Methods for treatment of non-small cell lung cancer (NSCLC)

Abstract

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

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480034635.5 (22) Application Date 2024.05.23 (30) Priority Data 63 / 468375 2023.05.23 US 63 / 540742 2023.09.27 US (85) PCT International Application Entering National Phase Date 2025.11.24 (86) PCT International Application Application Data PCT / IB2024 / 055039 2024.05.23 (87) PCT International Application Publication Data WO2024 / 241273 EN 2024.11.28 (71) Applicant: Jensen Biotechnology Co., Ltd. Address: Pennsylvania, USA (72) Inventor: R. Nobleauch (74) Patent Agency: China Patent Agency (Hong Kong) Ltd. 72001 Patent Attorney: Luo Wenfeng, Peng Chang (51) Int.Cl. A61K 31 / 506 (2006.01) A61P 35 / 00 (2006.01) C07K 16 / 32 (2006.01) C07K 16 / 28 (2006.01) (54) Invention Title: Method for Treating Non-Small Cell Lung Cancer (NSCLC) (57) Abstract: This disclosure provides a method for improving median progression-free survival (PFS) and overall survival in a treatment-naïve subject or a treatment-naïve subject population with EGFR-positive non-small cell lung cancer (NSCLC). Claims 3 pages, Description 70 pages, Sequence Listing (electronic publication), Drawings 25 pages, CN 121194785 A 2025.12.23 CN 1 21 19 47 85 A 1. A method for improving median progression-free survival (PFS) in a treatment-naïve population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the population of patients, the combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference population harboring one or more EGFR mutations, the reference population having been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody. 2. An improved localized...A method for assessing overall survival (OS) in subjects or populations of patients with advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering a combination therapy to the subjects or population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of latezitinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve NSCLC reference subject or population carrying one or more EGFR mutations, the reference subject or population having been administered osimertinib or latezitinib without the bispecific anti-EGFR / c-Met antibody. 3. The method of claim 1 or 2, wherein the latezitinib or a pharmaceutically acceptable salt or hydrate thereof is latezitinib mesylate. 4. The method of claim 1 or 2, wherein the latezitinib or a pharmaceutically acceptable salt or hydrate thereof is latezitinib mesylate monohydrate. 5. The method of any one of claims 1 to 4, wherein the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitutions, or any combination thereof. 6. The method of any one of claims 1 to 4, wherein the one or more EGFR mutations comprise one or more exon 19 deletions. 7. The method of any one of claims 1 to 4, wherein the one or more EGFR mutations comprise exon 21 L858R substitutions. 8. The method of any one of claims 1 to 7, wherein the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapy, the curative therapy comprising surgical resection or chemoradiotherapy. 9. The method of claim 8, wherein the curative therapy comprises surgical resection or chemoradiotherapy. 10. The method of any one of claims 1 to 9, wherein the method comprises oral administration of lazatinib or a pharmaceutically acceptable saponin or hydrate thereof once daily in an amount of about 80 mg to about 320 mg. 11. The method of any one of claims 1 to 10, wherein the method comprises oral administration of lazatinib or a pharmaceutically acceptable saponin or hydrate thereof once daily in an amount of about 240 mg. 12. The method of any one of claims 1 to 11, wherein the method elicits a clinical response in the subject according to RECIST v1.1 criteria. 13. The method of any one of claims 1 to 12, wherein the method achieves a partial or better response in the subject according to RECIST v1.1 criteria. 14. The method of any one of claims 1 to 13, wherein the clinical response comprises a median duration of response (DOR) of at least 25 months.Claim 1 / 3 Page 2 CN 121194785 A 15. The method of any one of claims 1 to 14, wherein the subject is progression-free after at least 11 months. 16. The method of any one of claims 1 to 15, wherein the subject is progression-free after at least 23 months. 17. The method of any one of claims 1 to 16, wherein the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations. 18. The method according to any one of claims 1 to 17, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12. 19. The method of claim 18, wherein the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16. 20. The method of claim 18 or 19, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. 21. The method of 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 containing SEQ ID NO: 19.NO: 20, second light chain (LC2). 22. The method of any one of claims 1 to 21, wherein the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%. 23. The method of any one of claims 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. 24. The method of claim 23, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg. 25. The method of claim 24, wherein the bispecific anti-EGFR / c-Met antibody is administered 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. 26. The method of claim 25, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. 27. The method of claim 26, wherein if the subject has a 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 of any one of claims 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. Claims 2 / 3 pages 3 CN 121194785 A 29. The method of claim 28, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject. 30. The method of any one of claims 1 to 29, wherein the bispecific anti-EGFR / c-Met antibody is administered twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. 31. The method of any one of claims 1 to 30, wherein the subject or subject population has baseline brain metastases, baseline liver metastases, TP53 co-mutation, detectable baseline EGFR mctDNA, or no EGFR mctDNA clearance at C3D1. Claims 3 / 3 pages 4 CN 121194785 A Method for treating non-small cell lung cancer (NSCLC)

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

[0002] Sequence List This application contains a sequence list that has been electronically submitted in XML format, and is incorporated herein by reference in its entirety. The XML copy was created on May 21, 2024, named 103693007299_SequenceListing.xml, and is 20,173 bytes in size. Technical Field

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

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

[0005] In NSCLC, specific mutations in the EGFR gene are associated with high response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Although most NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, in fact all patients acquire resistance that prevents durable responses. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors show increased c-Met expression, amplification of the c-Met gene, or an increase in its only known ligand, hepatocyte growth factor (Turke et al., Cancer Cell, 17:77-88, 2010). The five-year survival rate for all advanced NSCLC and EGFR-mutant patients treated with EGFR TKIs is less than 20%. Patients with EGFR ex19del or exon 21 L858R mutations have a real-world five-year overall survival of 19%.

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

[0007] In one aspect, this article provides a method for improving median progression-free survival (PFS) in a treatment-naïve population of locally advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring one or more epidermal growth factor receptor (EGFR) mutations, comprising administering to a subject or population of subjects a combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of latezatitinib or an acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference population harboring one or more EGFR mutations, who have been administered osimertinib or latezatitinib but not the bispecific anti-EGFR / c-Met antibody.

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

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

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

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

[0012] In some embodiments, the method comprises oral administration of latezetine once daily in a dose of about 80 mg to about 320 mg.Lazatinib or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the method includes oral administration of lazatinib or a pharmaceutically acceptable salt or hydrate thereof once daily in an amount of about 240 mg.

[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 or better response in subjects according to RECIST v1.1 criteria. In some embodiments, a 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 a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations.

[0015] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12. In some embodiments, the first domain specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments, the bispecific anti-EGFR / c-Met antibody contains a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14.The bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 18, a first light chain (LC1) containing SEQ ID NO: 19, a second heavy chain (HC2) containing SEQ ID NO: 20, and a second light chain (LC2) containing SEQ ID NO: 20. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0016] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at doses of 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, 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.

[0017] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the 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 weekly, once weekly, 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 EGFR mctDNA, or no EGFR mctDNA clearance at C3D1. Brief Description of the Drawings

[0020] Figure 1 shows an exemplary schematic overview of the MARIPOSA clinical study.

[0021] Figure 2 shows the Kaplan-Meier estimate of progression-free survival assessed by a blinded independent central review in the efficacy population of ervantuzumab-lazaitinib versus osimertinib (including the lazaitinib monotherapy group). PFS was shown by BICR results. The dashed line indicates the median progression-free survival in both groups, and the scale marks indicate censoring of data. The median progression-free survival in the lazatinib group was 18.5 months (95%).[CI, 14.8 to 20.1].

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

[0023] Figure 4 shows PFS by subgroup.

[0024] Figure 5 shows the Kaplan-Meier estimate of intermediate overall survival. The efficacy cohort includes all patients who underwent randomization. Scale markers indicate censoring of data.

[0025] Figure 6 shows a diagram of the Consolidated Standards for Reported Trials (CONSORT) for patient treatment. 1375 patients were screened, and 1074 patients underwent randomization (429 patients received ervantumab-lazaitinib, 429 patients received osimertinib monotherapy, and 216 patients received lazaitinib monotherapy); 1062 patients received at least one dose of the trial treatment.

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

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

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

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

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

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

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

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

[0034] Figure 15 shows the Kaplan-Meier estimate of progression-free survival after the first subsequent treatment, defined as the time from randomization to the date of objective disease progression (by the investigator) or death after the start of subsequent systemic anticancer therapy, based on the occurrence of the event described on page 4 / 70 of the specification, 8 CN 121194785 A. The efficacy cohort includes all patients who underwent randomization. Scale markers indicate data censoring.

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

[0036] Figure 17 shows progression-free survival as determined by BICR. Evantumab + lazatinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months.

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

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

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

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

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

[0042] Figure 23 shows progression-free survival in patients with detectable baseline ctDNA (Ex19del or L858R as determined by Biodesix ddPCR). Osimertinib showed a median PFS of 14.8 months in patients with detectable ctDNA at baseline, indicating a subgroup with poor prognosis. In patients with detectable baseline ctDNA, ervantumab + lazatinib reduced the risk of progression or death by 32% compared to osimertinib. In patients without detectable baseline ctDNAIn patients, ervantumab plus lazatinib showed a consistent benefit over osimertinib: median PFS: 27.7 months vs. 21.9 months and hazard ratio 0.72 (95% CI, 0.47–1.10); P = 0.132. In patients with baseline ctDNA detectable by Guardant360® NGS, ervantumab plus lazatinib showed a consistent benefit over osimertinib (HR, 0.71 [95% CI, 0.57–0.89]; P = 0.003).

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

[0044] Figure 25 shows progression-free survival in patients with high-risk characteristics. In the MARIPOSA study, 89% of patients had at least one high-risk characteristic detected at baseline (patients with ctDNA analyzable by NGS at baseline were included in this pooled analysis. High-risk characteristics included baseline detectable ctDNA by NGS or baseline metastases to the liver or brain. For patients with detectable ctDNA, it was assumed that a TP53 co-mutation was identified (if present)). Detailed Description

[0045] All publications referenced in this specification, including but not limited to patents and patent applications, are incorporated herein by reference as if fully set forth herein.

[0046] It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0047] While any methods and materials similar to or equivalent to those described herein may be used in the practice of testing the invention, exemplary materials and methods are described herein. The following terms will be used in describing and claiming the invention.

[0048] When a list is provided, it should be understood, unless otherwise indicated, that each individual element in the list and each combination of the list is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” will be understood as…The interpretation includes implementations “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

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

[0050] The connecting term “and / or” between a plurality of enumerated elements is understood to cover both individual and combined options. For example, in the case where two elements are connected by “and / or,” the first option means applying the first element in the absence of the second element. The second option means applying the second element in the absence of the first element. The third option means applying both the first and second elements together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term “and / or” as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term “and / or.”

[0051] The transitional terms “comprising,” “substantially consisting of,” and “consisting of” are intended to imply their accepted meanings in the Patent Terminology Specification, pages 6 / 70, 10 CN 121194785 A; that is, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open at the end, and does not exclude additional, unlisted elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claims; and (iii) “substantially consisting of” limits the scope of the claims to the specified material or step “and material or step that does not substantially affect the essential and novel features of the invention protected by the claims.” Embodiments described with the phrase “comprising” (or its equivalents) are also provided, as are those described independently with “consisting of” and “substantially consisting of.”

[0052] Terms such as “together with,” “together with,” “in combination with,” and “in combination with” encompass the administration of selected therapeutic agents or drugs to a single patient and are intended to include treatment regimens that administer these therapeutic agents or drugs via the same or different routes of administration or at the same or different times.

[0053] “Isolated” means a homogeneous population of molecules (such as synthetic polynucleotides, polypeptide carriers, or viruses) that have been substantially isolated and / or purified from other components of the system that produces the molecules (such as recombinant cells), as well as proteins that have undergone at least one purification or isolation step. “Isolated” means molecules that are substantially free of other cellular material and / or chemicals and encompasses isolation to higher purities (such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%).Molecules with a purity of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0054] “Treatment” of a disease or condition such as cancer means achieving one or more of the following: reducing the severity and / or duration of the condition, inhibiting the worsening of characteristic symptoms of the treated condition, limiting or preventing the recurrence of the condition in a subject who previously had the condition, or limiting or preventing the recurrence of symptoms in a subject who previously had symptoms of the condition.

[0055] “Prevention” of a disease or condition means preventing the occurrence of the condition in a subject.

[0056] “Diagnosis” means a method of determining whether a subject has a given disease or condition or is likely to develop a given disease or condition in the future or is likely to respond to treatment of a previously diagnosed disease or condition (i.e., stratifying a patient population based on the likelihood of responding to treatment). Diagnosis is usually performed by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating the subject’s likely response to a particular treatment.

[0057] “Response,” “responsiveness,” or “probable response” means any type of improvement or positive response, such as the reduction or improvement of one or more symptoms, a decrease in the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention of the spread of the disease, a delay or slowing of disease progression, an improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable.

[0058] “Newly diagnosed” means a subject who has been diagnosed with cancer (e.g., cancer expressing EGFR or c-Met) but has not yet received treatment (e.g., treatment for lung cancer).

[0059] “Therapeuticly effective dose” means the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeuticly effective doses can vary depending on factors such as an individual’s disease state, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in an individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0060] “Treatment refractory” means a disease that does not respond to treatment. Refractory diseases may be resistant to treatment before or at the start of treatment, or may become resistant during treatment.

[0061] “Relapse” means the recurrence of the disease or signs and symptoms of the disease after a period of improvement following previous treatment with a therapeutic agent.

[0062] “Subject” includes any human or non-human animal. “Non-human animal” includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” are used interchangeably herein. Specification 7 / 70 pages 11 CN 121194785 A

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

[0064] “About” means within an acceptable range of error for a particular value as determined by those skilled in the art, which will depend in part on how the value is measured or determined, i.e., limitations of the measurement system. In the context of a particular assay, result, or implementation, unless otherwise expressly stated in the implementation or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) according to convention in the art.

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

[0066] “Cancer expressing EGFR or c-Met” refers to cancer with detectable EGFR or c-Met expression or with EGFR or c-Met mutations or amplifications. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemistry, flow cytometry, or Western blotting.

[0067] “Epidermal growth factor receptor” or “EGFR” refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, and its naturally occurring variants.

[0068] As used herein, “hepatocyte growth factor receptor” or “c-Met” refers to human c-Met and its naturally occurring variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0069] “Bispecific anti-EGFR / c-Met antibody” or “bispecific EGFR / c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. Specific binding to EGFRThe c-Met domains are typically VH / VL pairs, and bispecific anti-EGFR / c-Met antibodies are monovalent in binding to both EGFR and c-Met.

[0070] "Specific binding" or "specifically binding" or "binding" means that an antibody binds to an antigen or an epitope within an antigen with a higher affinity than against other antigens. Typically, when an antibody binds to an antigen or an epitope within an antigen, the equilibrium dissociation constant (KD) is about 5 x 10⁻⁸ M or less, for example, about 1 x 10⁻⁹ M or less, about 1 x 10⁻¹⁰ M or less, about 1 x 10⁻¹¹ M or less, or about 1 x 10⁻¹² M or less, typically at least one hundred times lower than the KD when it binds to nonspecific antigens (e.g., BSA, casein). The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may exhibit cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, such as the cynomolgus macaque (Macaca fascicularis) or chimpanzee (Pan troglodytes). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0071] "Antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of an immunoglobulin molecule containing an antigen-binding site with desired specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, and their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with frame regions (FRs). Each VH and VL consists of three CDRs and four FR fragments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0072] The “complementarity-determining region” (CDR) is the antibody region that binds to the antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al., (1970) J Exp.Med 132: 211–50 (Kabat et al., “Sequences of Proteins of Immunological Interest”, 5th edition, Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., (1987) J Mol Biol 196: 901–17), IMGT (Lefranc et al., (2003) Dev Comp Immunol 27: 55–77) and AbM (Martin and Thornton (1996), J Bmol Biol 263: 800–15). The correspondence between various depictions and variable region numbers is described (see, for example, Lefranc et al., (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun (2001), J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resource, imgt_org). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3” include CDRs as defined by any of the above methods (Kabat, Chothia, IMGT, or AbM).

[0073] Immunoglobulins can be designated as five major classes based on the amino acid sequence of the heavy chain constant domain, namely IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subclassed into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domains, antibody light chains of any vertebrate species can be designated as one of two completely different types, namely κ and λ.

[0074] "Antigen-binding fragment" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtainable, or genetically engineered polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of a VH domain or a VL domain, shark variable IgNAR domains,The VH domain is a humped VL domain, the smallest recognition unit consisting of amino acid residues of CDRs of a mimic antibody, such as FR3-CDR3-FR4, HCDR1, HCDR2 and / or HCDR3, and LCDR1, LCDR2 and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, wherein, in cases where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0075] A “monoclonal antibody” is an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., the individual antibodies comprising that population are identical, differing only by possible well-known alterations, such as removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0076] A “recombinant” is a DNA, antibody, or other protein prepared, expressed, formed, or isolated by recombinant means when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins. Specification 9 / 70 pages 13 CN 121194785 A

[0077] “Bispecific” refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may be cross-reactive to other related antigens, for example, cross-reactive to the same antigens from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques or pan troglodytes), or may bind to epitopes shared between two or more different antigens.

[0078] (An approved reference product / biologic, i.e., a reference marketed drug) "Biosimilar" means a biologic that is highly similar to a reference drug based on data derived from studies in which there are no clinically significant differences in safety, purity, and potency between the biosimilar and the reference drug: (a) analytical studies demonstrating a high degree of similarity between the biologic and the reference drug; (b) animal studies (including assessments of toxicity); and / or (c) one or more clinical studies (including studies on the biosimilar and the reference drug).(Immunogenicity and pharmacokinetic or pharmacodynamic assessments) These clinical studies are sufficient to demonstrate the safety, purity, and potency of the reference product under one or more appropriate conditions of use, intended for use, and for which a license to use the biosimilar is sought. A biosimilar is an interchangeable product that can replace the reference product at the pharmacy without intervention from the prescribing healthcare professional. To meet the additional criterion of “interchangeability,” the biosimilar should be expected to produce the same clinical outcomes as the reference product in any given patient, and if the biosimilar is administered to an individual more than once, the risk of reduced safety or efficacy from substitution or exchange between the use of the biosimilar and the reference product is no greater than the risk of using the reference product without such substitution or exchange. The biosimilar utilizes the same mechanism of action for the proposed conditions of use, provided that these mechanisms are known to the reference product. One or more conditions of use specified, recommended, or suggested in the proposed labeling of the biosimilar have previously been approved for use with the reference product. The biosimilar has the same route of administration, dosage form, and / or strength as the reference product, and is manufactured, processed, packaged, or stored in a facility that meets standards designed to ensure that the biosimilar remains safe, pure, and potent. Compared to the reference product, the biosimilar may include minor modifications to the amino acid sequence, such as N-terminal or C-terminal truncation that is not expected to alter the biosimilar's properties.

[0079] An “antagonist” or “inhibitor” is a molecule that, when bound to a cellular protein, inhibits at least one reaction or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one reaction or activity is inhibited to at least 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the inhibition of at least one reaction or activity in the absence of an antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of an antagonist.

[0080] A “PD-(L)1 axis inhibitor” refers to a molecule that inhibits downstream signaling of PD-1. A PD-(L)1 axis inhibitor may be a molecule that binds to PD-1, PD-L1, or PD-L2.

[0081] A “biological sample” refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present in the subject’s body. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleural fluid, pericardial fluid, peritoneal fluid, peritoneal fluid and other body cavity fluids, fluids collected by bronchoalveolar lavage fluid, synovial fluid, and liquid solutions in contact with the subject or biological sources (e.g., cell and organ culture media (including cell or organ conditioned media)).Irrigation fluid, etc.), tissue biopsy material, tumor tissue biopsy material, tumor tissue sample, fine needle aspirate, surgically removed tissue, organ culture, or cell culture. As a non-limiting example, the biological sample is a blood sample. As another non-limiting example, the biological sample is a plasma sample. As another non-limiting example, the biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA), which 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.

[0082] As used herein, “low fucose” or “low fucose content” means that the fucose content of the antibody is about 1% to 15%.

[0083] As used herein, “normal fucose” or “normal fucose content” means that the fucose content of the antibody is about 50%, typically about 80% or 85%.

[0084] As used herein, “never treated” means a subject who has been diagnosed with locally advanced or metastatic NSCLC and has not yet received anticancer therapy for NSCLC; therefore, the subject is someone who has never received chemotherapy and has never received TKI therapy, for example, has not received chemotherapy or tyrosine kinase inhibitors (including first-generation, second-generation, or third-generation TKIs) or other anti-NSCLC therapy. The approach to treating a never treated subject may also be referred to as first-line or front-line therapy.

[0085] As used herein, RECIST v1.1 criteria refer to publicly available guidelines for response evaluation criteria in solid tumors as described in the following literature: Eisenhauer EA, Therasse P, Bogaerts J et al., New response evaluation criteria in solid tumours:revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-247, which is incorporated herein by reference. Eisenhauer et al. provided the following definitions for the criteria used to determine objective tumor response to target lesions: - Complete response (CR): Disappearance of all target lesions. Any pathological lymph node (target or non-target) must show a reduction in short axis to <10 mm. - Partial response (PR): A reduction of at least 30% in the total diameter of target lesions, using the baseline total diameter as a reference. - Progressive disease (PD): An increase of at least 20% in the total diameter of target lesions, using the smallest total diameter in the study as the reference.Reference (including the baseline sum if it is the minimum in the study). In addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). - Stable disease (SD): neither a reduction sufficient to meet the PR criteria nor an increase sufficient to meet the PD criteria, taking the minimum diameter sum in the study as a reference.

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

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

[0088] The inventors have developed novel methods for treating treatment-naïve patients with EGFR mutation-positive advanced NSCLC. The inventors have also developed methods for improving median progression-free survival (PFS) and / or improving overall survival in treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations. Therefore, embodiments of the present invention provide methods for treating patients and / or patient populations with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC), methods for improving median progression-free survival of patients and / or patient populations with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC), and methods for improving overall survival of patients and / or patient populations with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC). Specification 11 / 70 pages 15 CN 121194785 A

[0089] This document discloses methods for treating non-small cell lung cancer (NSCLC) in subjects in need of it, the method comprising administering a combination therapy to the subject comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody; and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has been diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations, and wherein the subject is

[0090] This article also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of latezatitinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference population harboring one or more EGFR mutations, the reference population having been administered osimertinib or latezatitinib without the bispecific anti-EGFR / c-Met antibody.

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

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

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

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

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

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

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

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

[0099] This document also discloses a method for improving median progression-free survival (PFS) in a treatment-naïve population of patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method comprises administering a combination therapy to the patient population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve reference population of patients with NSCLC without clearance of mutant EGFR circulating tumor DNA at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The alternative, the reference group, had been given osimertinib or lazatinib but not bispecific anti-EGFR / c-Met antibody.

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

[0101] This document discloses a method for improving overall survival (OS) in treatment-naïve subjects or populations of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the subject or population comprising: a therapeutically effective dose of dual...A specific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or its pharmaceutically acceptable salt or hydrate, wherein the improvement in OS is relative to the OS of a reference subject or reference subject population of NSCLC who has never received treatment and carries one or more EGFR mutations, and who has been given osimertinib or lazatinib but not bispecific anti-EGFR / c-Met antibody.

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

[0103] This article also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, the method comprising administering to the subject or population of subjects a combination therapy comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference population of NSCLC with no baseline brain metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or population of subjects has been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0104] This document also discloses improvements in overall survival (OS) in treatment-naïve subjects or a treatment-naïve population with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases (14 / 70 pages, CN 121194785 A).The method, wherein NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, comprises administering a combination therapy to a subject or subject population comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein improvement in OS is relative to OS in a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC having baseline liver metastases, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, and the reference subject or reference subject population has been administered osimertinib or lazatinib without bispecific anti-EGFR / c-Met antibody.

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

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

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

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

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

[0110] This document also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. The method comprises administering to the subject or subject population a combination therapy comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. L858R replacement, the reference subjects or reference subject population have been given osimertinib or lazatinib but not bispecific anti-EGFR / c-Met antibody.

[0111] This document also discloses a method for improving overall survival (OS) in treatment-naïve subjects or a treatment-naïve subject population with locally advanced or metastatic non-small cell lung cancer (NSCLC) having mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions, the method comprising administering to the subject or subject population a combination therapy comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve reference subject or a treatment-naïve reference subject population with NSCLC having mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC carries one or more exon 19 deletions or exon 21 L858R substitutions. L858R replacement, the reference subjects or reference subject population have been given osimertinib or lazatinib but not bispecific anti-EGFR / c-Met antibody.

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

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

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

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

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

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

[0118] In some embodiments of the disclosed method, the subject has no progression after at least 20 months. In some embodiments of the disclosed method, the subject has no progression after at least 24 months. In some embodiments of the disclosed method, the subject has no progression after at least 30 months. In some embodiments of the disclosed method, the subject has no progression after at least 11 months.In some embodiments of the disclosed method, the subject is progression-free after at least 23 months. In some embodiments of the disclosed method, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed method, the method achieves a PFS rate of 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed method, the method achieves a PFS rate of 86% in a treatment-naïve subject population diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations.

[0119] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain specifically binding to EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, and the second domain specifically binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.The second heavy chain (HC2) of SEQ ID NO: 19 and the second light chain (LC2) of SEQ ID NO: 20. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

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

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

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

[0123] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is administered twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

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

[0125] In some embodiments of the disclosed method, the subject or subject population does not have baseline brain metastases, baseline liver metastases, TP53 co-mutations, detectable baseline EGFR m ctDNA, or does not have EGFR m ctDNA clearance at C3D1. In some embodiments, the subject or subject population does not have baseline brain metastases. In some embodiments, the subject or subject population does not have baseline liver metastases. In some embodiments, the subject or subject population does not have TP53 co-mutations. In some embodiments, the subject or subject population does not have detectable baseline EGFR m ctDNA. In some embodiments, the subject or subject population has EGFR m ctDNA clearance at C3D1.

[0126] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain that binds to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12. In some embodiments of the disclosed method, the first domain specifically binding to EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

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

[0128] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the second heavy chain (HC1) of SEQ ID NO: 18, and the third heavy chain (CH) of SEQ ID NO: 19.The first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

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

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

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

[0132] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 2% and about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 3% and about 13%. In some embodiments...In this invention, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 4% to about 12%. (See specification page 19 / 70, 23 CN 121194785 A). In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 4%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content of about 15%.

[0133] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI), such as, but not limited to, epidermal growth factor receptor (EGFR TKI). Non-limiting examples of TKIs are erlotinib, gefitinib, lapatinib, vandetanib, and afatinib.Nifedipine, osimertinib, lazatinib, poziotinib, critinib, cabozantinib, carmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met disclosed herein may be administered in combination with lazatinib.

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

[0135] Lazazinib is described in WO 2016 / 060443 as N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinylphenyl)acrylamide, and is described below as a compound of formula I. Specification 20 / 70 pages 24 CN 121194785 A

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

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

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

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

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

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

[0142] In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a domain containing SEQ ID NO:The heavy chain complementarity determination region 1 (HCDR1), HCDR2 containing SEQ ID NO: 2, HCDR3 containing SEQ ID NO: 3, 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, wherein the second structural domain binding c-Met includes 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 specifically binding to EGFR comprises a heavy chain variable region (VH) containing SEQ ID NO: 13 and a light chain variable region (VL) containing SEQ ID NO: 14, and the second domain specifically binding to c-Met comprises a VH containing SEQ ID NO: 15 and a VL containing SEQ ID NO: 16. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) containing SEQ ID NO: 17, a first light chain (LC1) containing SEQ ID NO: 18, a second heavy chain (HC2) containing SEQ ID NO: 19, and a second light chain (LC2) containing SEQ ID NO: 20. In some embodiments of the disclosed method, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0143] Bispecific anti-EGFR / c-Met antibodies can be administered in pharmaceutically acceptable carriers. “Carrier” refers to a diluent, adjuvant, excipient, or medium with which the antibody of the present invention is administered. Such mediators can be liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR / c-Met antibodies. These solutions are sterile and generally free of particulate matter. They can be sterilized using conventional, known sterilization techniques, such as filtration. For parenteral administration, the carrier may comprise sterile water, and other excipients may be added to increase solubility or preservative properties. Injectable suspensions or solutions can also be prepared using water-based carriers along with appropriate additives. Other human proteins (e.g., human blood) may also be included.Suitable media and formulations, including albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Troy, DB editor, Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing, pp. 691-1092 (see especially pp. 958-989).

[0144] The administration method may be any suitable route of delivery of the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, for example, intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, nasal, vaginal, rectal), using formulations in tablet, capsule, solution, powder, gel, or granule form; and contained in syringes, implants, osmotic pumps, cartridges, micropumps; or other methods as understood by a person skilled in the art. Site-specific administration can be achieved, for example, by intratumoral, parenteral, bronchial, abdominal, cystic, cartilaginous, intracavitary, intracavitary, intrabody cavity, intracerebellum, intravenous, colonic, cervical canal, stomach, liver, heart, bone, pelvis, pericardium, peritoneum, pleura, prostate, lung, rectum, kidney, retina, spine, synovium, thoracic, uterus, blood vessel, bladder, lesion, vagina, rectum, oral cavity, sublingual, nasal, or percutaneous delivery.

[0145] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0146] 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 can be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0147] In some embodiments, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous preparation as disclosed in PCT International Publication No. WO 2022 / 224187A1.

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

[0149] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 1400 mg and about 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 1400 mg and about 1750 mg.

[0150] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at doses between 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 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 336 ... 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 620mg, approximately 630mg, approximately 640mg, approximately 650mg, approximately 660mg, approximately 670mg, approximately 680mg, approximately 690mg, approximately 700mg, approximately 710mg, approximately 720mg, approximately 730mg, approximately 740mg, approximately 750mg, approximately 760mg, approximately 770mg, approximately 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg, approximately 840mg, approximately 850mg, approximately 860mg, approximately 870mg, approximately 880mg, approximately 890mg, approximately 900mg, approximately 910mg, approximately 920mg, approximately 930mg, approximately 940mg, approximately 950mg, approximately 960mg, approximately 970mg, approximately 980mg, approximately 990mg, approximately 1000mg, approximately 1010mg, approximately 1020mg g, approximately 1030mg, approximately 1040mg, approximately 1050mg, approximately 1060mg, approximately 1070mg, approximately 1080mg, approximately 1090mg, approximately 1100mg, approximately 1110mg, approximately 1120mg, approximately 1130mg, approximately 1140mg, approximately 1150mg, approximately 1160mg, approximately 1170mg, approximately 1180mg, approximately 1190mg, approximately 1200mg, approximately 1210mg, approximately 1220mg, approximately 1230mg, approximately 1240mg, approximately 1250mg, approximately 1260mg, approximately 1270mg, approximately1280mg, approximately 1290mg, approximately 1300mg, approximately 1310mg, approximately 1320mg, approximately 1330mg, approximately 1340mg, approximately 1350mg, approximately 1360mg, approximately 1370mg, approximately 1380mg, approximately 1390mg, approximately 1400mg, approximately 1410mg, approximately 1420mg, approximately 1430mg, approximately 1440mg, approximately 1450mg, approximately 1460mg, approximately 1470mg, approximately 1480mg, approximately 1490mg, approximately 1500mg, approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, 1575mg, approximately 1580mg, approximately 1590mg Approximately 1600mg, approximately 1610mg, 1620mg, approximately 1630mg, approximately 1640mg, approximately 1650mg, approximately 1660mg, approximately 1670mg, approximately 1680mg, approximately 1690mg, approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, approximately 1860mg, approximately 1870mg, approximately 1880mg, 1890mg, approximately 1900mg, approximately 1910mg, approximately 1920mg Approximately 1930mg, approximately 1940mg, approximately 1950mg, approximately 1960mg, approximately 1970mg, approximately 1980mg, approximately 1990mg, approximately 2000mg; Instructions for use, page 23 / 70, 27 CN 121194785 A; 2100mg, 2110mg, 2120mg, 2130mg, 2140mg, 2150mg, 2160mg, 2170mg, 2180mg, 2190mg, 2200mg, 2210mg, 2220mg, 2230mg, 2240mg, 2250mg, 2260mg, 2270mg, 2280mg, 2290mg, 2300mg, 2310mg. The bispecific anti-EGFR / c-Met antibody is administered at doses of 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, or 2410 mg.

[0151] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at doses of about 350 mg, about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg.In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 1400 mg.

[0152] In some embodiments, if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg. In some embodiments, 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.

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

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

[0155] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice weekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once weekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every three weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every four weeks.

[0156] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0157] In some embodiments, a suitable route of administration for delivering lazatinib to a subject may be oral administration, such as oral tablets. Lazatinib tablet formulations suitable for oral administration according to the invention are described, for example, in WO2021 / 209893 and WO2020 / 079637, which are incorporated herein by reference.

[0158] In some embodiments, latezatitinib is administered at a dose ranging from about 10 mg to about 400 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 20 mg to about 320 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 50 mg to about 300 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 100 mg to about 300 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 150 mg to about 280 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 200 mg to about 250 mg. In some embodiments, latezatitinib is administered at a dose ranging from about 220 mg to about 250 mg.

[0159] In some embodiments, lazatinib is administered at doses of about 20 mg, about 50 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, 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, or about 400 mg. In some embodiments, lazatinib is administered at a dose of about 240 mg.

[0160] In some embodiments, lazatinib is administered daily. In some embodiments, lazatinib is administered twice weekly.In some embodiments, latezitinib is administered once weekly. In some embodiments, latezitinib is administered once every two weeks. In some embodiments, latezitinib is administered once every three weeks. In some embodiments, latezitinib is administered once every four weeks.

[0161] In some embodiments, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with latezitinib, which may be administered using any of the doses and dosage forms disclosed herein. In some embodiments, latezitinib is administered at a dose ranging from about 10 mg to about 400 mg. In some embodiments, latezitinib is administered at a dose ranging from about 20 mg to about 320 mg. In some embodiments, lazatinib is administered at doses of approximately 20 mg, approximately 50 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, or approximately 400 mg. In some embodiments, lazatinib is administered at a dose of approximately 240 mg.

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

[0163] In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein may be administered in combination with latezitinib, wherein latezitinib is administered daily, every other day, twice a week, or once a week. In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lavatinib, wherein lavatinib is administered daily. In some embodiments, the bispecific anti-EGFR / c-Met disclosed herein can be administered in combination with lavatinib, wherein lavatinib is administered orally.

[0164] In some embodiments, the bispecific anti-EGFR / c-Met bispecific antibody and EGFR are included.Combination therapy with TKIs may further include one or more additional anticancer therapies.

[0165] In some embodiments, the methods of this disclosure include administering a cancer therapy to a subject, which does not include a combination therapy comprising a bispecific anti-EGFR / c-Met bispecific antibody and an EGFR TKI disclosed herein. In some embodiments, the cancer therapy may include any of those therapies described herein. As a non-limiting example, cancer therapies that may be administered in the methods of this disclosure may include any number of various platinum-based chemotherapy therapies or combinations thereof. As a non-limiting example, platinum-based chemotherapy therapies include carboplatin, cisplatin, or combinations thereof. Specification 25 / 70 pages 29 CN 121194785 A

[0166] Additional anticancer therapies that may be administered in the methods of this disclosure may include any one or more of chemotherapeutic agents or other anticancer therapeutic agents known to those skilled in the art. Chemootherapeutic agents are chemical compounds that can be used to treat cancer and include growth inhibitors or other cytotoxic agents, and include alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, etc. Examples of chemotherapy drugs include: alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; and nitrogen mustards, such as chlornaphazine, cholophosphamide, estradiol, ifosfamide, dichloroethylmethylamine, and mechlorethamine oxide. hydrochloride, melphalan, novobichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosourea(nitrosoureas), such as carmustine, chloruremycin, formostine, lomustine, nimustine, ranimnustine; antibiotics, such as aclacinomysins, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid. Drugs containing: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-FU; folic acid analogues. Examples of purine analogs include: dempterin, methotrexate, pteropterin, and trimetrexate; purine analogs include: fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs include: ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluorouridine; and androgens include: calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testrolide.(testolactone); anti-adrenergic drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglucanolactone; aldophosphamide glycoside; aminolevulinic acid; acridine; bestrabucil; bisantrene; edatrazine; defofamide; demecolcine; diaconitine; elfornithine; elliptinium acetate); etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidanmol; nitrarine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK®; razoxane; sizofiran; spiral germanium instruction manual 26 / 70 pages 30 CN 121194785 A (spirogermanium); tenuazonic acid; triaziquone; 2,2', 2''-Trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; novel taxanes or members of the taxane family, such as paclitaxel (TAXOL® docetaxel (TAXOTERE®)) and its analogues; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinca alkaloids; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; norvincristine; novantrone; teniposide; daunomycin; aminopterin; capecitabine; ibenphosphonateibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; receptor tyrosine kinase and / or angiogenesis inhibitors, including sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), tocinib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY 73-4506), axitinib (AG013736), lintatinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA®), afatinib (BIBW 2992), lapatinib (TYKERB®). The definition also includes, for example, neratinib (HKI-272), and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. This definition also includes anti-hormonal agents used to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trivoxifen, keoxifene, LY 117018, onanasone, and toremifene (FARESTON®); and anti-androgens, such as flutamide, nilumet, bicalutamide, leuprorelin, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. Other conventional cytotoxic chemical compounds, such as those disclosed in Wiemann et al., 1985, in Medical Oncology (edited by Calabresi et al.), Chapter 10, McMillan Publishing, are also applicable to the methods of this invention.

[0167] The generation of bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure is an exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of this disclosure. Evantumab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164, the entire contents of which are incorporated herein by reference. Evantumab is characterized by the following amino acid sequences: EGFR binding arm > SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH > SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG > SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY > SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV>SEQ ID NO: 5 (LCDR2, EGFR bonding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR bonding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met bonding arm) Specification 27 / 70 pages 31 CN 121194785 A SYGIS >SEQ ID NO: 8 (HCDR2, c-Met bonding arm) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met bonding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met bonding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met bonding arm) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met bonding arm) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR bonding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGT DFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO:15 (VH, c‑Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVT MTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO:16 (VL, c‑Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17HC1QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGT DFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVT MTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD Description 28 / 70 Page 32 CN 121194785 AKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; and the second domain comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0168] In some embodiments, the first domain that specifically binds to EGFR 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.

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

[0170] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0171] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a heavy chain complementarity-determining region 1 (HCDR1) containing SEQ ID NO: 1, an HCDR2 containing SEQ ID NO: 2, an HCDR3 containing SEQ ID NO: 3, a light chain complementarity-determining region 1 (LCDR1) containing SEQ ID NO: 4, an LCDR2 containing SEQ ID NO: 5, and an LCDR3 containing SEQ ID NO: 6; and the second domain comprises an HCDR1 containing SEQ ID NO: 7, an HCDR2 containing SEQ ID NO: 8, an HCDR3 containing SEQ ID NO: 9, an LCDR1 containing SEQ ID NO: 10, an LCDR2 containing SEQ ID NO: 11, and an LCDR3 containing SEQ ID NO: 12.

[0172] In some embodiments, the first domain that specifically binds to EGFR 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.

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

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

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

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

[0177] In some embodiments, non-limiting examples of biosimilars of amivantamab can be found in the online resource of publicly available specification 29 / 70 pages 33 CN 121194785 A: thermofisher_com / antibody / product / Amivantamab-Antibody-Recombinant-Monoclonal / MA5-42260.

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

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

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

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

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

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

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

[0185] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a bibranched glycan structure with a fucose content between about 1% and about 15%. Antibodies with reduced fucose content can be prepared using various methods reported for the successful expression of relatively high defucosylation antibodies with bibranched complex-type Fc oligosaccharides, such as controlling culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65,2012), using the variant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; electronic version before print publication; PMID:20562582), using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introducing small interfering RNA specifically targeting the α-1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expressing β-1,4-N-acetylglucosamine transferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitor chifine (Ferrara et al., J Biol Chem281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, reducing the fucose content in the antibody's glycan enhances antibody-mediated cytotoxicity (ADCC).

[0186] Other publicly available bispecific anti-EGFR / c-Met antibodies may also be used in the methods of this disclosure, provided that they exhibit similar properties when compared to ervantomatase, as described in U.S. Patent No. 9,593,164. Bispecific anti-EGFR / c-Met antibodies that can be used in the methods of this disclosure can also be generated by binding a publicly available EGFR-binding VH / VL domain and a c-Met-binding VH / VL domain and testing the characteristics of the resulting bispecific antibody, as described in U.S. Patent No. 9,593,164.

[0187] Bispecific anti-EGFR / c-Met antibodies that can be used in the methods of this disclosure can be generated, for example, by using a Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies in the following manner: a substitution is introduced at the heavy chain CH3 interface in each half-molecule to facilitate the formation of heterodimers of two antibody half-molecules with different specificities in an in vitro cell-free environment or by using co-expression. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and CH3 domain dissociation-association. The heavy chain disulfide bond in the hinge region of the parent monospecific antibody is reduced. The resulting free cysteine ​​of one parent monospecific antibody is combined with the cysteine ​​residue of the second parent monospecific antibody molecule. (30 / 70 pages, 34 CN)121194785 A forms interchain disulfide bonds, while the CH3 domain of the parent antibody is released and reformed through dissociation-association. The CH3 domain of the Fab arm can be engineered to better support heterodimerization than homodimerization. The resulting product is a bispecific antibody with two Fab arms or half-molecules, each binding different epitopes (i.e., epitopes on EGFR and c-Met). For example, the bispecific antibody of this invention can be produced using the technique described in International Patent Publication No. WO2011 / 131746. In the case of IgG1 antibodies, mutant F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild-type IgG2 and IgG4 antibodies with F405L and R409K substitutions can be used. For IgG4 antibodies, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions can be used. To generate bispecific antibodies, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region. The antibodies are then incubated together under reducing conditions sufficient to allow disulfide isomerization of cysteine ​​residues in the hinge region; thereby generating bispecific antibodies via Fab arm exchange. Ideally, the incubation conditions can be restored to non-reducing conditions. Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation for at least 90 minutes at a pH of 5-8, such as pH 7.0 or pH 7.4, in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a temperature of at least 20°C.

[0188] The bispecific anti-EGFR / c-Met antibodies used in the methods of this disclosure can also be generated using designs such as kon-in-Hole (Genentech), CrossMAb (Roche), and electrostatic matching (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange engineered domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0189] In the kon-in-Hole strategy (see, for example, International Publication WO 2006 / 028936), selected amino acids at the interface forming the CH3 domain in human IgG can be mutated at sites affecting CH3 domain interactions, thereby promoting heterodimer formation. The amino acid having a small side chain (kon-in-Hole) is introduced into the heavy chain of the antibody that specifically binds to the first antigen, andAmino acids with large side chains (grooves) are 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 due to the preferential interaction between the grooves-containing heavy chain and the grooves-containing heavy chain. Exemplary CH3 substitution pairs forming grooves and grooves (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain) are: T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0190] In addition to utilizing a "mortar and pestle" strategy to facilitate Fab wall exchange, the CrossMAb technology also utilizes CH1 / CL domain replacement in one half-arm to ensure correct light chain pairing of the resulting bispecific antibody (see, for example, U.S. Patent No. 8,242,247).

[0191] Other exchange strategies can be used to generate the full-length bispecific antibody of the present invention as follows: in one or both arms of the bispecific antibody, a variable domain or a constant domain, or both, is exchanged between or within the heavy chain. These exchanges include, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1, as described in International Patent Publications Nos. WO2009 / 080254, WO2009 / 080251, WO2009 / 018386, and WO2009 / 080252.

[0192] Other strategies may also be used, such as promoting heavy chain heterodimerization by electrostatic interaction through substitution of a positively charged residue on one CH3 surface and substitution of a negatively charged residue on a second CH3 surface, as described in U.S. Patent Publication No. US2010 / 0015133; U.S. Patent Publication No. US2009 / 0182127; U.S. Patent Publication No. US2010 / 028637; or U.S. Patent Publication No. US2011 / 0123532. In other strategies, heterodimerization can be promoted through the following substitutions (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F.Y407A / T366A_K409F or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in U.S. Patent Publication No. US2012 / 0149876 or U.S. Patent Publication No. US2013 / 0195849.

[0193] SEEDbody technology can be used to generate the bispecific antibodies of the present invention. SEEDbody has selected IgG residues substituted with IgA residues in its constant structural domain to facilitate heterodimerization, as described in U.S. Patent No. US20070287170.

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

[0195] Exemplary Embodiments The following list of exemplary embodiments is provided: 1a. A method for improving median progression-free survival (PFS) in a treatment-naïve subject population carrying one or more epidermal growth factor receptor (EGFR) mutations in locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering a combination therapy to the subject population comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of lazatinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to the median PFS of a treatment-naïve NSCLC reference subject population carrying one or more EGFR mutations, the reference population having been administered osimertinib or lazatinib without the bispecific anti-EGFR / c-Met antibody.

[0196] 2a. A method for improving overall survival (OS) in a treatment-naïve subject or population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering a combination therapy to the subject or population of patients, the combination therapy comprising: (i) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and (ii) a therapeutically effective amount of latezitinib or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to the OS of a treatment-naïve NSCLC reference subject or population of patients harboring one or more EGFR mutations, the reference subject or population of patients having been administered osimertinib or latezitinib without the bispecific anti-EGFR / c-Met antibody.

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

[0198] 4a.According to the method of embodiment 1a or 2a, wherein the lazatinib or a pharmaceutically acceptable salt or hydrate thereof is lazatinib mesylate monohydrate.

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

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

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

[0202] 8a. According to any one of embodiments 1a to 7a, wherein the subject has a newly diagnosed locally advanced or metastatic NSCLC that is not readily treatable with curative therapy, the curative therapy comprising surgical resection or chemoradiotherapy.

[0203] 9a. According to the method of embodiment 8a, wherein the curative therapy comprises surgical resection or chemoradiotherapy. Instructions for Use, Pages 32 / 70, 36, CN 121194785 A

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

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

[0206] 12a. A method according to any one of embodiments 1a to 11a, wherein the method elicits a clinical response in the subject according to RECIST v1.1 criteria.

[0207] 13a. A method according to any one of embodiments 1a to 12a, wherein the method achieves a partial or better response in the subject according to RECIST v1.1 criteria.

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

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

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

[0211] 17a. The method according to any one of embodiments 1a to 16a, wherein the method is used to diagnose a carrier.In a treatment-naïve population of patients with locally advanced or metastatic NSCLC who had one or more epidermal growth factor receptor (EGFR) mutations, PFS rates were achieved at 87% at 6 months, 73% at 12 months, 60% at 18 months, 48% at 24 months, and 41% at 30 months.

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

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

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

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

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

[0217] 23a24a. The method according to any one of embodiments 1a to 22a, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously to the subject.

[0218] 24a. The method according to embodiment 23a, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose between about 140 mg and about 2240 mg. Instructions for Use, Pages 33 / 70, CN 121194785 A

[0219] 25a. The method according to embodiment 24a, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg.

[0220] 26a. The method according to embodiment 25a, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0221] 27a. The method according to embodiment 26a, wherein if the subject has a weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

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

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

[0224] 30a. The method according to any one of embodiments 1a to 29a, wherein the bispecific anti-EGFR / c-Met antibody is administered twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

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

[0226] A list of further exemplary embodiments is provided below: 1b. A method of treating non-small cell lung cancer (NSCLC) in a subject in need of treatment, the method comprising administering a combination therapy to the subject, the combination therapy comprising (i)(ii) a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody; and (ii) a therapeutically effective amount of latezatinib or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has been diagnosed with locally advanced or metastatic NSCLC carrying one or more epidermal growth factor receptor (EGFR) mutations, and wherein the subject has never received treatment.

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

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

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

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

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

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

[0233] 8b. The method according to embodiment 7b, wherein the curative therapy comprises surgical resection or chemoradiotherapy.

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

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

[0236] 11b. The method according to any one of embodiments 1b to 10b, wherein the method elicits a clinical response in the subject according to RECIST v1.1 criteria.

[0237] 12b. The method according to any one of embodiments 1b to 11b, wherein the method achieves a partial or better response in the subject according to RECIST v1.1 criteria.

[0238] 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 1 year, or at least 2 years, or at least 3 years.

[0239] 14b. The method according to any one of embodiments 1b to 13b, wherein the subject is progression-free after at least 20 months.

[0240] 15b. The method according to any one of embodiments 1b to 13b, wherein the subject is progression-free after at least 30 months.

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

[0242] 17b. The method according to any one of embodiments 1b to 16b, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain specifically binding to EGFR and a second domain specifically binding to c-Met, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and wherein the second domain binding to c-Met comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.

[0243] 18b. The method according to embodiment 17b, wherein the first domain specifically binding EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain specifically binding c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

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

[0245] 20b. The method according to any one of embodiments 1b to 19b, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the second domain specifically binding c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.18. The first light chain (LC1), SEQ ID NO: 19. The second heavy chain (HC2), and SEQ ID NO: 20.

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

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

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

[0249] 24b. The method according to embodiment 23b, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1575 mg, 1600 mg, 2100 mg, or 2240 mg.

[0250] 25b. The method according to embodiment 24b, wherein if the subject has a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1050 mg.

[0251] 26b. The method according to embodiment 25b, wherein if the subject has a weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

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

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

[0254] 29b. The method according to any one of embodiments 1b to 28b, wherein the bispecific anti-EGFR / c-Met antibody is administered twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. Examples

[0255] The following examples are provided to further describe some embodiments of the embodiments disclosed herein. These examples are intended to illustrate and not limit the disclosed embodiments.

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

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

[0258] To further characterize the safety, tolerability, and preliminary efficacy of ervantumab and lazatinib under RP2D, an additional expansion cohort (Cohort E) was initiated. Forty-five subjects were enrolled who met the following criteria: diagnosed with an activating EGFR mutation of exon 19del or exon 21 L858R, who had progressed after first- or second-line treatment with a third-generation TKI and had never received chemotherapy. Limited prior treatment with a platinum-based chemotherapy regimen was permitted in the metastatic setting if no more than 2 cycles were required, and administered before starting the first EGFR TKI.

[0259] Description: The purpose of this study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of ervantumab as monotherapy and in combination with lazatinib, and to determine the recommended phase 2 dose (RP2D) (monotherapy), the recommended phase 2 combination dose (RP2CD) (combination therapy), and to determine the optimal combination therapy in participants with advanced non-small cell lung cancer (NSCLC) during a 21-day treatment cycle.The recommended Phase 2 dose (RP2Q3W) of eptamab (in combination with standard of care carboplatin and pemetrexed).

[0260] This open-label (all participants are known to be aware of the investigational drug), multicenter (more than one study site), first-in-human study consists of two parts. Part 1 is eptamab monotherapy and combination dose escalation, and Part 2 is eptamab monotherapy and combination dose expansion. In Part 1, participants with evaluable NSCLC will be enrolled in a cohort for eptamab monotherapy dose escalation, eptamab and lazatinib combination (to be administered in 28-day treatment cycles) RP2Q3W, and eptamab with standard of care carboplatin and pemetrexed (chemotherapy combination) (to be administered in 21-day treatment cycles). The dose will be escalated until the maximum tolerated dose (MTD, or maximum administered dose (MAD), if no MTD is found). Part 1 will follow a conventional 3+3 design. At each dose level, 3 participants will complete cycle 1. If no dose-limiting toxicity (DLT) occurs in these 3 participants, the cycle will continue to be incremented in a new cohort of 3 participants. Data from section 1 will be used to determine one or more RP2D regimens. In section 2, participants with documented epidermal growth factor receptor (EGFR) mutations and measurable disease (whose disease has progressed after prior treatment) will be enrolled and will receive ervatumab, the RP2D identified in section 1, either as monotherapy in an RP2D regimen or in combination with lazatinib in an RP2CD regimen. For both sections, the study will consist of the following cycles: an optional pre-screening period; a screening period (up to 28 days before the first dose of the study drug); a treatment period (from the first dose of the study drug until 30 (+7) days after the last dose of the study drug or before the start of any subsequent anticancer therapy, whichever comes first); and a follow-up period (approximately 6 months). Survival of all participants will be tracked during the post-treatment follow-up period until the end of the study, and safety will be monitored throughout the study.

[0261] Study Design Study type: Intervention (clinical trial). Estimated inclusion: 780 participants. Assignment: Non-randomized. Intervention model: Parallel assignment. Masking: None (open label). Primary objective: Treatment.

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

[0263] Groups and interventions Table 1 Instructions for Use 37 / 70 pages 41 CN 121194785 A Outcome measures Preliminary outcome measures Instructions for Use 38 / 70 pages 42 CN 121194785 A 1. Part 1: Number of participants with dose-limiting toxicities (DLT) [Time range: up to 28 days]. DosageLimiting toxicities (DLT) are based on drug-related adverse events and include unacceptable hematologic toxicity, grade 3 or higher non-hematologic toxicity, or elevated liver enzymes suggesting drug-induced liver injury.

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

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

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

[0267] 5. Part 2: Percentage of participants with clinical benefit [Time range: up to the EOT follow-up period (30[+7] days after the last dose)]. Clinical benefit rate is defined as the percentage of participants who achieve a complete response (CR): all target diseasesThe disappearance of focal and non-target lesions. The size of all lymph nodes must be non-pathological (short axis less than 10 mm) and normalized or partially responsive to tumor marker levels: with reference to the total diameter at baseline and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limit or the disease that is persistently stable (neither shrinking sufficiently to qualify for PR nor increasing sufficiently to qualify for progressive disease (PD), with reference to the minimum total diameter during the study period and the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limit), the total diameter of target lesions is reduced by at least 30% (%).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0283] Eligibility criteria: Age eligible for the study: 18 years and older (adults, older adults). Gender eligible for the study: All. Acceptance of healthy volunteers: No.

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

[0285] • For Part 1 combination with lazatinib dose escalation only: Participants must have been diagnosed with an activating mutation in exon 19del or exon 21 L858R of EGFR and (a) have never been treated for metastatic disease and have not been exposed to a third-generation TKI in the first-line setting, or (b) have progressed after first-line therapy with a first-generation (erlotinib or gefitinib) or second-generation (afatinib) TKI and are not eligible for inclusion in cohort MET-1, or (c) have been treated with a third-generation TKI (e.g., osimertinib) in the first-line or second-line setting and are not eligible for inclusion in cohort C or MET-1. For Part 1 chemotherapy combination cohort: Participants can be diagnosed with EGFR-mutant or EGFR-wild-type NSCLC. For Part 2 cohorts C, D, MET-1, and MET-2 only: Participants must also have a previously diagnosed disease with an activating epidermal growth factor receptor (EGFR) mutation (including inhibitor-sensitive major mutations such as exon 19 deletion and exon 21 L858R (cohorts C, E, and MET-1), and commercially available anti-TKI mutations such as exon 20 insertion (cohorts C, D, and MET-1) or activating cMet exon 14 skipping mutations (cohort MET-2). Primary activating EGFR or cMet mutation eligibility requires documentation by a CLIA-certified laboratory (or equivalent). For Part 2 cohorts WT-Ad and WT-Sq: Participants must have wild-type EGFR, anaplastic lymphoma kinase (ALK), and no MET exon 14 skipping mutations, as per US Food and Drug Administration (FDA) guidelines.Tested by an FDA-approved test or CLIA-certified laboratory (or equivalent). Pathology reports or equivalents must be in the medical record for verification. Documentation of the absence of these mutations is not required for inclusion in the WT-Sq cohort if EGFR and ALK testing is not part of the criteria of care for participants with squamous cell carcinoma histology.

[0286] • For Part 1: Participants must have evaluable disease. For Part 2: Participants must have measurable disease according to the Responsive Criteria in Solid Tumors (RECIST) v1.1.

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

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

[0289] Exclusion criteria: • Participants have uncontrolled intervening diseases, including but not limited to poorly controlled hypertension or diabetes, persistent or active infections (i.e., all antibiotics have been discontinued for at least one week prior to the first dose of the study drug), or mental illness / social conditions that would limit study requirement compliance. Participants whose medical condition requires chronic continuous oxygen therapy were excluded. For the Part 1 chemotherapy combination cohort only: Additionally, participants with an active bleeding tendency.

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

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

[0292] • Participants with a history of malignancy other than the study disease within 3 years prior to screening (exceptions include squamous cell carcinoma and basal cell carcinoma of the skin, cervical carcinoma in situ, or malignancy deemed curable or with minimal risk of recurrence within one year of screening, according to the investigator's opinion and in agreement with the sponsor's medical monitor).

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

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

[0295] Results of the treatment-naïve cohort (N=20): CHRYSALIS (NCT02609776) evaluated the combination of ervantumab (ami) and lazatinib (laz) in treatment-naïve patients (pt) with epidermal growth factor receptor (EGFR) mutant NSCLC. As previously reported, 20 pts achieved partial response (100% overall response rate), but the interpretation of long-term results was limited by the length of follow-up (Cho Ann Oncol 2020; 31: suppl_4, 1258O; Cho J Thorac Oncol 2022; 17:S126, P1.16-01). In this paper, long-term results from this treatment-naïve cohort are presented.

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

[0297] Of the 20 patients (median age 62.5 years, 55% female, all Asian) in the treatment-naïve cohort, 11 had EGFR ex19del NSCLC and 9 had exon 21 L858R NSCLC. The median follow-up and treatment duration were 33.6 months and 33.5 months, respectively. Ten patients (50%) remained on treatment without progression, of whom 7 out of 11 (64%) had ex19del and 3 out of 9 (33%) had exon 21 L858R. Median duration of response (DOR), median progression-free survival (PFS), and median overall survival (OS) were not estimable. The estimated threshold PFS rates were 85% at 12 months, 65% at 24 months, and 51% at 36 months. Notably, two patients (10%) received treatment after progression. The longest-lasting patient had a treatment duration of 37.2 months and a DOR of 35.7 months. Treatment-related dose interruptions, reductions, and discontinuations occurred in 7 (35%), 8 (40%), and 1 (5%) patients, respectively. The safety profile was consistent with previous reports, primarily involving adverse events related to targeted EGFR or MET.

[0298] Of the 10 patients who discontinued treatment, 4 submitted samples for ctDNA analysis at baseline and EOT. One patient developed a new PIK3CA mutation, one patient developed low-level HER2 amplification, one patient developed new CCNE1 and EGFR amplification, and one patient did not have a new mutation detected. Updated ctDNA data at EOT will be available at the conference presentation.

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

[0300] Example 2. MARIPOSA Clinical Study MARIPOSA (NCT04487080) was a clinical trial in approximately 1000 patients with EGFR-mutant locally advanced or metastatic NSCLC comparing ervantumab and lazatinib in combination with osimertinib.An international phase 3 randomized study (Study 73841937NSC3003, also known as NSC3003 and Mariposa) as first-line treatment.

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

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

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

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

[0305] Study Design: Study Type: Intervention (Clinical Trial). Estimated Enrollment: 1074 participants. Allocation: Randomization. Intervention Model: Parallel allocation. Masking: Triple (participant, researcher, outcome assessor). Masking Description: Only Groups B and C will be fully masked (double-blind). Primary Objective: Treatment.

[0306] Official Name: Evantumab and Lazatinib Combination Therapy vs. Osimertinib vs. Lazatinib asPhase 3 randomized study of first-line treatment in patients with EGFR-mutant locally advanced or metastatic non-small cell lung cancer.

[0307] Groups and Interventions Table 2 Instructions for Use Page 44 / 70 48 CN 121194785 A Outcome Scale Preliminary Outcome Scale 1. Progression-free survival (PFS) as determined by blinded independent central review (BICR) according to RECIST v1.1 [Time range: up to approximately 42 months]. PFS is defined as the time from randomization to the date of objective disease progression or death (whichever occurs first) based on BICR using the Solid Tumor Response Assessment Criteria (RECIST) v1.1.

[0308] Secondary Outcome Scale 1. Overall survival (OS) [Time range: up to approximately 60 months (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 a participant from any cause.

[0309] 2. Objective response rate (ORR) [Time range: up to approximately 42 months]. ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR), as defined by BICR using RECIST v1.1 criteria.

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

[0311] 4. Progression-Free Survival 2 (PFS2) after First Subsequent Treatment [Time range: up to approximately 42 months]. PFS2 is defined as the time from randomization until the date of the second objective disease progression, based on investigator assessment (after the assessment used for PFS) or death (whichever occurs first).

[0312] 5. Time to Progression of Symptoms (TTSP) [Time range: up to approximately 42 months]. TTSP is defined as the time from randomization to the date of recording any of the following in the electronic case report form (eCRF), whichever occurs first: the researcher considers the onset of a new symptom or symptom exacerbation to be associated with lung cancer and requires a change in anticancer treatment and / or clinical intervention to manage the symptoms. Instructions 45 / 70 pages 49 CN 121194785 A

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

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

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

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

[0317] 10. Number of participants with abnormal physical examinations [time range: up to approximately 60 months]. The number of participants with abnormal physical examinations will be reported.

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

[0319] 12. Plasma concentration of lazatinib [Time range: up to approximately 42 months]. Plasma samples will be analyzed to determine the concentration of lazatinib.

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

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

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

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

[0324] Eligibility criteria: Age eligible for study: 18 years and older (adults, older adults). Gender eligible for study: All. Acceptance of healthy volunteers: No.

[0325] Inclusion criteria: • Participants must have a newly diagnosed, histologically or cytologically confirmed, treatment-naïve, and non-curatively advanced or metastatic non-small cell lung cancer (NSCLC) that is not readily available for curative therapy, including surgical resection orChemotherapy and radiotherapy.

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

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

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

[0329] • Participants must have at least one measurable lesion that has not previously received radiotherapy, according to the Responsive Evaluation Criteria for Solid Tumor Response (RECIST) v1.1. Biopsies of measurable lesions should not be performed during screening, but if only one radiotherapy-free measurable lesion is present, it is acceptable for diagnostic biopsy and as a target lesion, provided that a baseline tumor assessment scan is performed at least 14 days after the biopsy.

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

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

[0332] • Participants must have untreated spinal cord compression. Participants who have received definitive treatment via surgery or radiation therapy prior to randomization and whose neurological status has been stable for at least 2 weeks are eligible, provided they have discontinued corticosteroid therapy or are receiving low-dose corticosteroid therapy of less than or equal to (≤) 10 mg / day of prednisone or an equivalent drug.

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

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

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

[0336] Evantumab plus lazatinib versus osimertinib for EGFR-mutant advanced non-small cell lung cancerFirst-line treatment for patients with NSCLC: Preliminary results from MARIPOSA, a pivotal phase 3, global, randomized, controlled trial, met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients receiving RYBREVANT® plus lazatinib compared to osimertinib. The combination of RYBREVANT® and lazatinib demonstrated a safety profile consistent with previously reported data on the combination.

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

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

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

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

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

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

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

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

[0345] Table 3: Summary of progression-free survival (PFS) determined by BICR Table 4: Summary of overall survival results Instruction manual 48 / 70 pages 52 CN 121194785 A Table 5: Summary of objective response determined by BICR Table 6: Summary of DOR results confirmed by BICR Instruction manual 49 / 70 pages 53 CN 121194785 A Table 7: Summary of PFS2 results Table 8: Summary of time to progression of symptoms (TTSP) results Instruction manual 50 / 70 pages 54 CN 121194785 A Table 9: Summary of time to subsequent treatment (TTST) results Table 10: Summary of intracranial PFS results in participants with baseline brain metastases Instruction manual 51 / 70 pages 55 CN 121194785 A Table 11: Demographic characteristics and baseline disease characteristics* Instruction manual 52 / 70 pages 56 CN 121194785 A *ECOG stands for Eastern Cooperative Oncology and EGFR epidermal growth factor receptor. †Ethnicity or race is reported by the patient. ‡Russia is considered part of Europe, and Turkey is considered part of Asia. §Other histological types include: adenocarcinoma and squamous cell carcinoma, lepidic adenocarcinoma, non-small cell lung cancer, pleomorphic carcinoma, and unknowns. (Instructions for use, 53 / 70 pages, 57)CN 121194785 A ∥ One patient in the ervantumab-lazatinib group had two EGFR mutation types (exon 19 deletion and exon 21 L858R).

[0346] Table 12: Efficacy endpoints* *The efficacy cohort includes all patients who underwent randomization. NE indicates non-estimateable. †Progression-free survival (preliminary results) was assessed through a blinded independent central review. ‡Objective response (complete or partial response) and duration of response were assessed through a blinded independent central review. The analysis included 421 patients with measurable disease at baseline in the ervantumab-lazatinib group and 414 patients in the osimertinib group. §Among confirmed responders.

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

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

[0349] Table 13: Adverse Events* Prescription 54 / 70 pages 58 CN 121194785 A Prescription 55 / 70 pages 59 CN 121194785 A *The safety population includes all patients who underwent randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the decrease in incidence in the ervantumab-lazatinib group.

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

[0351] Table 14: Representative information sheet of study participants 56 / 70 pages 60 CN 121194785 A EGFR, epidermal growth factor receptor; Ex19del, exon 19 deletion; NSCLC, non-small cell lung cancer. * Obtained from a systematic review and meta-analysis of 456 NSCLC patient studies. † Co-occurrence of EGFR mutations in NSCLC patients; data obtained from a systematic review of 87 studies.‡In 74 studies using EGFREx19del and L858R NSCLC, values ​​were obtained from linear mixed-effects models fitted to the EGFR mutation endpoint using logistic transformation, assuming a binomial distribution.

[0352] Most patients were female, Asian, or Caucasian and never smoked, representing the EGFR-mutant NSCLC population (Table 14).

[0353] Table 15: First Subsequent Systemic Therapy* Instructions for Use 57 / 70 pages 61 CN 121194785 A Instructions for Use 58 / 70 pages 62 CN 121194785 A *The efficacy population includes all patients who underwent randomization (Evantumab-Lazatinib n=429, and Osimertinib n=429); the percentages shown are 116 patients in the vonutumab-Lazatinib group and 171 patients in the osimertinib group who were assessed for disease progression and discontinued their randomization during randomization. Instructions for Use, pages 59 / 70, 63 CN 121194785 A

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

[0355] Table 16: Response Endpoints* *The efficacy cohort includes all patients who underwent randomization. NE indicates non-estimateable. †Objective response (complete or partial response) and duration of response were assessed through a blinded, independent central review. The analysis included 421 patients with measurable disease at baseline in the ervantumab-lazaitinib group and 414 patients in the osimertinib group. ‡All responders are included.

[0356] Table 17: Serious Adverse Events Occurring in at Least 1% of Patients After Treatment* Prescription 60 / 70 pages 64 CN 121194785 A *The safety cohort includes all patients who underwent randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the decrease in incidence in the ervantumab-lazaitinib group.

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

[0358] Table 18: Incidence and median time to onset of selected adverse events of interest* Prescription 61 / 70 pages 65 CN 121194785 A *The safety population includes all patients who underwent randomization and received at least one dose of any trial treatment. †Includes the following preferred terms: rash, acneiform dermatitis, folliculitis, maculopapular rash, skin lesion, acne, erythema, pustular rash, dermatitis, pruritic rash, papular rash, erythematous rash, punctate rash, infectious dermatitis, erythema multiforme, papule, drug eruption, follicular rash, herpetic rash, epidermal exfoliation, epidermal detachment. ‡Includes the following preferred terms: pulmonary embolism, deep vein thrombosis, venous thromboembolic limb, thrombosis, venous thrombosis, superficial vein thrombosis, thrombophlebitis, embolism, venous thrombosis, jugular vein thrombosis, pulmonary infarction, axillary vein thrombosis, portal vein thrombosis, post-thrombotic syndrome, sigmoid sinus thrombosis, superior sagittal sinus thrombosis, vena cava thrombosis, pelvic vein thrombosis, pulmonary thrombosis. §Includes the following preferred terms: pneumonia and interstitial lung disease.

[0359] Table 19: Venous Thromboembolic Events and Use of Anticoagulation Therapy* Instructions for Use 62 / 70 pages 66 CN 121194785 A Instructions for Use 63 / 70 pages 67 CN 121194785 A *The safety population includes all patients who underwent randomization and received at least one dose of any trial treatment. †Events in this category are listed based on the reduced incidence in the ervantumab-lazetinib group.

[0360] Venous thromboembolic (VTE) events were reported in 37% of patients in the ervantumab-lazetinib group and 9% of patients in the osimertinib group (Table 18), the most common being pulmonary embolism and deep vein thrombosis (Table 19). Notably, 5% of patients in both groups received anticoagulation therapy at baseline. Few patients received anticoagulation therapy at the first VTE (1% for ervantumab-lazetinib and 0% for osimertinib). In VTE events, 62% occurred in the ervantumab-lazatinib group within the first 4 months of treatment, compared to 33% in the osimertinib group. In both groups, 3% of patients reported interstitial lung disease / pneumonia, of which 1% were grade 3 or higher.

[0361] Table 20: Adverse events following treatment leading to interruption, reduction, and discontinuation* Prescription 64 / 70 pages 68 CN 121194785 A*The safety population includes all patients who have undergone randomization and received at least one dose of any trial treatment. †Adverse events reported in at least 3% of patients in any group are listed. ‡Adverse events reported in at least 1% of patients in any group are listed. Prescription 65 / 70 pages 69 CN 121194785 A

[0362] The most common adverse events leading to discontinuation of any treatment are infusion-related reactions and paronychia (Table 20). Discontinuation of all treatments due to treatment-related adverse events was 10% in the ervantumab-lazaitinib group and 3% in the osimertinib group.

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

[0364] Table 22: All Grade 5 Adverse Events* Prescription 66 / 70 pages 70 CN 121194785 A Prescription 67 / 70 pages 71 CN 121194785 A *The safety population includes all patients who underwent randomization and received at least one dose of any investigational treatment. All Grade 5 adverse events correspond to adverse events following treatment that resulted in death, and vice versa. †One event in the ervantumab-lazatinib group was considered to be related to any of the investigator's investigational treatments. ‡Two events in the ervantumab-lazatinib group were considered to be related to any of the investigator's investigational treatments. §Considered to be related to any of the investigator's investigational treatments.

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

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

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

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

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

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

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

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

[0373] Next-generation sequencing (NGS) pathogenic mutation patterns in circulating tumor DNA (ctDNA) at baseline: 85% (540 / 636 samples) had pathogenic alterations detected in ctDNA by NGS at baseline. TP53 co-mutations were observed in 56% of patients from the ervantumab + lazatinib group and 53% of patients from the osimertinib group. MET amplification occurred in 1 patient in each group (no high-level amplification occurred). (Figure 20).

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

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

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

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

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

[0379] In patients with high-risk traits, EGFR-mutant (Ex19del / L858R) advanced NSCLC in first-line patients...Ventozab plus lazatinib significantly improved PFS compared to osimertinib. These high-risk characteristics included: (Prescription page 69 / 70, CN 121194785 A) a.) Baseline brain metastases (HR, 0.69; P=0.010) b.) Baseline liver metastases (HR, 0.58; P=0.017) c.) TP53 co-mutation (HR, 0.65; P=0.003) d.) Detectable baseline EGFR mctDNA (Ex19del and L858R as determined by Biodesix ddPCR) (HR, 0.68; P=0.002) e.) No EGFR mctDNA at C3D1 (cycle 28) (as determined by Biodesix ddPCR) Clearance of Ex19del and L858R (determined by ddPCR) (HR, 0.49; P = 0.015) (Figure 25).

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

[0381] In the corresponding subgroup without high-risk trait, epantuzumab + lazatinib showed a consistent PFS benefit superior to osimertinib. Evanuzumab + lazatinib effectively overcame the effects of high-risk trait and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

[0382] The invention is not limited to the specific embodiments described herein. In fact, various modifications of the invention will become apparent to those skilled in the art in addition to those described herein, based on the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0383] All patents, applications, publications, test methods, documents and other materials cited herein are incorporated herein by reference in their entirety as if they were physically present in this specification. Specification 70 / 70 pages 74 CN 121194785 A Figure 1 Specification Figure 1 / 25 pages 75 CN 121194785 A Figure 2 Specification Figure 2 / 25 pages 76 CN 121194785 A Figure 3 Specification Figure 3 / 25 pages 77 CN 121194785 A Figure 4 Specification Figure 4 / 25 pages 78 CN 121194785 A Figure 5 Specification Figure 5 / 25 pages 79 CN 121194785 A Figure 6 Specification Figure 6 / 25 pages80 CN 121194785 A Figure 7, Appendix 7 / 25 of the instruction manual 81 CN 121194785 A Figure 8, Appendix 8 / 25 of the instruction manual 82 CN 121194785 A Figure 9, Appendix 9 / 25 of the instruction manual 83 CN 121194785 A Figure 10, Appendix 10 / 25 of the instruction manual 84 CN 121194785 A Figure 11, Appendix 11 / 25 of the instruction manual 85 CN 121194785 A Figure 12, Appendix 12 / 25 of the instruction manual 86 CN 121194785 A Figure 13, Appendix 13 / 25 of the instruction manual 87 CN 121194785 A Figure 14, Appendix 14 / 25 of the instruction manual 88 CN 121194785 A Figure 15, Appendix 15 / 25 of the instruction manual 89 CN 121194785 A Figure 16 Figure 17 of the instruction manual, page 16 / 25, CN 121194785 A; Figure 18 of the instruction manual, page 17 / 25, CN 121194785 A; Figure 19 of the instruction manual, page 19 / 25, CN 121194785 A; Figure 20 of the instruction manual, page 20 / 25, CN 121194785 A; Figure 21 of the instruction manual, page 21 / 25, CN 121194785 A; Figure 22 of the instruction manual, page 22 / 25, CN 121194785 A; Figure 23 of the instruction manual, page 23 / 25, CN 121194785 A; Figure 24 of the instruction manual, page 24 / 25, CN 121194785 A; Figure 25 of the instruction manual, page 25 / 25, CN 121194785 A; Figure 25 of the instruction manual, page 25 / 25, CN 121194785 A; Figure 26 of the instruction manual, CN 121194785 A; Figure 27 of the instruction manual, page 24 ... 121194785 A

Claims

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12.

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

16.

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

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

20.

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

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

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

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

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

27. The method of claim 26, wherein if the subject has a weight of 80 kg or more, the bispecific anti-EGFR / c-Met antibody is administered at a dose of 1400 mg.

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

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

30. The method according to any one of claims 1 to 29, wherein the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

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

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