Amivantamab in combination with lazertinib for the treatment of non-small cell lung cancer (NSCLC)

Abstract

The present disclosure provides methods of using amivantamab in combination with lazertinib to treat non-small cell lung cancer (NSCLC).

Description

JBI6942WOPCT1 / 103693.007549 AMIVANTAMAB IN COMBINATION WITH LAZERTINIB FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC) CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional Patent Application No.63 / 684,836, filed on August 19, 2024, United States Provisional Patent Application No.63 / 685,182, filed on August 20, 2024, United States Provisional Patent Application No.63 / 691,757, filed on September 6, 2024, United States Provisional Patent Application No.63 / 742,129, filed on January 6, 2025, and United States Provisional Patent Application No.63 / 770,403, filed on March 12, 2025, the disclosures of each of which are incorporated herein by reference in their entireties. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which is being submitted herewith electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on August 6, 2025, is named JBI6942WOPCT1_SL.xml and is 20,096 bytes in size. FIELD

[0003] The present disclosure provides methods of using amivantamab in combination with lazertinib to treat non-small cell lung cancer (NSCLC). BACKGROUND

[0004] Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients. EGFR ex19del or EGFR exon 21 L858R mutations are the most common EGFR mutations.

[0005] In NSCLC, specific mutations in the EGFR gene are associated with high response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Although the majority of NSCLC patients with EGFR mutations initially respond to EGFR TKI therapy, virtually allJBI6942WOPCT1 / 103693.007549 acquire resistance that prevents a durable response. Nearly 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors increase c-Met expression, amplify the c-Met gene, or increase its only known ligand, Hepatocyte Growth Factor (Turke et al., Cancer Cell, 17:77-88, 2010). The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent. Patients with EGFR ex19del or exon 21 L858R mutations have a real-world five-year overall survival of 19 percent.

[0006] Progression of acquired resistance to EGFR-TKI such as osimertinib in epidermal growth factor receptor mutant (EGFRm) NSCLC likely arises from complex and heterogenous patterns of resistance together with co-occurrence of multiple resistance mechanisms, and as such the details of such mechanisms remain elusive. Thus, targeted therapies pose unique challenges, and there remains a need for new treatment paradigms for patients that are newly diagnosed with NSCLC. SUMMARY

[0007] Disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in the OS is at least about 36.7 months.

[0008] Disclosed herein are methods of reducing the risk of death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and 2JBI6942WOPCT1 / 103693.007549 (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the risk of death is reduced by at least about 25%.

[0009] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0010] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or 3JBI6942WOPCT1 / 103693.007549 who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

[0011] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 2 or grade 3 venous thromboembolic event (VTE): withholding administration of the amivantamab and lazertinib, administering anticoagulant treatment, and resuming the amivantamab at the same dose as prior to the withholding and the lazertinib at the same dose as prior to the withholding; or who experiences a grade 4 or recurrent grade 2 or grade 3 VTE despite therapeutic level anticoagulation: withholding lazertinib and permanently discontinuing amivantamab, administering anticoagulant treatment, and continuing treatment with lazertinib at the same dose as prior to the withholding.

[0012] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or 2 dermatologic adverse reaction: administering a reduced dose of the amivantamab to the subject if the grade 1 or 2 dermatologic adverse reaction does not improve after two weeks; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or 4JBI6942WOPCT1 / 103693.007549 who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0013] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 adverse reaction is a recurrent grade 4 adverse reaction.

[0014] Disclosed herein are methods of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising administering to the subject an approved drug product comprising amivantamab, in combination with lazertinib.

[0015] Disclosed herein are methods of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising 5JBI6942WOPCT1 / 103693.007549 administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib.

[0016] Disclosed herein are methods of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib.

[0017] Disclosed herein are methods of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib.

[0018] In one aspect, provided herein is a method of improving overall survival (OS) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved OS is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in overall survival (OS) at 24 or 36 months of treatment, wherein the increase in the OS is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0019] In another aspect, provided herein is a method of improving time to subsequent therapy (TTST) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved TTST is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering 6JBI6942WOPCT1 / 103693.007549 to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in time to subsequent therapy (TTST) at 24 or 36 months of treatment, wherein the increase in the TTST is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0020] In another aspect, provided herein is a method of improving intracranial duration of response (icDoR) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved icDoR is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial duration of response (icDoR) at 24 or 36 months of treatment, wherein the increase in the icDoR is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0021] In another aspect, provided herein is a method of improving intracranial progression free survival (icPFS) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved icPFS is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial progression free survival (icPFS) at 24 or 36 months of treatment, 7JBI6942WOPCT1 / 103693.007549 wherein the increase in the icPFS is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0022] In another aspect, provided herein is method of improving time to treatment discontinuation (TTD) in a population of subjects with locally advanced or metastatic non- small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved TTD is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in time to treatment discontinuation (TTD) at 24 or 36 months of treatment, wherein the increase in the TTD is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0023] In another aspect, provided herein is a method of improving intracranial progression free survival after subsequent therapy (PFS2) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations, the method comprising administering to the subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib, wherein at 24 or 36 months the improved PFS2 is greater compared to a population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In another aspect, provided herein is a method comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial progression free survival after subsequent therapy (PFS2) at 24 or 36 months of treatment, wherein the increase in the PFS2 is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0024] In some embodiments, at 24 months the OS of the population of subjects administered with the combination therapy is about 75%. In some embodiments, at 36 8JBI6942WOPCT1 / 103693.007549 months the OS of the population of subjects administered with the combination therapy is about 61%.

[0025] In some embodiments, at 24 months the TTST of the population of subjects administered with the combination therapy is about 57%. In some embodiments, at 36 months the TTST of the population of subjects administered with the combination therapy is about 45%.

[0026] In some embodiments, at 24 months the icPFS of the population of subjects administered with the combination therapy is about 51%. In some embodiments, at 36 months the icPFS of the population of subjects administered with the combination therapy is double the icPFS of the population of subjects who received an EGFR tyrosine kinase inhibitor (TKI). In some embodiments, at 36 months the icPFS of the population of subjects administered with the combination therapy is about 38%.

[0027] In some embodiments, at 24 months the TTD of the population of subjects administered with the combination therapy is about 52%. In some embodiments, at 36 months the TTD of the population of subjects administered with the combination therapy is about 40%.

[0028] In some embodiments, at 24 months the PFS2 of the population of subjects administered with the combination therapy is about 73%. In some embodiments, at 36 months the PFS2 of the population of subjects administered with the combination therapy is about 57%. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed methods, there are shown in the drawings exemplary embodiments of the methods; however, the methods are not limited to the specific embodiments disclosed. In the drawings:

[0030] FIG.1 shows an exemplary schematic overview of the MARIPOSA clinical study.

[0031] FIG.2 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in the efficacy population of amivantamab- lazertinib versus osimertinib including the lazertinib monotherapy arm. PFS is shown by BICR results. The dashed lines indicate the median progression-free survival in the two 9JBI6942WOPCT1 / 103693.007549 groups and the tick marks indicate censoring of data. The median progression-free survival in the lazertinib group was 18.5 months (95% CI, 14.8 to 20.1).

[0032] FIG.3 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in the efficacy population of amivantamab- lazertinib versus osimertinib. The dashed lines indicate the median progression-free survival in the two groups and the tick marks indicate censoring of data. PFS by BICR is prolonged by 7.1 months for amivantamab+lazertinib vs osimertinib.

[0033] FIG.4 shows PFS by subgroup.

[0034] FIG.5 shows a Kaplan-Meier estimate of interim overall survival. The efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.

[0035] FIG.6 shows a Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition.1375 patients were screened and 1074 underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib monotherapy, and 216 to lazertinib monotherapy); 1062 received at least one dose of trial treatment.

[0036] FIG.7 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients with EGFR Exon 19 deletions (top) and in patients with EGFR Exon 21 L858R (bottom). The efficacy population included all patients who had undergone randomization. In both panels, the hazard ratio for disease progression or death was obtained from an unstratified proportional hazards model; tick marks indicate censoring of data.95% confidence interval (CI) widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. EGFR denotes epidermal growth factor receptor.

[0037] FIG.8 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients who are of Asian race (top) and in patients who are of non-Asian race (bottom). The efficacy population included all patients who had undergone randomization. In both panels, the hazard ratio (HR) for disease progression or death was obtained from an unstratified proportional hazards model; tick marks indicate censoring of data.95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.

[0038] FIG.9 shows Kaplan-Meier estimates of progression-free survival as assessed by blinded independent central review in patients with a history of brain metastases (top) and in patients without history of brain metastases (bottom). The efficacy population included all patients who had undergone randomization. In both panels, the hazard ratio for 10JBI6942WOPCT1 / 103693.007549 disease progression or death was obtained from an unstratified proportional hazards model; tick marks indicate censoring of data.95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.

[0039] FIG.10 shows Kaplan-Meier estimates of extracranial progression-free survival as assessed by blinded independent central review in the efficacy population. The efficacy population included all patients who had undergone randomization. Extracranial progression-free survival was defined as time from randomization to disease progression (detected by extracranial scans) or death. If first progression was detected solely in the CNS, these patients were censored at the time of CNS disease progression. The dashed lines indicate the median extracranial progression-free survival in the two groups; tick marks indicate censoring of data.95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. CNS denotes central nervous system. Since MARIPOSA performed serial brain imaging, a sensitivity analysis was conducted censoring CNS-only, first progression events. The median extracranial progression-free survival was 27.5 months (95% CI, 22.1 to not estimable) in the amivantamab-lazertinib group and 18.4 months (95% CI, 16.5 to 20.2) in the osimertinib group.

[0040] FIG.11 shows waterfall plots of the best percent change from baseline in target lesions in the amivantamab-lazertinib group (top) and in the osimertinib group (bottom). The number of patients with measurable disease at baseline was 421 in amivantamab-lazertinib group and 414 in the osimertinib group, as determined by blinded independent central review. Target lesions were measured as the sum of the diameters. The objective response rate was 86% (95% CI, 83 to 89) in the amivantamab-lazertinib group and 85% (95% CI, 81 to 88) in the osimertinib group.

[0041] FIG.12 shows a Kaplan-Meier estimate of response duration among confirmed responders in the efficacy population. The efficacy population included all patients who had undergone randomization. Included in this analysis were the 336 confirmed responders (out of the 421 patients with measurable disease at baseline by blinded independent central review) in the amivantamab-lazertinib group and the 314 confirmed responders (out of 414 patients) in the osimertinib group. Tick marks indicate censoring of data. The objective response rate was 86% (95% CI, 83 to 89) in the amivantamab-lazertinib group and 85% (95% CI, 81 to 88) in the osimertinib group, with median response duration among confirmed responders of 25.8 months (95% CI, 20.1 to not estimable) and 16.8 months (95% CI, 14.8 to 18.5), respectively. 11JBI6942WOPCT1 / 103693.007549

[0042] FIG.13 shows a Kaplan-Meier estimate of time to treatment discontinuation in the efficacy population. The efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.

[0043] FIG.14 shows Kaplan-Meier estimates of time to subsequent therapy in the efficacy population. The efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.

[0044] FIG.15 shows a Kaplan-Meier estimate of progression-free survival after first subsequent therapy, which was defined from the time from randomization until the date of objective disease progression (by investigator) or death after initiation of subsequent anticancer systemic therapy, whichever occurs first. The efficacy population included all patients who had undergone randomization. Tick marks indicate censoring of data.

[0045] FIG.16 shows MARIPOSA study design and methods for high risk subgroups. Detection of circulating tumor (ctDNA) and co-mutations were analyzed by next- generation sequencing (NGS) of blood at baseline. Detection and clearance of Ex19del and L858R ctDNA in blood were analyzed with droplet digital PCR (ddPCR) at baseline and C3D1.aDosing (in 28-day cycles): Amivantamab: 1050 mg (1400 mg if ≥80 kg) weekly for the first 4 weeks, then every 2 weeks; Lazertinib: 240 mg daily; Osimertinib: 80 mg daily.bLazertinib monotherapy arm was included to assess the contribution of components.cEfficacy assessments were analyzed per RECIST v1.1 every 8 weeks (±1 week) for the first 30 months and then every 12 weeks (±1 week).dEx19del or L858R by Biodesix ddPCR.

[0046] FIG.17 shows progression-free survival by BICR. Amivantamab + Lazertinib reduced the risk of progression or death by 30% and improved median PFS by 7.1 months.

[0047] FIG.18 shows progression-free survival in patients with brain metastases. Osimertinib showed a median PFS of 13.0 months among patients with brain metastases at baseline, indicating a poor prognostic subgroup. Among patients with brain metastases at baseline, amivantamab + lazertinib reduced the risk of progression or death by 31% vs osimertinib. Among patients without brain metastases at baseline, amivantamab + lazertinib showed a consistent benefit over osimertinib: Median PFS: 27.5 vs 19.9 months and HR 0.69 (95% CI, 0.53–0.89); P=0.005.

[0048] FIG.19 shows progression-free survival in patients with liver metastases. Osimertinib showed a median PFS of 11.0 months among patients with liver metastases at baseline, indicating a poor prognostic subgroup. Among patients with liver metastases at baseline, amivantamab + lazertinib reduced the risk of progression or death by 42% vs 12JBI6942WOPCT1 / 103693.007549 osimertinib. Among patients without liver metastases at baseline, amivantamab + lazertinib showed a consistent benefit over osimertinib: Median PFS: 24.0 vs 18.3 months and HR 0.74 (95% CI, 0.60–0.91); P=0.004.

[0049] FIG.20 shows next-generation sequencing circulating tumor DNA (ctDNA) pathogenic mutation patterns at baseline.85% (540 / 636 samples) had pathogenic alterations detected in ctDNA at baseline by NGS. TP53 co-mutations were observed in 56% from the amivantamab + lazertinib arm and 53% from the osimertinib arm. MET amplification occurred in 1 patient in each arm (neither with high-level amplification). Only pathogenic mutations occurring in ≥2% of patients are shown. Pathogenic mutations were detected with the Guardant Health G360® panel.

[0050] FIG.21 shows progression-free survival in patients with TP53 co-mutations. Osimertinib showed a median PFS of 12.9 months among patients with TP53 co-mutations at baseline, indicating a poor prognostic subgroup. Among patients with TP53 co-mutations at baseline, amivantamab + lazertinib reduced the risk of progression or death by 35% vs osimertinib. Among patients with wild-type TP53 at baseline, amivantamab + lazertinib showed a consistent benefit over osimertinib: Median PFS: 22.1 vs 19.9 months and HR 0.75 (95% CI, 0.52–1.07); P=0.114.

[0051] FIG.22 shows detectable EGFR mutant (EGFRm) ctDNA at baseline and on treatment. Detection and clearance of Ex19del and L858R ctDNA in the blood were analyzed by ddPCR. At baseline, 336 patients in both the amivantamab + lazertinib and osimertinib arms provided analyzable ctDNA samples. Approximately 70% of patients in both arms had detectable EGFRm ctDNA at baseline.192 patients in the amivantamab + lazertinib arm and 212 in the osimertinib arm had matched samples at baseline and C3D1 (Week 9). At C3D1 (Week 9), detectable EGFRm ctDNA was observed in 15% of these patients in both arms.

[0052] FIG.23 shows progression-free survival in Patients With Detectable Baseline ctDNA (Ex19del or L858R by Biodesix ddPCR). Osimertinib showed a median PFS of 14.8 months among patients with detectable ctDNA at baseline, indicating a poor prognostic subgroup. Among patients with detectable baseline ctDNAa, amivantamab + lazertinib reduced the risk of progression or death by 32% vs osimertinib. Among patients without detectable baseline ctDNA, amivantamab + lazertinib showed a consistent benefit over osimertinib: Median PFS: 27.7 vs 21.9 months and hazard ratio 0.72 (95% CI, 0.47– 1.10); P=0.132. Among patients with detectable baseline ctDNA by Guardant360® NGS, 13JBI6942WOPCT1 / 103693.007549 amivantamab + lazertinib showed a consistent benefit over osimertinib (HR, 0.71 [95% CI, 0.57–0.89]; P=0.003).

[0053] FIG.24 shows progression-free survival in patients without cleared ctDNA at C3D1 (Ex19del or L858R by Biodesix ddPCR. Cycles were 28 days). Osimertinib showed a median PFS of 9.1 months among patients without cleared ctDNA at C3D1, indicating a poor prognostic subgroup. Among patients without cleared ctDNA at C3D1, amivantamab + lazertinib reduced the risk of progression or death by 51% vs osimertinib. Among patients with cleared ctDNA at C3D1, amivantamab + lazertinib showed a consistent benefit over osimertinib: Median PFS: 24.0 vs 16.5 months and HR 0.64 (95% CI, 0.48–0.87); P=0.004.

[0054] FIG.25 shows progression-free survival for patients with high-risk features. In the MARIPOSA study, 89% of patients had at least 1 high-risk feature detected at baseline (Patients with analyzable ctDNA by NGS at baseline were included in this pooled analysis. High-risk features included baseline detectable ctDNA by NGS or baseline metastases of the liver or brain. For patients with detectable ctDNA, it was assumed TP53 co-mutations would be identified if present).

[0055] FIG.26 shows a Kaplan-Meier Plot of Overall Survival for Amivantamab + Lazertinib vs Osimertinib.

[0056] FIG.27 shows a Kaplan-Meier Plot of Overall Survival for Amivantamab + Lazertinib vs Osimertinib, including 24 and 36 months values, etc. specified.

[0057] FIG.28 shows subgroup analysis.

[0058] FIG.29 Shows Kaplan-Meier estimate of time to symptomatic progression in the efficacy population.

[0059] FIG.30 Shows Kaplan-Meier estimate of time to treatment discontinuation in the efficacy population.

[0060] FIG.31 Shows Kaplan-Meier estimates of the time to subsequent therapy in the efficacy population.

[0061] FIG.32 Shows First Subsequent Therapies and Progression-free Survival After First Subsequent Therapy: bar plot illustrating the percentage of participants who received a first subsequent therapy after discontinuation of their assigned treatment. The bar plot shows the type of therapy that the participants subsequently received. One participant in the osimertinib arm received quadruplet chemotherapy and is included in the doublet chemotherapy category. Three participants in the osimertinib arm received triplet chemotherapy + IO / VEGFi and are included in the doublet chemotherapy + IO / VEGFi category. “Other” therapy included IO alone, herbals, antibody-drug conjugates, ALK 14JBI6942WOPCT1 / 103693.007549 tyrosine kinase inhibitorsTKIs, c-MET tyrosine kinase inhibitorsTKIs, amivantamab, (1 participant received amivantamab-chemotherapy after amivantamab-lazertinib; after osimertinib, 1 participant received amivantamab-chemotherapy, 1 participant received amivantamab-lazertinib, and 1 participant received amivantamab monotherapy), and investigational agents. Percentages may not total 100 due to rounding. One participant in the osimertinib arm was re-challengedrechallenged with osimertinib in combination with afatinib as a subsequent therapy. IO denotes immuno-oncology, TKI tyrosine kinase inhibitor, and VEGFi vascular endothelial growth factor inhibitor.

[0062] FIG.33 Shows First Subsequent Therapies and Progression-free Survival After First Subsequent Therapy: a Kaplan-Meier estimate of median progression-free survival after first subsequent therapy, which was defined as the time from randomization until the date of second objective disease progression (by investigator) or death after initiation of subsequent anticancer systemic therapy, whichever occured first. Tick marks indicate censoring of data.

[0063] FIG.34 Shows a Kaplan-Meier estimate of intracranial progression-free survival in participants with a history of brain metastases.

[0064] FIG.35 Shows duration of intracranial response in confirmed responders.

[0065] FIG.36 shows a Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment.

[0066] FIG.37 shows a Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – Papillon Study.

[0067] FIG.38 shows a monitoring schedule for the amivantamab + lazertinib versus osimertinib treatment.

[0068] FIG.39 shows Consolidated Standards of Reporting Trials (CONSORT) Diagram of Participant Disposition.

[0069] FIG.40 shows a Kaplan-Meier curves of OS in patients with previously untreated NSCLC.

[0070] FIG.41 shows intracranial duration of response (icDoR). MARIPOSA required serial brain imaging for all patients, which provides robust evaluation of CNS outcomes. Intracranial Overall Response Rate (icORR) was 77% for both arms; however, amivantamab + lazertinib demonstrated greater durability of response, with improved icDoR vs osimertinib. 15JBI6942WOPCT1 / 103693.007549

[0071] FIG.42 shows intracranial progression free survival (icPFS). Amivantamab + lazertinib showed a favorable trend in icPFS with durable CNS control at 3 years. At the 3- year landmark icPFS was double for amivantamab + lazertinib vs osimertinib (38% vs 18%).

[0072] FIG.43 shows time to treatment discontinuation (TTD). Amivantamab + lazertinib demonstrated significantly longer TTD vs osimertinib. More patients remained on treatment at 3 years with amivantamab + lazertinib (40% vs 29%).

[0073] FIG.44 shows time to subsequent therapy (TTST). Amivantamab + lazertinib had significantly longer TTST. Fewer patients at the 3-year landmark on the amivantamab + lazertinib arm started a subsequent therapy versus osimertinib (45% vs 32%).

[0074] FIG.45 shows intracranial progression free survival after subsequent therapy (PFS2). Amivantamab + lazertinib significantly reduced the risk of 2nd disease progression or death by 27%. At the 3-year landmark PFS2 was 57% for amivantamab + lazertinib vs 49% for osimertinib.

[0075] FIG.46 shows updated overall survival analysis. Amivantamab + lazertinib showed a clinically meaningful, improved trend in survival. The curves separate early and widen over time favoring amivantamab + lazertinib, with 61% of patients alive at 3 years vs 53% with osimertinib. DETAILED DESCRIPTION

[0076] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0077] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0078] Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used. 16JBI6942WOPCT1 / 103693.007549

[0079] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0080] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0081] The conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0082] The transitional terms “comprising,” “consisting essentially of,” and “consisting of” are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of” and “consisting essentially of.”

[0083] “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of the selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time. “In combination with,” as it relates to amivantamab in combination with lazertinib, is synonymous with a combination therapy 17JBI6942WOPCT1 / 103693.007549 comprising amivantamab and lazertinib, wherein the amivantamab and lazertinib are administered via different routes of administration on the same or different days.

[0084] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides, polypeptides vectors or viruses) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated” refers to a molecule that is substantially free of other cellular material and / or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0085] “Treat,” “treating,” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and / or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.

[0086] “Prevent,” “preventing,” “prevention,” or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in subject.

[0087] “Diagnosing” or “diagnosis” refers to methods to determine if a subject is suffering from a given disease or condition, or may develop a given disease or condition in the future, or is likely to respond to treatment for a prior diagnosed disease or condition, i.e., stratifying a patient population on likelihood to respond to treatment. Diagnosis is typically performed by a physician based on the general guidelines for the disease to be diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.

[0088] “Responsive,” “responsiveness,” or “likely to respond” refers to any kind of improvement or positive response, such as alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

[0089] “Newly diagnosed” refers to a subject who has been diagnosed with cancer (e.g., EGFR or c-Met expressing cancer) but has not yet received treatment (e.g., treatment for lung cancer). 18JBI6942WOPCT1 / 103693.007549

[0090] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0091] “Refractory” refers to a disease that does not respond to a treatment. A refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment.

[0092] “Relapsed” refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic.

[0093] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” are used interchangeably herein.

[0094] “Reference subject” or “reference population of subjects” refers to a subject or population of subjects having a locally advanced or metastatic EGFR-mutated NCSLC harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve and who have been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody instead of a combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lazertinib. The reference subject or the reference population of subjects can have substantially the same disease progression as the subject or population of subjects that are treated with the combination therapy comprising the disclosed bispecific anti-EGFR / c-Met antibody and lazertinib. In some embodiments, the population of subjects and reference population of subjects contain at least two subjects. In some embodiments, the population of subjects and reference population of subjects contain a number of subjects that allow for a statistically significant analysis of the improvement in safety and efficacy.

[0095] “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger. 19JBI6942WOPCT1 / 103693.007549

[0096] “Cancer” refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.

[0097] “EGFR or c-Met expressing cancer” refers to cancer that has detectable expression of EGFR or c-Met or has EGFR or c-Met mutation or amplification. EGFR or c- Met expression, amplification and mutation status can be detected using know methods, such as sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or western blotting. In some embodiments, the EGFR or c-Met expressing cancer is associated with a wild-type EGFR, an EGFR mutation, an EGFR gene amplification, increased levels of circulating HGF, a wild-type c-Met, a c-Met mutation, a c-Met gene amplification or a mutant KRAS. The EGFR mutation may be an activating mutation such as exon 19 deletion or L858R mutation. In some embodiments, the EGFR mutation is one or more deletions in exon 19, one or more insertions in exon 19, or exon 21 L858R substitution or any combination thereof. Exemplary exon 19 deletions are delE746-A750, delE746_T751InsKV, delE746_A750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE746_T751InsAPT, delE746_T751InsVA, delE746_S752InsV, delE746_P753InsVS, delE746_K754InsGG, delE746_E749, delE746_E749InsP, delL747_E749, delL747_A750InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, delL747_T751InsS, delL747_T751, delL747_P753InsS, delA750_I759InsPT, delT751_I759InsT, delS752_I759, delT751_I759InsN, delT751_D761InsNLY, delS752_I759, delR748-P753 and delL747- P753insS, delL747-T751.

[0098] “Epidermal growth factor receptor” or “EGFR” refers to the human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) having the amino acid sequence shown in GenBank accession number NP_005219, as well as naturally- occurring variants thereof.

[0099] “Hepatocyte growth factor receptor” or “c-Met” as used herein refers to the human c-Met having the amino acid sequence shown in GenBank Accession No: NP_001120972 and natural variants thereof.

[0100] “Bispecific anti-EGFR / c-Met antibody” or “bispecific EGFR / c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met. The domains specifically binding EGFR 20JBI6942WOPCT1 / 103693.007549 and c-Met are typically VH / VL pairs, and the bispecific anti-EGFR / c-Met antibody is monovalent in terms of binding to EGFR and c-Met.

[0101] “Specific binding” or “specifically binds” or “specifically binding” or “binds” refer to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 5x10-8M or less, for example about 1x10-9M or less, about 1x10-10M or less, about 1x10-11M or less, or about 1x10-12M or less, typically with the KD that is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The dissociation constant may be measured using known protocols. Antibodies that bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). While a monospecific antibody binds one antigen or one epitope, a bispecific antibody binds two distinct antigens or two distinct epitopes.

[0102] “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0103] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs may be defined using various delineations such as Kabat (Wu et al. (1970) J Exp Med 132: 211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), 21JBI6942WOPCT1 / 103693.007549 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 the various delineations and variable region numbering are described (see e.g., 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 resources, imgt_org). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification.

[0104] Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0105] “Antigen binding fragment” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0106] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of 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 22JBI6942WOPCT1 / 103693.007549 deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0107] “Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0108] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0109] “Biosimilar” (of an approved reference product / biological drug, i.e., reference listed drug) refers to a biological drug that is highly similar to the reference drug with no clinically meaningful differences between the biosimilar and the reference drug in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference drug; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar. The biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional standard of “interchangeability,” the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. The biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extend the mechanisms are known for the reference product. The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. The route of administration, the dosage form, and / or the strength of the biosimilar 23JBI6942WOPCT1 / 103693.007549 are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent. The biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.

[0110] “Antagonist” or “inhibitor” refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein. A molecule is an antagonist when the at least one reaction or activity is suppressed by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.

[0111] “PD-(L)1 axis inhibitor” refers to a molecule that inhibits PD-1 downstream signaling. PD-(L)1 axis inhibitor may be a molecule that binds PD-1, PD-L1 or PD-L2.

[0112] “Biological sample” refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissue, organ cultures or cell cultures. 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 yet another non-limiting example, the biological sample is a tumor sample. In some embodiments, the biological sample is circulating tumor DNA (ctDNA) that may be isolated from various other biological samples disclosed herein such as, but not limited to, a blood or plasma sample. In some embodiments, the biological sample is tumor DNA that may be isolated from, e.g., a tumor sample.

[0113] “Low fucose” or “low fucose content” as used in the application refers to antibodies with fucose content of about between 1%-15% or less than about 20%. 24JBI6942WOPCT1 / 103693.007549

[0114] “Normal fucose” or “normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 80% or over 85%.

[0115] As used herein, “treatment naïve” refers to a subject that has been diagnosed with locally advanced or metastatic NSCLC and has not yet received anti-cancer treatment for the NSCLC; the subject is therefore chemotherapy naïve and TKI naïve, e.g., has not received chemotherapy, or a tyrosine kinase inhibitor (including 1st generation TKI, 2nd generation TKI or 3rd generation TKI), or other anti-NSCLC treatment. A method of treating a treatment naïve subject may also be referred to as first-line or front line treatment.

[0116] As used herein, RECIST v1.1 criteria refer to publicly available guidelines for response evaluation criteria in solid tumors as described by 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 by reference herein. Eisenhauer et al., provide the following definitions of criteria used to determine objective tumor response for target lesions: - Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. - Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). - Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[0117] As used herein, a partial response or better refers to a partial response (PR) or complete response (CR); and progression-free refers to lack of disease progression.

[0118] “Overall Survival” as used herein refers, for example, to the time from the date of randomization to the date of participant's death due to any cause,the time from the date of first administration of study drug to the date of participant’s death due to any cause, and the like.

[0119] “Approved drug product” as used herein refers to a product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental 25JBI6942WOPCT1 / 103693.007549 authority, e.g., the Food and Drug Administration (FDA) or the similar authority in other countries.

[0120] New treatment options for patients that are newly diagnosed with EGFR mutation-positive advanced NSCLC represent a significant unmet medical need. The EGFR- TKI TAGRISSO® (osimertinib) is a standard of care in the front-line patient population. Results of the FLAURA clinical trial showed that in patients with previously untreated EGFR mutation–positive advanced NSCLC, osimertinib treatment resulted in a median progression- free survival (mPFS) of 18.9 months (Soria et al., N Engl J Med 2018; 378:113-125).

[0121] The present disclosure provides novel methods for treating EGFR mutation-positive advanced NSCLC in patients that are treatment naïve. The present disclosure provides, for example, methods of improving median progression free survival and / or improving overall survival for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve. Thus, embodiments of the present disclosure provide methods for treating, methods of improving median progression free survival, and methods of improving overall survival for patients and / or populations of patients with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC).

[0122] Disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in the OS is at least about 36.7 months.

[0123] The improvement in OS in the subject or the population of subjects can be OS greater than the OS of a reference subject or a reference population of subjects with NSCLC having EGFR exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib without the amivantamab. The improvement in OS can be OS that is 26JBI6942WOPCT1 / 103693.007549 at least about 36.7 months and is greater than the OS of the reference subject or the reference population of subjects.

[0124] Disclosed herein are methods of reducing the risk of death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the risk of death is reduced by at least about 25%.

[0125] The risk of death in the subject or the population of subjects can be reduced relative to the risk of death in a reference subject or a reference population of subjects with NSCLC having EGFR exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib without the amivantamab. The risk of death in the subject or the population of subjects can be reduced by at least about 25% and be lower than the the risk of death in the reference subject or the reference population of subjects.

[0126] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in overall survival (OS) at 24 or 36 months of treatment, wherein the increase in the OS is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI). Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving at 24 months of treatment an overall survival (OS) of about 75% or achieving at 36 months of treatment an overall survival (OS) of about 61%. 27JBI6942WOPCT1 / 103693.007549

[0127] Disclosed herein are methods of improving time to subsequent therapy (TTST) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0128] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0129] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC 28JBI6942WOPCT1 / 103693.007549 harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0130] Also disclosed here are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0131] Also disclosed here are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0132] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the population of subjects a combination 29JBI6942WOPCT1 / 103693.007549 therapy comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0133] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0134] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population 30JBI6942WOPCT1 / 103693.007549 of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0135] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0136] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0137] Also disclosed herein are methods of improving time to subsequent therapy (TTST) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions 31JBI6942WOPCT1 / 103693.007549 or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTST is relative to TTST of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0138] In some embodiments, the methods are performed on a subject and the methods provide an improvement in TTST compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in TTST compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in TTST compared to a reference population of subjects.

[0139] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in time to subsequent therapy (TTST) at 24 or 36 months of treatment, wherein the increase in the TTST is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI). Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving at 24 months of treatment a time to subsequent therapy (TTST) of about 57% or achieving at 36 months of treatment a time to subsequent therapy (TTST) of about 45%.

[0140] Disclosed herein are methods of improving intracranial duration of response (icDoR) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the 32JBI6942WOPCT1 / 103693.007549 subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0141] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0142] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody. 33JBI6942WOPCT1 / 103693.007549

[0143] Also disclosed here are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0144] Also disclosed here are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0145] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co- mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR 34JBI6942WOPCT1 / 103693.007549 is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0146] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co- mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0147] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0148] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects 35JBI6942WOPCT1 / 103693.007549 with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0149] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0150] Also disclosed herein are methods of improving intracranial duration of response (icDoR) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein 36JBI6942WOPCT1 / 103693.007549 the improvement in icDoR is relative to icDoR of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0151] In some embodiments, the methods are performed on a subject and the methods provide an improvement in icDoR compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in icDoR compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in icDoR compared to a reference population of subjects.

[0152] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial duration of response (icDoR) at 24 or 36 months of treatment, wherein the increase in the icDoR is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI).

[0153] Disclosed herein are methods of improving intracranial progression free survival (icPFS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0154] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain 37JBI6942WOPCT1 / 103693.007549 metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0155] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0156] Also disclosed here are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference 38JBI6942WOPCT1 / 103693.007549 subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0157] Also disclosed here are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0158] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co- mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0159] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co- mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the population of subjects a combination therapy comprising: a therapeutically effective amount of a bispecific 39JBI6942WOPCT1 / 103693.007549 anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0160] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0161] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population 40JBI6942WOPCT1 / 103693.007549 of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0162] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0163] Also disclosed herein are methods of improving intracranial progression free survival (icPFS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in icPFS is relative to icPFS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0164] In some embodiments, the methods are performed on a subject and the methods provide an improvement in icPFS compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in icPFS compared to a reference population of subjects. In some embodiments, 41JBI6942WOPCT1 / 103693.007549 the methods are performed on a population of subjects and the methods provide an improvement in icPFS compared to a reference population of subjects.

[0165] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial progression free survival (icPFS) at 24 or 36 months of treatment, wherein the increase in the icPFS is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI). Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving at 24 months of treatment an intracranial progression free survival (icPFS) of about 51% or achieving at 36 months of treatment an intracranial progression free survival (icPFS) of about 38%.

[0166] Disclosed herein are methods of improving time to treatment discontinuation (TTD) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0167] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the population of subjects a combination therapy comprising: a therapeutically effective amount 42JBI6942WOPCT1 / 103693.007549 of a bispecific anti-EGFR / c-Met antibody, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0168] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0169] Also disclosed here are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody. 43JBI6942WOPCT1 / 103693.007549

[0170] Also disclosed here are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0171] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment- naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0172] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is 44JBI6942WOPCT1 / 103693.007549 relative to TTD of a treatment-naïve reference subject or a reference population of treatment- naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0173] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0174] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody. 45JBI6942WOPCT1 / 103693.007549

[0175] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0176] Also disclosed herein are methods of improving time to treatment discontinuation (TTD) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in TTD is relative to TTD of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0177] In some embodiments, the methods are performed on a subject and the methods provide an improvement in TTD compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in TTD compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in TTD compared to a reference population of subjects. 46JBI6942WOPCT1 / 103693.007549

[0178] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in time to treatment discontinuation (TTD) at 24 or 36 months of treatment, wherein the increase in the TTD is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI). Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving at 24 months of treatment a time to treatment discontinuation (TTD) of about 52% or achieving at 36 months of treatment a time to treatment discontinuation (TTD) of about 40%.

[0179] Disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naive, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0180] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein 47JBI6942WOPCT1 / 103693.007549 the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0181] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0182] Also disclosed here are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0183] Also disclosed here are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer 48JBI6942WOPCT1 / 103693.007549 (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0184] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0185] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R 49JBI6942WOPCT1 / 103693.007549 substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0186] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0187] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0188] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the 50JBI6942WOPCT1 / 103693.007549 NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0189] Also disclosed herein are methods of improving intracranial progression free survival after subsequent therapy (PFS2) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in PFS2 is relative to PFS2 of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0190] In some embodiments, the methods are performed on a subject and the methods provide an improvement in PFS2 compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in PFS2 compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in PFS2 compared to a reference population of subjects.

[0191] Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination 51JBI6942WOPCT1 / 103693.007549 with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in intracranial progression free survival after subsequent therapy (PFS2) at 24 or 36 months of treatment, wherein the increase in the PFS2 is greater than subjects who received an EGFR tyrosine kinase inhibitor (TKI). Also disclosed herein are methods comprising: a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving at 24 months of treatment an intracranial progression free survival after subsequent therapy (PFS2) of about 73% or achieving at 36 months of treatment an intracranial progression free survival after subsequent therapy (PFS2) of about 57%.

[0192] Disclosed herein are methods comprising a) administering to a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, in combination with a therapeutically effective amount of oral lazertinib; and b) achieving an increase in a clinical endpoint at 24 or 36 months of treatment, wherein the clinical endpoint is selected from the group consisting of overall survival (OS), time to subsequent therapy (TTST), intracranial duration of response (icDoR), intracranial progression free survival (icPFS), time to treatment discontinuation (TTD), and intracranial progression free survival after subsequent therapy (PFS2).

[0193] In some embodiments of the disclosed methods, the method achieves a PFS rate that is double compared to a population of pateints treated with osimertinib. In some embodiments of the disclosed methods, the method achieves a PFS rate of at least 35% at 36 months.

[0194] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the 52JBI6942WOPCT1 / 103693.007549 grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion- related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate; or who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0195] Amivantamab comprises a first domain that specifically binds EGFR and a second domain that specifically binds 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 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. The first domain that specifically binds 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 c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. Amivantamab is an IgG1 isotype that 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, amivantamab comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%.

[0196] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or grade 2 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 1 or grade 2 infusion-related adverse reaction resolves, resuming the intravenous 53JBI6942WOPCT1 / 103693.007549 amivantamab infusion at 50% of the infusion rate at which the grade 1 or grade 2 infusion- related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

[0197] In some embodiments, the methods comprise, to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 3 infusion-related adverse reaction: interrupting the intravenous amivantamab infusion, monitoring the subject until the grade 3 infusion-related adverse reaction resolves, resuming the intravenous amivantamab infusion at 50% of the infusion rate at which the grade 3 infusion-related adverse reaction occurred, and, if there are no additional infusion-related adverse reactions after 30 minutes, increasing the infusion rate.

[0198] In some embodiments, the methods comprise for grade 1, grade 2, or grade 3 infusion-related reactions, administering an antihistamine, an antipyretic, and a glucocorticoid prior to resuming the intravenous amivantamab infusion. Below is a list of “premedications” that can be administered prior to resuming the intravenous amivantamab infusion. Table 1. Premedications* Required at all doses. Required at initial dose (Week 1 Day 1) + Required at second dose (Week 1 Day 2); optional for subsequent doses.

[0199] The antihistamine can comprise diphenhydramine. The antipyretic can comprise acetaminophen. The glucocorticoid can comprise dexamethasone. 54JBI6942WOPCT1 / 103693.007549

[0200] In some embodiments, the methods comprise permanently discontinuing administration of the amivantamab if the grade 3 infusion-related adverse reaction is a recurrent grade 3 infusion-related adverse reaction.

[0201] Infusion rates of amivantamab are provided below: Table 2. Infusion Rates of amivantamab in combination with lazertinib† In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours.

[0202] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or 55JBI6942WOPCT1 / 103693.007549 metastatic NSCLC and who experiences a grade 4 infusion-related adverse reaction: permanently discontinuing administration of the amivantamab.

[0203] The recommended dosage and dosing schedule for amivantamab to be administered in combination with lazertinib are provided below: Table 3. Recommended dosage schedule for amivantamab in combination with lazertinibaDose adjustments not required for subsequent body weight changes. Another embodiment of doses and dosing schedule.

[0204] In some embodiments, the methods described herein are not dependent on the route of administration or the dosing interval so long as the exposure of the bispecific anti-EGFR / c-Met antibody is an equivalent thereof. For example, a subcutaneous dose can be considered an equivalent thereof of an intravenous dose so long as the exposure demonstrates the same or substantially similar levels in the blood stream. Likewise, for example, different dosing intervals (e.g., 2QW and 4QW) can be considered equivalents thereof when the drug exposure demonstrates the same or substantially similar levels in the blood stream. 56JBI6942WOPCT1 / 103693.007549

[0205] For example for dosing schedules for subcutaneous dosing: • Q2W dosing regimen if BW <80kg is 1,600 mg (2,240 mg if BW ≥80 kg) on Cycle 1 Days 1, 8, 15, and 22 then on Days 1 and 15 of each 28-day cycle starting at Cycle 2. • Q3W dosing regimen if BW <80kg is 1,600 mg (2,240 mg if BW ≥80 kg) on Cycle 1 Day 1, 2,400 mg (3,360 mg if BW ≥80 kg) on Cycle 1 Days 8 and 15 and then on Day 1 of each subsequent 21-day cycle starting at Cycle 2. • Q4W dosing regimen if BW <80kg is 1,600 mg (2,240 mg if BW ≥80 kg) on Cycle 1 Days 1, 8, 15, and 22 then 3,520 mg (4,640 mg if BW ≥80 kg) on Day 1 of each subsequent 28-day cycle starting at Cycle 2.

[0206] The therapeutically effective amount of amivantamab comprises 1050 mg for subjects who weigh less than 80 kg, or 1400 mg for subjects who weigh greater than or equal to 80 kg, and the therapeutically effective amount of lazertinib comprises 240 mg.

[0207] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab; or who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab.

[0208] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who is suspected of experiencing interstitial lung disease / pneumonitis of any grade: withholding administration of the amivantamab.

[0209] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences interstitial lung disease / pneumonitis of any grade: permanently discontinuing administration of the amivantamab. 57JBI6942WOPCT1 / 103693.007549

[0210] The therapeutically effective amount of amivantamab comprises 1050 mg for subjects who weigh less than 80 kg, or 1400 mg for subjects who weigh greater than or equal to 80 kg, and the therapeutically effective dose of lazertinib comprises 240 mg.

[0211] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the method comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 2 or grade 3 venous thromboembolic event (VTE): withholding administration of the amivantamab and lazertinib, administering anticoagulant treatment, and resuming the amivantamab at the same dose as prior to the withholding and the lazertinib at the same dose as prior to the withholding; or who experiences a grade 4 or recurrent grade 2 or grade 3 VTE despite therapeutic level anticoagulation: withholding lazertinib and permanently discontinuing amivantamab, administering anticoagulant treatment, and continuing treatment with lazertinib at the same dose as prior to the withholding.

[0212] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 2 or grade 3 venous thromboembolic event (VTE): withholding administration of the amivantamab and lazertinib, administering anticoagulant treatment, and resuming the amivantamab at the same dose as prior to the withholding and the lazertinib at the same dose as prior to the withholding.

[0213] In some embodiments, the methods comprise administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. The antihistamine can comprise diphenhydramine and the antipyretic can comprise acetaminophen.

[0214] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 4 or recurrent grade 2 or grade 3 VTE despite therapeutic level anticoagulation: withholding lazertinib and permanently 58JBI6942WOPCT1 / 103693.007549 discontinuing amivantamab, administering anticoagulant treatment, and continuing treatment with lazertinib at the same dose as prior to the withholding.

[0215] The therapeutically effective amount of amivantamab comprises 1050 mg for subjects who weigh less than 80 kg, or 1400 mg for subjects who weigh greater than or equal to 80 kg, and the therapeutically effective dose of lazertinib comprises 240 mg.

[0216] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or 2 dermatologic adverse reaction: administering a reduced dose of the amivantamab to the subject if the grade 1 or 2 dermatologic adverse reaction does not improve after two weeks; who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks; or who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0217] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 1 or 2 dermatologic adverse reaction: administering a reduced dose of the amivantamab to the subject if the grade 1 or 2 dermatologic adverse reaction does not improve after two weeks.

[0218] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or 59JBI6942WOPCT1 / 103693.007549 metastatic NSCLC and who experiences a grade 3 dermatologic adverse reaction: withholding the amivantamab and resuming administration of the amivantamab at a reduced dose if the grade 3 dermatologic adverse reaction becomes a grade 2 or lower dermatologic adverse reaction, or permanently discontinuing the treatment if no improvement in the grade 3 dermatologic adverse reaction occurs within 2 weeks.

[0219] Amivantamab dose reductions for adverse reactions are provided below: Table 4. Dose reductions for adverse reactions for amivantamab

[0220] The reduced dose of amivantamab comprises 700 mg or 350 mg if the adverse reactions occurred at an amivantamab dose of 1050 mg, or 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg.

[0221] The methods can further comprise administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. The antihistamine can comprise diphenhydramine and the antipyretic can comprise acetaminophen.

[0222] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences a grade 4 dermatologic adverse reaction or severe bullous, blistering, or exfoliating skin: permanently discontinuing administration of the amivantamab.

[0223] The therapeutically effective amount of amivantamab comprises 1050 mg for subjects who weigh less than 80 kg, or 1400 mg for subjects who weigh greater than or equal to 80 kg, and the therapeutically effective dose of lazertinib comprises 240 mg.

[0224] Disclosed herein are methods of reducing an adverse reaction associated with the use of amivantamab in combination with lazertinib to treat locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising: to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and 60JBI6942WOPCT1 / 103693.007549 who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks; or who experiences at least one other grade 4 adverse reaction: withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 adverse reaction is a recurrent grade 4 adverse reaction.

[0225] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences at least one other grade 3 adverse reaction: withholding amivantamab until the at least one other grade 3 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at the same dose if the subject recovers from the grade 3 adverse reaction within 1 week; resuming the amivantamab at a reduced dose if the subject recovers from the grade 3 adverse reaction after 1 week but within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 3 adverse reaction within 4 weeks.

[0226] In some embodiments, the methods comprise to a subject who has received a therapeutically effective amount of an intravenous amivantamab infusion in combination with a therapeutically effective amount of oral lazertinib to treat the locally advanced or metastatic NSCLC and who experiences at least one other grade 4 adverse reaction: 61JBI6942WOPCT1 / 103693.007549 withholding amivantamab until the at least one other grade 4 adverse reaction reduces to less than or equal to grade 1 or baseline and resuming the amivantamab at a reduced dose if the subject recovers from the grade 4 adverse reaction within 4 weeks; or permanently discontinuing the amivantamab if the subject does not recover from the grade 4 adverse reaction within 4 weeks or if the grade 4 adverse reaction is a recurrent grade 4 adverse reaction.

[0227] The therapeutically effective amount of amivantamab comprises 1050 mg for subjects who weigh less than 80 kg, or 1400 mg for subjects who weigh greater than or equal to 80 kg, and the therapeutically effective dose of lazertinib comprises 240 mg.

[0228] The reduced dose of amivantamab can comprise 700 mg or 350 mg if the adverse reactions occurred at an amivantamab dose of 1050 mg, or 1050 mg or 700 mg if the adverse reactions occurred at an amivantamab dose of 1400 mg.

[0229] In some embodiments, the methods further comprise administering an antihistamine and an antipyretic prior to resuming the intravenous amivantamab infusion. The antihistamine can comprise diphenhydramine and the antipyretic can compris acetaminophen.

[0230] Disclosed herein are methods of treating locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in a subject, the methods comprising administering to the subject an approved drug product comprising amivantamab, in combination with lazertinib.

[0231] The approved drug product comprising amivantamab is described in the approved drug product label provided in Example 4 herein.

[0232] Disclosed herein are methods of improving median progression free survival (PFS) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib. The median PFS can be 19.1 months to 27.7 months. The median PFS can be 23.7 months.

[0233] Disclosed herein are methods of improving overall response rate (ORR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib. The ORR can be 74% to 82%. The ORR can be 78%. 62JBI6942WOPCT1 / 103693.007549

[0234] Disclosed herein are methods of improving median duration of response (DOR) in a population of subjects having locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the methods comprising administering to the population of subjects an approved drug product comprising amivantamab, in combination with lazertinib. The DOR can be at least 20.1 months. The DOR can be 25.8 months.

[0235] The methods can comprise administering the amivantamab intravenously at 1050 mg for patients having a body weight of less than 80 kg or 1400 mg for patients having a body weight of greater than or equal to 80 kg once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5, in combination with lazertinib administered at 240 mg orally once daily.

[0236] Disclosed herein are methods of treating non-small cell lung cancer (NSCLC) in a subject in need thereof comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody; and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has been diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations, and wherein the subject is treatment naïve.

[0237] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment- naïve, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0238] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the population of subjects a combination therapy comprising: a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody, and 63JBI6942WOPCT1 / 103693.007549 a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naive subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0239] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naive subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0240] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naive subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0241] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the 64JBI6942WOPCT1 / 103693.007549 methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naive subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0242] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0243] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0244] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or 65JBI6942WOPCT1 / 103693.007549 metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0245] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0246] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the 66JBI6942WOPCT1 / 103693.007549 NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0247] Also disclosed herein are methods of improving median progression free survival (PFS) in a population of treatment-naïve subjects diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in median PFS is relative to median PFS of a reference population of treatment-naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference population having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0248] Disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a reference subject or a reference population of subjects with NSCLC harboring one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0249] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically 67JBI6942WOPCT1 / 103693.007549 acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0250] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline brain metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0251] Also disclosed here are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0252] Also disclosed here are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or 68JBI6942WOPCT1 / 103693.007549 metastatic non-small cell lung cancer (NSCLC) without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without baseline liver metastases, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0253] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0254] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without TP53 co-mutation, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population 69JBI6942WOPCT1 / 103693.007549 of subjects having been administered osimertinib or lazertinib without the bispecific anti- EGFR / c-Met antibody.

[0255] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC with detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0256] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without detectable baseline mutant EGFR circulating tumor DNA, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0257] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an 70JBI6942WOPCT1 / 103693.007549 exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment-naïve subjects with NSCLC without mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0258] Also disclosed herein are methods of improving overall survival (OS) in a treatment-naïve subject or a population of treatment-naïve subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the methods comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS is relative to OS of a treatment-naïve reference subject or a reference population of treatment- naïve subjects with NSCLC with mutant EGFR circulating tumor DNA clearance at C3D1, wherein the NSCLC harbors one or more exon 19 deletions or an exon 21 L858R substitution, the reference subject or the reference population of subjects having been administered osimertinib or lazertinib without the bispecific anti-EGFR / c-Met antibody.

[0259] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in about a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of 71JBI6942WOPCT1 / 103693.007549 subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0260] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results results in a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0261] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0262] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 72JBI6942WOPCT1 / 103693.007549 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0263] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0264] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0265] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung 73JBI6942WOPCT1 / 103693.007549 cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0266] Also disclosed herein are methods of improving overall survival (OS) in death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0267] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and about a 25% risk reduction in death relative to OS of a 74JBI6942WOPCT1 / 103693.007549 reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0268] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0269] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0270] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations 75JBI6942WOPCT1 / 103693.007549 who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0271] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0272] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and a 25% risk reduction in death relative to OS of a reference subject or a 76JBI6942WOPCT1 / 103693.007549 reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0273] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in about a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0274] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results results in a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0275] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 77JBI6942WOPCT1 / 103693.007549 population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0276] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0277] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of 78JBI6942WOPCT1 / 103693.007549 subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0278] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0279] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0280] Also disclosed herein are methods of improving overall survival (OS) in death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically 79JBI6942WOPCT1 / 103693.007549 effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0281] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0282] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or 80JBI6942WOPCT1 / 103693.007549 the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0283] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a hazard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0284] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0285] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount 81JBI6942WOPCT1 / 103693.007549 of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0286] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0287] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in about a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, 82JBI6942WOPCT1 / 103693.007549 the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0288] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results results in a 25% risk reduction in death relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0289] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0290] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 83JBI6942WOPCT1 / 103693.007549 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0291] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0292] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate 84JBI6942WOPCT1 / 103693.007549 thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0293] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0294] Also disclosed herein are methods of improving overall survival (OS) in death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference 85JBI6942WOPCT1 / 103693.007549 subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0295] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0296] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and about a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0297] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung 86JBI6942WOPCT1 / 103693.007549 cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0298] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0299] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as 87JBI6942WOPCT1 / 103693.007549 an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0300] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and a 25% risk reduction in death relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0301] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in about a 25% risk reduction in death and an improvement in about 12 months OS relative to a 88JBI6942WOPCT1 / 103693.007549 reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0302] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results results in a 25% risk reduction in death and an improvement in about 12 months OS relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0303] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody. 89JBI6942WOPCT1 / 103693.007549

[0304] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0305] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0306] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 90JBI6942WOPCT1 / 103693.007549 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0307] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 and about a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0308] Also disclosed herein are methods of improving overall survival (OS) in death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of 91JBI6942WOPCT1 / 103693.007549 lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and about a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0309] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and about a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0310] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and about a 25% 92JBI6942WOPCT1 / 103693.007549 risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0311] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a hazard ratio of 0.75 and a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0312] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75 and a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are 93JBI6942WOPCT1 / 103693.007549 treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0313] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value less than or equal to 0.05, and a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti- EGFR / c-Met antibody.

[0314] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement in OS results in a statistically significant harzard ratio of 0.75, with a p-value equal to 0.0048, and a 25% risk reduction in death and an improvement in about 12 months OS relative to OS of a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody. 94JBI6942WOPCT1 / 103693.007549

[0315] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement in OS results in a three survival rate of about 60% compared to about 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0316] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the 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 lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement results in a three survival rate of 60% compared to 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0317] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib or a generic of lazertinib, or a 95JBI6942WOPCT1 / 103693.007549 pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement results in a three survival rate of about 60% compared to about 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0318] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab, and a therapeutically effective amount of lazertinib or a generic of lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, and wherein the improvement results in a three survival rate of 60% compared to 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0319] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement results in a three survival rate of about 60% compared to about 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0320] Also disclosed herein are methods of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung 96JBI6942WOPCT1 / 103693.007549 cancer (NSCLC) harboring one or more epidermal growth factor receptor (EGFR) mutations who are treatment-naïve, wherein the NSCLC harbors one or more exon 19 deletions or exon 21 L858R substitution mutations, the method comprising administering to the subject or the population of subjects a combination therapy comprising a therapeutically effective amount of the bispecific anti-EGFR / c-Met antibody amivantamab or a biosimilar of amivantamab as an approved drug product, and a therapeutically effective amount of lazertinib or a generic of lazertinib as an approved drug product, or a pharmaceutically acceptable salt or hydrate thereof as an approved drug product, and wherein the improvement results in a three survival rate of 60% compared to 51% relative to a reference subject or a reference population of subjects with NSCLC harboring the one or more EGFR mutations who are treatment-naïve, the reference subject or the reference population of subjects having been administered osimertinib without the bispecific anti-EGFR / c-Met antibody.

[0321] In some embodiments, the methods are performed on a subject and the methods provide an improvement in OS compared to a reference subject. In some embodiments, the methods are performed on a subject and the methods provide an improvement in OS compared to a reference population of subjects. In some embodiments, the methods are performed on a population of subjects and the methods provide an improvement in OS compared to a reference population of subjects.

[0322] The term "pharmaceutically acceptable salt" in relation to lazertinib includes pharmaceutically acceptable acidic / anionic or basic / cationic salts, or equivalents thereof. Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. Pharmaceutically acceptable basic / cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, Larginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

[0323] A pharmaceutically acceptable acid salt is formed by reaction of the free base form of lazertinib with a suitable inorganic or organic acid including, but not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, 97JBI6942WOPCT1 / 103693.007549 propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, ptoluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid. A pharmaceutically acceptable acid addition salt of lazertinib can comprise or be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2- naphthalenesulfonate) or hexanoate salt.

[0324] In some embodiments, the pharmaceutically acceptable salt in relation to lazertinib is obtained from multiple salt formers, including methanesulfonic acid, p- toluenesulfonic acid, citric acid, succinic acid, tartaric acid, glycolic acid, maleic acid, oxalic acid, malonic acid, phosphoric acid, ethanesulfonic acid, benzenesulfonic acid, 2- naphtalenesulfonic acid, fumaric acid, pyruvic acid, malic acid, dichloroacetic acid and (1S)- +-10 camphorsulfonic acid.

[0325] In some embodiments, the lazertinib salt is mesylate.

[0326] In some embodiments of the disclosed methods, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate. In some embodiments of the disclosed methods, the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.

[0327] In some embodiments of the disclosed methods, the one or more EGFR mutations comprise one or more exon 19 deletions, or exon 21 L858R substitution, or any combination thereof. In some embodiments of the disclosed methods, the one or more EGFR mutations comprise one or more exon 19 deletions. In some embodiments of the disclosed methods, the one or more EGFR mutations comprise exon 21 L858R substitution.

[0328] In some embodiments of the disclosed methods, the subject has newly diagnosed, locally advanced or metastatic NSCLC that is not amenable to curative therapy including surgical resection or chemoradiation. In some embodiments of the disclosed methods, the curative therapy includes surgical resection or chemoradiation.

[0329] In some embodiments of the disclosed methods, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg orally once daily. In some embodiments of the disclosed methods, the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg orally once daily. 98JBI6942WOPCT1 / 103693.007549

[0330] In some embodiments of the disclosed methods, the method elicits a clinical response in the subject according to RECIST v1.1 criteria. In some embodiments of the disclosed methods, the method achieves a partial response or better in the subject according to RECIST v1.1 criteria. In some embodiments of the disclosed methods, the clinical response comprises 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 methods, the clinical response comprises a median duration of response (DOR) of at least 25 months.

[0331] In some embodiments of the disclosed methods, the subject is progression- free after at least 20 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 24 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 30 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 11 months. In some embodiments of the disclosed methods, the subject is progression-free after at least 23 months. In some embodiments of the disclosed methods, the method achieves a PFS rate of 85% at 12 months, 65% at 24 months, and 51% at 36 months in a population of the treatment naïve subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations. In some embodiments of the disclosed methods, 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 population of the treatment naïve subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations In some embodiments of the disclosed methods, the method achieves a PFS rate of 86% in a population of the treatment naïve subjects diagnosed with locally advanced or metastatic NSCLC harboring one or more epidermal growth factor receptor (EGFR) mutations.

[0332] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds 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 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 methods, the first domain that specifically binds EGFR comprises the heavy 99JBI6942WOPCT1 / 103693.007549 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 c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed methods, 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 methods, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%.

[0333] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5 and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12. In some embodiments of the disclosed methods, the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c- Met antibody is an IgG1 isotype. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19 and a second light chain (LC2) comprising SEQ ID NO: 20. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%.

[0334] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody is administered intravenously to the subject. In some embodiments of 100JBI6942WOPCT1 / 103693.007549 the disclosed methods, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 140 mg to about 2240 mg. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1575 mg, about 1600 mg, about 2100 mg, or about 2240 mg. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose of 1050 mg if the subject has a body weight of less than 80 kg. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is administered intravenously at a dose of 1400 mg if the subject has a body weight of greater than or equal to 80 kg.

[0335] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. In some embodiments of the disclosed methods, 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 methods, the bispecific anti- EGFR / c-Met antibody is admistered subcutaneously at a dose of 1600 mg if the subject has a body weight of less than 80 kg or at a dose of 2240 mg if the subject has a body weight of greater than or equal to 80 kg. In some embodiements of the disclosed methods, the dosing can be once in two weeks. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is admistered subcutaneously at a dose of 2400 mg if the subject has a body weight of less than 80 kg or at a dose of 3360 mg if the subject has a body weight of greater than or equal to 80 kg. In some embodiements of the disclosed methods, the dosing can be once in three weeks.

[0336] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks, or once in four weeks.

[0337] In some embodiments of the disclosed methods, the subject or population of subjects has a baseline brain metastasis, baseline liver metastasis, TP53 co-mutation, detectable baseline EGFRm ctDNA, or is without EGFRm ctDNA clearance at C3D1. In some embodiments, the the subject or population of subjects has a baseline brain metastasis. In some embodiments, the the subject or population of subjects has a baseline liver metastasis. In some embodiments, the the subject or population of subjects has a TP53 co- mutation. In some embodiments, the the subject or population of subjects has detectable 101JBI6942WOPCT1 / 103693.007549 baseline EGFRm ctDNA. In some embodiments, the the subject or population of subjects is without EGFRm ctDNA clearance at C3D1.

[0338] In some embodiments of the disclosed methods, the subject or population of subjects does not have a baseline brain metastasis, baseline liver metastasis, TP53 co- mutation, detectable baseline EGFRm ctDNA, or is without EGFRm ctDNA clearance at C3D1. In some embodiments, the the subject or population of subjects does not have a baseline brain metastasis. In some embodiments, the the subject or population of subjects does not have a baseline liver metastasis. In some embodiments, the the subject or population of subjects does not have a TP53 co-mutation. In some embodiments, the the subject or population of subjects does not have detectable baseline EGFRm ctDNA. In some embodiments, the the subject or population of subjects has EGFRm ctDNA clearance at C3D1.

[0339] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds 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 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 methods, the first domain that specifically binds 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 c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0340] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody is an IgG1 isotype.

[0341] In some embodiments of the disclosed methods, 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.

[0342] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain 102JBI6942WOPCT1 / 103693.007549 complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12. In some embodiments of the disclosed methods, the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16.

[0343] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody is an IgG1 isotype.

[0344] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19, and a second light chain (LC2) comprising SEQ ID NO: 20.

[0345] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 2% to about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 3% to about 13%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 4% to about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 5% to about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 1%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 2%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 3%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of 103JBI6942WOPCT1 / 103693.007549 about 4%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 5%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 6%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 7%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 8%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 9%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 10%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 11%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 12%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 13%. In some embodiments, the bispecific anti- EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 14%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 15%. In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of less than about 20%.

[0346] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody disclosed herein may be administered in combination with a tyrosine kinase inhibitor (TKI) such as, but not limited to an epidermal growth factor receptor (EGFR TKI). Non-limiting examples of TKI are erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody disclosed herein may be administered in combination with lazertinib.

[0347] Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild type- EGFR. An analysis of the efficacy and safety of lazertinib from the Phase 3 LASER301 (NCT04248829) study demonstrated that lazertinib improved PFS compared to the first generation EGFR TKI gefitinib in all prespecified subgroups, including Asian patients, those with exon 21 L858R mutations and those with a history of brain metastases. 104JBI6942WOPCT1 / 103693.007549

[0348] Lazertinib 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- morpholinophenyl)acrylamide, depicted below as a compound of Formula I.Formula I

[0349] In addition, WO2018 / 194356 describes salts, hydrates and crystalline forms thereof; and WO2019 / 022485, WO2019 / 022486 and WO2019 / 022487 disclose processes for the production of lazertinib.

[0350] Lazertinib mesylate monohydrate is depicted below as a compound of Formula Ia,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.

[0351] In some embodiments, the methods of the present disclosure useful for treating a cancer in a subject in need thereof may comprise administering to a 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).

[0352] In some embodiments, the methods of the present disclosure useful for improving median progression free survival (PFS) in a population of subjects with a cancer 105JBI6942WOPCT1 / 103693.007549 may comprise administering to a 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).

[0353] In some embodiments, the methods of the present disclosure useful for improving overall survival (OS) in a subject or a population of subjects with a cancer may comprise administering to a 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).

[0354] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds 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 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 methods, the first domain that specifically binds 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 c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. In some embodiments of the disclosed methods, 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 methods, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%.

[0355] In some embodiments of the disclosed methods, the bispecific anti- EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 4, a LCDR2 106JBI6942WOPCT1 / 103693.007549 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6, and wherein the second domain that binds c-Met comprises a HCDR1 comprising SEQ ID NO: 7, a HCDR2 comprising SEQ ID NO: 8, a HCDR3 comprising SEQ ID NO: 9, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12. In some embodiments of the disclosed methods, the first domain that specifically binds EGFR comprises a heavy chain variable region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 14, and the second domain that specifically binds c-Met comprises a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO: 16. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c- Met antibody is an IgG1 isotype. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) comprising SEQ ID NO: 17, a first light chain (LC1) comprising SEQ ID NO: 18, a second heavy chain (HC2) comprising SEQ ID NO: 19, and a second light chain (LC2) comprising SEQ ID NO: 20. In some embodiments of the disclosed methods, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about between 1% to about 15% or less than about 20%.

[0356] The bispecific anti-EGFR / c-Met antibody may be administered in a pharmaceutically acceptable carrier. “Carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, 0.4% saline and 0.3% glycine may be used to formulate the bispecific anti-EGFR / c-Met antibody. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may comprise sterile water and other excipients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp.958-989.

[0357] The mode of administration may be any suitable route that delivers the bispecific anti-EGFR-c-Met antibody to the host, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, 107JBI6942WOPCT1 / 103693.007549 transmucosal (oral, intranasal, intravaginal, rectal), using a formulation in a tablet, capsule, solution, powder, gel, particle; and contained in a syringe, an implanted device, osmotic pump, cartridge, micropump; or other means appreciated by the skilled artisan, as well known in the art. Site specific administration may be achieved by for example intratumoral, intra- articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intracardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery.

[0358] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0359] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously or intradermally to the subject. The bispecific anti-EGFR / c-Met antibody may be administered subcutaneously or intradermally at a dose sufficient to achieve a therapeutic effect in the subject.

[0360] In some embodiments, the bispecific anti-EGFR / c-Met antibody is formulated as a subcutaneous formulation as disclosed in PCT International Publication No. WO 2022 / 224187A1.

[0361] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously to the subject at a dose between about 1600 mg to about 3360 mg. The subcutaneous administration can be once in two weeks (Q2W) or once in three weeks (Q3W). Q2W dosing is administered at 1600 mg (2240 mg if the subject is ≥80 kg). Q3W dosing is administered at 2400 mg (3360 mg if the subject is ≥80 kg).

[0362] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 1400 mg to about 3360 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of between about 1400 mg to about 1750 mg.

[0363] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, 108JBI6942WOPCT1 / 103693.007549 about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg, 1575 mg, about 1580 mg, about 1590 mg, about 1600 mg, about 1610 mg, 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, 1890 mg, about 1900 mg, about 1910 mg, about 1920 mg, about 1930 mg, about 1940 mg, about 1950 mg, about 1960 mg, about 1970 mg, about 1980 mg, about 1990 mg, about 2000 mg, 2100 mg, 2110 mg, 2120 mg, 2130 mg, 2140 mg, 2150 mg, 2160 mg, 2170 mg, 2180 mg, 2190 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg , 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, or 2410 mg.

[0364] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is 109JBI6942WOPCT1 / 103693.007549 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 about 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR / c- Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg.

[0365] In some embodiments, the bispecific anti...

Claims

103693.007549 / JBI6942WOPCT1 What is claimed is:

1. A method of improving overall survival (OS) in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the improvement in the OS is at least about 36.7 months.

2. A method of reducing the risk of death in a subject or a population of subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations who are treatment-naïve, the method comprising administering to the subject or the population of subjects a combination therapy comprising: (i) a therapeutically effective amount of amivantamab, or a biosimilar thereof, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof, wherein the risk of death is reduced by at least about 25%.

3. The method of claim 1 or 2, wherein the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate.

4. The method of any one of the previous claims, wherein the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, is lazertinib mesylate monohydrate.

5. The method of any one of the previous claims, wherein the NSCLC has one or more EGFR mutations comprise one or more exon 19 deletions.

6. The method of any one of the previous claims, wherein the NSCLS has an exon 21 L858R substitution. 251103693.007549 / JBI6942WOPCT1 7. The method of any one of the previous claims, wherein the subject has newly diagnosed, locally advanced or metastatic NSCLC that is not amenable to curative therapy including surgical resection or chemoradiation.

8. The method of any one of the previous claims, wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 80 mg to about 320 mg orally once daily.

9. The method of any one of the previous claims, wherein the method comprises administering the lazertinib, or pharmaceutically acceptable salt or hydrate thereof, in an amount of about 240 mg orally once daily.

10. The method of any one of claims 1 or 3-9, wherein the improvement in the OS of the subject or the population of subjects is at least about 12 months greater than the OS of a reference subject or a reference population of subjects.

11. The method of any one of the previous claims, wherein the combination therapy comprises: (i) a therapeutically effective amount of amivantamab, and (ii) a therapeutically effective amount of oral lazertinib, or a pharmaceutically acceptable salt or hydrate thereof.

12. The method of any one of the previous claims, wherein the amivantamab is administered at a dose of 1050 mg if the subject has a body weight of less than 80 kg or at a dose of 1400 mg if the subject has a body weight of greater than or equal to 80 kg.

13. The method of any one of the previous claims, wherein the subject or population of subjects has a baseline brain metastasis, baseline liver metastasis, TP53 co-mutation, detectable baseline EGFRm ctDNA, or is without EGFRm ctDNA clearance at C3D1. 252

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