontinuation of either drug were infusion-related reactions and paronychia (Table 20). All drug discontinuations due to treatment-related adverse events occurred in 10% of the amivantamab-lazertinib group and 3% of the osimertinib group.

[0296] [Table 21] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. †Events in this category are listed in order of the decrease in incidence in the amivantamab-lazertinib group.

[0297] [Table 22] * The safety population included all patients who were randomized and received at least one dose of any of the study treatments. All grade 5 adverse events correspond to adverse events that occurred under treatment that resulted in death, and vice versa. †One event in the amivantamab-lazertinib group was considered to be related to any investigational treatment chosen by the principal investigator. ‡Two events in the amivantamab-lazertinib group were considered to be related to the investigator's choice of study treatment. § Any treatment deemed relevant by the principal investigator to be an investigational treatment.

[0298] Fatal adverse events occurred in 34 patients (8%) in the amivantamab-lazertinib group and 31 patients (7%) in the osimertinib group (Table 22).

[0299] This analysis demonstrated a statistically and clinically significant improvement in PFS in the amivantamab + lasertinib group, with a 30% reduction in the risk of progression or death compared to the osimertinib group. At a median follow-up of 22.0 months, the median PFS in the amivantamab + lasertinib 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). The strong trend in OS favored the amivantamab + lasertinib combination over osimertinib (HR: 0.80; 95% CI: [0.61, 1.05], p=0.1099). The safety profile of amivantamab is well-defined and tolerable, and is largely consistent with its on-target activity against the EGFR and MET pathways. The safety profile of lasertinib is also well-defined and tolerable, and is largely consistent with that seen with other third-generation EGFR TKIs.

[0300] Example 3. Secondary analysis from the Phase 3 MARIPOSA trial of amivantamab + razertinib vs. osimertinib in first-line EGFR-mutated advanced non-small cell lung cancer (NSCLC) with high-risk disease biomarkers. MARIPOSA (NCT04487080) is an international phase 3 randomized trial comparing amivantamab and lasertinib combination therapy versus osimertinib versus lasertinib as first-line treatment in approximately 1,000 patients with EGFR-mutated locally advanced or metastatic NSCLC (also known as Trial 73841937 NSC3003, NSC3003, and Mariposa).

[0301] Amivantamab plus lazertinib significantly improved PFS, PFS2, and DoR compared to osimertinib in the Mariposa study.

[0302] Primary eligibility criteria: locally advanced or metastatic NSCLC, prior treatment history for progressive disease, recorded EGFR Ex19del or L858R, and ECOG PS 0 or 1. Primary endpoint for progression-free survival (PFS) by BICR according to RECIST v1.1c: amivantamab + razertinib vs. osimertinib. High-risk subgroups analyzed: liver metastases, brain metastases, TP53 comutation, EGFRm ctDNAd detectable at baseline, and no EGFRm ctDNAd clearance at C3D1 (week 9) (Figure 16). Detection of ctDNA and comutations was performed by next-generation sequencing (NGS) of blood at baseline. Detection and clearance of Ex19del and L858R ctDNA in blood were analyzed using ddPCR at baseline and C3D1.

[0303] Primary endpoint: Progression-free survival by BICR. Amivantamab plus lazertinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months (Figure 17).

[0304] Patients with brain metastases: Osimertinib showed a median PFS of 13.0 months in patients with brain metastases at baseline, indicating a poor prognosis subgroup. In patients with brain metastases at baseline, amivantamab plus lazertinib reduced the risk of progression or death by 31% compared to osimertinib (Figure 18). In patients without brain metastases at baseline, amivantamab plus lazertinib showed a consistent benefit compared to osimertinib: median PFS: 27.5 vs. 19.9 months and HR 0.69 (95% CI, 0.53–0.89); P=0.005 (Figure 18).

[0305] Patients with liver metastases: Osimertinib showed a median PFS of 11.0 months in patients with liver metastases at baseline, indicating a poor prognosis subgroup. In patients with liver metastases at baseline, amivantamab plus lasertinib reduced the risk of progression or death by 42% compared to osimertinib (Figure 19). In patients without liver metastases at baseline, amivantamab plus lasertinib showed a consistent benefit compared to osimertinib: median PFS: 24.0 vs. 18.3 months and HR 0.74 (95% CI, 0.60-0.91); P=0.004 (Figure 19).

[0306] Baseline next-generation sequencing (NGS) circulating tumor DNA (ctDNA) pathogenicity mutation patterns: 85% (540 / 636 samples) had pathogenic changes detected in ctDNA at baseline by NGS. TP53 comutas were observed in 56% of the amivantamab + lazertinib group and 53% of the osimertinib group. MET amplification occurred in one patient in each group (none of which were accompanied by high-level amplification) (Figure 20).

[0307] Patients with TP53 comutas: Osimertinib showed a median PFS of 12.9 months in patients with TP53 comutas at baseline, indicating a poor prognosis subgroup. In patients with TP53 comutas at baseline, amivantamab plus lasertinib reduced the risk of progression or death by 35% compared to osimertinib (Figure 21). In patients with wild-type TP53 at baseline, amivantamab plus lasertinib showed consistent benefit over osimertinib: median PFS: 22.1 vs. 19.9 months and HR 0.75 (95% CI, 0.52–1.07); P=0.114 (Figure 21).

[0308] Detectable EGFRm ctDNA at baseline and treatment: Detection and clearance of Ex19del and L858R ctDNA in blood were analyzed by ddPCR (Ex19del or L858R by Biodesix ddPCR). At baseline, 336 patients in both the amivantamab + lazertinib group and the osimertinib group provided analyzable ctDNA samples. Approximately 70% of patients in both groups had detectable EGFRm ctDNA (Ex19del or L858R by Biodesix ddPCR) at baseline (Figure 22). 192 patients in the amivantamab + lazertinib group and 212 patients in the osimertinib group had matched samples at baseline and C3D1 (week 9) (cycle was 28 days). At C3D1 (week 9) (cycle was 28 days), detectable EGFRm ctDNAa was observed in 15% of these patients in both groups (Figure 22).

[0309] In patients with detectable baseline ctDNA (Ex19del or L858R by Biodesix ddPCR): Osimertinib showed a median PFS of 14.8 months among patients with detectable baseline ctDNAa, indicating a poor prognosis subgroup. Among patients with detectable baseline ctDNA (Ex19del or L858R by Biodesix ddPCR), amivantamab + lasertinib reduced the risk of progression or death by 32% compared to osimertinib (Figure 23). Among patients without detectable baseline ctDNA (Ex19del or L858R by Biodesix ddPCR), amivantamab + lasertinib showed a consistent benefit compared to osimertinib: median PFS: 27.7 months vs. 21.9 months and HR 0.72 (95% CI, 0.47 to -1.10); P=0.132 (Figure 23). In patients with baseline ctDNA detectable by Guardant360® NGS, amivantamab plus razertinib demonstrated consistent benefit over osimertinib (HR, 0.71 [95% CI, 0.57~0.89]; P=0.003). (Figure 23).

[0310] In patients whose ctDNA was not cleared by C3D1 (Ex19del or L858R by Biodesix ddPCR; cycle was 28 days): Osimertinib showed a median PFS of 9.1 months in patients whose ctDNA was not cleared by C3D1 (Ex19del or L858R by Biodesix ddPCR; cycle was 28 days) and represented a subgroup with a poor prognosis. In patients whose ctDNA was not cleared by C3D1 (Ex19del or L858R by Biodesix ddPCR; cycle was 28 days), amivantamab + lazertinib reduced the risk of progression or death by 51% compared to osimertinib (Figure 24). In patients with C3D1a ctDNA removal, amivantamab plus razertinib demonstrated a consistent benefit over osimertinib: median PFS: 24.0 vs. 16.5 months and HR 0.64 (95% CI, 0.48–0.87); P=0.004. (Figure 24).

[0311] Regarding PFS in patients with high-risk features: In the MARIPOSA trial, 89% of patients had at least one high-risk feature detected at baseline (patients with NGS-analyzable ctDNA at baseline were included in this pooled analysis. High-risk features included NGS-analyzable ctDNA at baseline, or baseline metastases in the liver or brain. For patients with detectable ctDNA, it was assumed that the TP53 comutase would be identified if present).

[0312] In first-line EGFR-mutated (Ex19del / L858R) progressive NSCLC, amivantamab plus lazertinib significantly improved PFS compared to osimertinib in patients with high-risk features, including: a.) Presence of baseline brain metastases (HR, 0.69; P=0.010) b.) Presence of baseline liver metastases (HR, 0.58; P=0.017) c.) Has TP53 comutation (HR, 0.65; P=0.003) d.) Presence of detectable baseline EGFRm ctDNA (Ex19del and L858R by Biodesix ddPCR) (HR, 0.68; P=0.002) e.) No clearance of EGFRm ctDNA (Ex19del and L858R by Biodesix ddPCR) in C3D1 (cycle was 28 days) (HR, 0.49; P=0.015) (Figure 25).

[0313] An estimated 89% of patients had at least one high-risk feature at baseline (patients with NGS-analyzable ctDNA at baseline were included in this pooled analysis. High-risk features included NGS-detectable ctDNA at baseline or baseline liver or brain metastases. For patients with detectable ctDNA, it was assumed that the TP53 comutase would be identified if present).

[0314] In the corresponding subgroup without high-risk features, amivantamab plus lasertinib demonstrated a consistent PFS benefit over osimertinib. Amivantamab plus lasertinib effectively overcomes the effects of high-risk features and represents a promising new standard of treatment for patients with EGFR-mutated progressive NSCLC.

[0315] The present invention is not limited to the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims.

[0316] 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 herein.

Claims

1. A method for improving the median progression-free survival (PFS) in a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, wherein the target population includes: (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof. This includes administering combination therapy that includes, A method in which the improvement in median PFS is compared to the median PFS of a reference population having NSCLC with one or more EGFR mutations and who have not received prior treatment, wherein the reference population is administered osimertinib or razertinib without the bispecific anti-EGFR / c-Met antibody.

2. A method for improving overall survival (OS) in subjects or a target population having locally advanced non-small cell lung cancer (NSCLC) or metastatic non-small cell lung cancer with one or more epidermal growth factor receptor (EGFR) mutations, wherein the subject or target population (i) A therapeutically effective dose of bispecific anti-EGFR / c-Met antibody, and (ii) A therapeutically effective dose of razertinib, or a pharmaceutically acceptable salt or hydrate thereof. This includes administering combination therapy that includes, A method in which the improvement in OS is compared to the OS of a reference subject or reference population having NSCLC with one or more EGFR mutations and who has not received treatment, wherein the reference subject or reference population is administered osimertinib or razertinib without a bispecific anti-EGFR / c-Met antibody.

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

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

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

8. The method according to any one of claims 1 to 7, wherein the subject has newly diagnosed locally advanced NSCLC or metastatic NSCLC that is unsuitable for curative therapy including surgical resection or chemoradiotherapy.

9. The method according to claim 8, wherein the curative therapy includes surgical excision or chemoradiation.

10. The method according to any one of claims 1 to 9, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally 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, comprising administering razertinib, or a pharmaceutically acceptable salt or hydrate thereof, orally once daily in an amount of about 240 mg.

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

13. The method according to any one of claims 1 to 12, for achieving partial response or better response in the subject in accordance with the RECIST v1.1 criteria.

14. The method according to any one of claims 1 to 13, wherein the clinical response includes 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 is progression-free after at least 11 months.

16. The method according to any one of claims 1 to 15, wherein the subject is progression-free after at least 23 months.

17. The method according to any one of claims 1 to 16, achieving 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 the treatment-naive population of patients diagnosed with locally progressive NSCLC or metastatic NSCLC having 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 that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising a heavy chain complementarity determining region 1 (HCDR1) including SEQ ID NO: 1, an HCDR2 including SEQ ID NO: 2, an HCDR3 including SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) including SEQ ID NO: 4, an LCDR2 including SEQ ID NO: 5, and an LCDR3 including SEQ ID NO: 6, and the second domain that binds to c-Met comprises an HCDR1 including SEQ ID NO: 7, an HCDR2 including SEQ ID NO: 8, an HCDR3 including SEQ ID NO: 9, an LCDR1 including SEQ ID NO: 10, an LCDR2 including SEQ ID NO: 11, and an LCDR3 including SEQ ID NO:

12.

19. The method according to claim 18, wherein the first domain that specifically binds 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 that specifically binds 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 branched glycan structure having a fucose content of about 1% to 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 according to claim 23, wherein the bispecific anti-EGFR / c-Met antibody is administered in a dose of approximately 140 mg to approximately 2240 mg.

25. The method according to claim 24, wherein the bispecific anti-EGFR / c-Met antibody is administered in doses of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1575 mg, approximately 1600 mg, approximately 2100 mg, or approximately 2240 mg.

26. The method according to claim 25, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in a dose of 1050 mg.

27. The method according to claim 26, wherein if the subject has a body weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 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 according to claim 28, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally in 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 target population has baseline brain metastases, baseline liver metastases, TP53 comutas, detectable baseline EGFRm ctDNA, or does not have EGFRm ctDNA clearance in C3D1.

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