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Duration of PFS in the patient subgroup with MET amplification

Representativeness of study population

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Purpose:The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021).Patients and Methods:Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned.Results:Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35–1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04–0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02–0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1–56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy.Conclusions:Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

Supplementary Figure S1. CONSORT diagram showing patient disposition.

Purpose:Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups.Patients and Methods:This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity.Results:152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies.Conclusions:Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.See related commentary by Rosner and Spira, p. 1055

Purpose:Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and Methods:Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.Results:One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.Conclusions:Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-αv integrin inhibitor abituzumab in chemotherapy-naïve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS).Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR = 0.89; 95% confidence interval (CI), 0.57–1.39; abituzumab 1,500 mg, 4.3 months, HR = 0.81; 95% CI, 0.52–1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms.Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancer–associated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192–200. ©2016 AACR.

Supplementary information showing details of study criteria, bioasssays, preclinical modelling, PK data, safety and efficacy.

Supplementary Data from Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

Background MET exon 14 skipping is an oncogenic driver occurring in 3–4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib. Methods In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned. Results As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months’ follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients’ quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively). Conclusions Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable., In VISION, tepotinib demonstrated robust efficacy in Japanese patients with MET exon 14 skipping NSCLC. The safety profile was tolerable, with mostly mild–moderate adverse events and few treatment discontinuations.

Summary Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov , NCT01982955 , and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9–6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2–6·8; hazard ratio [HR] 0·67, 90% CI 0·35–1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1–37·3) versus 18·7 months in the chemotherapy group (15·9–20·7; HR 0·69, 0·34–1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1–16·6] vs 4·4 months [4·1–6·8]; HR 0·35, 0·17–0·74; median OS 37·3 months [90% CI 24·2–37·3] vs 17·9 months [12·0–20·7]; HR 0·33, 0·14–0·76) or MET amplification (n=19; median PFS 16·6 months [8·3–not estimable] vs 4·2 months [1·4–7·0]; HR 0·13, 0·04–0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25–not estimable]; HR 0·08, 0·01–0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. Funding Merck KGaA.

BACKGROUND Brain metastases (BMs) occur in 20–40% of patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, demonstrated an objective response rate (ORR) of 49.1% and median duration of response (mDOR) of 13.8 months, in METex14 skipping NSCLC patients in the Phase II VISION study (Cohorts A+C; N=275). Here, we report the intracranial activity of tepotinib in VISION. METHODS Patients with METex14 skipping NSCLC received oral tepotinib 500 mg QD (450 mg active moiety). Patients with BM (asymptomatic and symptomatic/stable) were eligible. Primary endpoint was systemic ORR (RECIST v1.1); a subgroup analysis in patients with BM was predefined (data cut-off: February 1, 2021). An ad-hoc retrospective analysis of brain lesions was conducted by an IRC using RANO-BM criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For those with only non-target lesions (NTLs) per RANO-BM (enhancing and non-enhancing NTLs), disease control was defined as non-complete response (CR)/nonprogressive disease (PD). Data cut-off: July 1, 2020. RESULTS Fifty-one patients had baseline BM (Cohorts A+C). Systemic efficacy was consistent with the overall population (ORR 52.9% [95% CI: 38.5, 67.1], mDOR 9.0 months [95% CI: 5.6, not estimable]). Fifteen patients were evaluable by RANO-BM (Cohort A); 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and PD (n=3). Seven patients had target CNS lesions per RANO-BM (all with prior radiotherapy); intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. 13/15 patients achieved intracranial disease control. CONCLUSIONS Tepotinib demonstrated robust systemic activity in patients with METex14 skipping NSCLC with BM, complemented by intracranial activity in an ad-hoc analysis using RANO-BM.

Introduction: In the INSIGHT trial primary analysis (NCT01982955; median follow-up: 21.8 months), tepotinib (a potent, highly selective, once daily [QD] MET inhibitor) + gefitinib improved efficacy vs chemotherapy (CTX) in patients with EGFR-mutant NSCLC and resistance to anti-EGFR therapy due to MET amplification (Wu et al, Lancet Respir Med 2020). Here we report final analyses from INSIGHT (data cut-off: September 3, 2021; median follow-up: 57.5 months). Methods: Patients with EGFR-mutant (T790M-negative) NSCLC and anti-EGFR resistance, with MET gene copy number (GCN) ≥5 and/or MET:CEP7 ≥2 by FISH and/or MET IHC 2+/3+, were randomized to tepotinib 500 mg (450 mg active moiety) + gefitinib 250 mg QD or CTX. Primary endpoint was progression-free survival (PFS) per investigator. Preplanned analyses evaluated patients with MET amplification. Results: In the 19/55 randomized patients (34.5%) with MET amplification (GCN ≥5, n=18; MET:CEP7 ≥2, n=13; MET IHC 3+, n=17), median age was 60.4 years, 68.4% were never-smokers, and prior EGFR inhibitors were gefitinib (57.9%), afatinib (21.1%), erlotinib (10.5%) and icotinib (10.5%). Median duration of tepotinib + gefitinib was 11.3 months (range: 1.1-56.5), with treatment duration >1 year in 6 patients (31.6%) and >4 years in 3 patients (15.8%). Two patients continued treatment outside the study. Tepotinib + gefitinib improved PFS (hazard ratio [HR] 0.13; 95% confidence interval [CI] 0.04, 0.43), overall survival (HR 0.10; 95% CI 0.02, 0.36), objective response rate and duration of response vs CTX (Table). Treatment-related Grade ≥3 AEs occurred in 7 patients (58.3%) with tepotinib + gefitinib and 5 (71.4%) with CTX. Most common post-study therapies were kinase inhibitors (n=2 in the tepotinib + gefitinib arm; n=3 in the CTX arm). In patients with MET IHC 3+ (n=34; including 17 patients with MET amplification), tepotinib + gefitinib also markedly improved PFS (HR 0.35; 95% CI 0.17, 0.74) and OS (HR 0.44; 95% CI 0.23, 0.84) vs CTX. Conclusions: Tepotinib + gefitinib greatly improved PFS and OS vs CTX in patients with EGFR-mutant NSCLC with MET amplification. INSIGHT 2 is evaluating tepotinib + osimertinib in this setting. Table. Summary of efficacy and safety data in patients with MET amplification Endpoint Tepotinib + gefitinib (n=12) CTX (n=7) PFS Events, n (%) 7 (58) 7 (100) Median, months (90% CI) 16.6 (8.3, 22.1) 4.2 (1.4, 7.0) HR (90% CI) 0.13 (0.04, 0.43) OS* Events, n (%) 7 (58) 7 (100) Median, months (90% CI) 37.3 (21.1, 52.1) 13.1 (3.3, 22.6) HR (90% CI) 0.10 (0.02, 0.36) ORR n (%) [90% CI] 8 (66.7) [39.1, 87.7] 3 (42.9) [12.9, 77.5] OR (90% CI) 2.67 (0.37, 19.56) DOR Median, months (90% CI) 19.9 (7.0, NE) 2.8 (2.8, NE) Treatment-related Grade ≥3 AEs†, n (%) Amylase increased 4 (33.3) 0 Lipase increased 4 (33.3) 0 Anemia 0 2 (28.6) Neutrophil count decreased 0 2 (28.6) WBC count decreased 0 2 (28.6) *Post-study therapy included an EGFR inhibitor ± a MET inhibitor in two patients in each arm (tepotinib + gefitinib arm: osimertinib ± cabozantinib [n=1], gefitinib + cabozantinib [n=1]; CTX arm: erlotinib, afatinib, and osimertinib ± crizotinib [n=1], osimertinib [n=1]). Post-study CTX was received by one patient in the tepotinib + gefitinib arm and two patients in the CTX arm.†Reported in >20% of patients in either arm. AE, adverse event; CI, confidence interval; CTX, chemotherapy; DOR, duration of response; HR, hazard ratio; NE, not estimable; ORR, objective response rate; OR, odds ratio; OS, overall survival; PFS, progression-free survival; WBC, white blood cell. Citation Format: Chong Kin Liam, Azura Rozila Ahmad, Te-Chun Hsia, Jianying Zhou, Dong-Wan Kim, Ross Andrew Soo, Ying Cheng, Shun Lu, Sang Won Shin, James Chih-Hsin Yang, Yiping Zhang, Jun Zhao, Rolf Bruns, Andreas Johne, Yi-Long Wu. Tepotinib + gefitinib in patients with EGFR-mutant NSCLC with MET amplification: Final analysis of INSIGHT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT538.

Introduction: In the primary analysis of VISION, tepotinib — a highly selective, potent MET inhibitor — demonstrated durable efficacy, and a tolerable safety profile in patients (pts) with METex14 skipping NSCLC. We report updated outcomes, with interim analyses from a confirmatory cohort. Methods: In the Phase II VISION study, pts with advanced/metastatic METex14 skipping NSCLC, identified by liquid (L+) and/or tissue (T+) biopsy, received 500 mg (450 mg active moiety) tepotinib once daily. All pts were assessed for safety; pts with ≥3 months’ follow-up were assessed for efficacy. Primary endpoint was objective response by independent review (RECIST v1.1). Secondary endpoints were disease control (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of Feb 1, 2021, 7,882 pts were pre-screened, and 275 pts were analyzed for efficacy. Patients analyzed for efficacy had a median age of 72.4 years (range, 41-94]), 50.9% were female, 46.5% had smoking history, and median tumor load [target lesions by IRC] was 57.4 mm [range, 10.2-227.8]). Tumor load in L+ pts was 68.0 mm (11.6-227.8) and 52.9 mm (10.2-227.8) in T+ pts. In treatment-naïve pts (n=137), ORR was 54.0% (95% CI: 45.3, 62.6), DCR was 74.5% (66.3, 81.5), and >90% of pts had tumor shrinkage. Median (m) DOR was 32.7 months (9.0, not estimable), mPFS was 10.4 months (8.4, 15.3), and mOS was 17.6 months (13.4, 29.7). In previously treated pts (n=138), ORR was 44.2% (35.8, 52.9), DCR was 75.4% (67.3, 82.3), and >90% of pts had tumor shrinkage. mDOR was 11.1 months (8.4, 18.5), mPFS was 11.0 months (8.2, 12.4), and mOS was 19.9 months (15.8, 22.3). Meaningful clinical activity was observed in L+ and T+ pts (Table). Overall, 14.1% of pts discontinued due to TRAEs; tepotinib was well-tolerated across treatment lines (Table). Conclusions: Tepotinib demonstrated robust and durable clinical activity across treatment lines in pts with METex14 skipping NSCLC, with particularly durable efficacy in first line. TRAEs were manageable with few discontinuations. Table 1. Tepotinib efficacy and safety in patients with METex14 skipping NSCLC (VISION) Tepotinib efficacy (pts with ≥3 months’ follow-up in Cohorts A+C) Overall Treatment-naϊve (n=137) Previously treated (n=138) Combined (N=275) Liquid biopsy* (n=81) Tissue biopsy* (n=86) Liquid biopsy* (n=78) Tissue biopsy* (n=88) Objective response rate, % (95% CI) 49.1 (43.0, 55.2) 54.3 (42.9, 65.4) 54.7 (43.5, 65.4) 43.6 (32.4, 55.3) 47.7 (37.0, 58.6) Disease control rate, % (95% CI) 74.9 (69.4, 79.9) 71.6 (60.5, 81.1) 80.2 (70.2, 88.0) 69.2 (57.8, 79.2) 79.5 (69.6, 87.4) Median duration of response, months (95% CI) 13.8 (9.9, 19.4) 13.8 (7.2, ne) 32.7 (10.8, 32.7) 11.1 (8.4, 19.4) 10.1 (8.3, 15.7) Median progression-free survival, months (95% CI) 10.8 (8.5, 12.4) 8.5 (6.9, 11.3) 15.3 (9.6, ne) 8.3 (5.7, 11.0) 11.1 (8.2, 16.8) Median overall survival, months (95% CI) 19.7 (15.6, 22.1) 15.1 (9.5, 22.1) 29.7 (15.3, ne) 19.9 (12.8, 22.3) 22.3 (17.0, 27.2) Tepotinib safety (all pts who received tepotinib in Cohorts A+C) Overall (N=291) Treatment-naϊve (n=148) Previously treated (n=143) Treatment-related AEs†, n (%) Any grade 264 (90.7) 137 (92.6) 127 (88.8) Grade ≥3 86 (29.6) 49 (33.1) 37 (25.9) Leading to death 2 (0.7) 1 (0.7) 1 (0.7) Leading to a dose reduction 90 (30.9) 51 (34.5) 39 (27.3) Leading to temporary discontinuation 114 (39.2) 63 (42.6) 51 (35.7) Leading to permanent discontinuation 41 (14.1) 24 (16.2) 17 (11.9) All-cause AEs† in ≥20% of patients, n (%) Peripheral edema 191 (65.6) 98 (66.2) 93 (65.0) Nausea 88 (30.2) 51 (34.5) 37 (25.9) Diarrhea 81 (27.8) 42 (28.4) 39 (27.3) Hypoalbuminemia 81 (27.8) 41 (27.7) 40 (28.0) Blood creatinine increase 76 (26.1) 34 (23.0) 42 (29.4) Dyspnea 60 (20.6) 40 (27.0) 20 (14.0) Data cut-off: Feb 1, 2021. *Patients with METex14 skipping detected by both liquid and tissue biopsy are included in both analysis sets (overall, n=59; treatment-naïve, n=30; previously treated, n=29); testing by both methods was not required for enrollment. †AEs were defined as events that started within the day of first dose of trial treatment until 30 days after last dose of treatment or started prior to first dose but worsened during the treatment period. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. AE, adverse event; CI, confidence interval; MET, mesenchymal-epithelial transition factor; METex14; MET exon 14; ne, not estimable. Citation Format: Marina C. Garassino, Xiuning Le, Wade T. Iam, Enriqueta Felip, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Julien Mazieres, Jo Raskin, Alexis B. Cortot, Karin Berghoff, Rolf Bruns, Gordon Otto, Paul K. Paik. Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT536.

9121 Background: Tepotinib, a potent, highly selective, oral, MET inhibitor, showed meaningful activity in patients (pts) with NSCLC with high-level METamp by LBx in VISION. Exploratory biomarker analyses are presented herein. Methods: Pts had 0–2 prior therapy lines, high-level METamp by LBx (Guardant360; MET copy number ≥2.5), and no MET exon 14 skipping or EGFR/ ALK alterations. Pts received tepotinib 500 mg once daily (450 mg active moiety). Primary endpoint was objective response by independent review; data cut-off: Aug 20, 2021. Exploratory biomarker analysis included LBx at baseline (BL), on treatment, and end of treatment (EOT). Early molecular response (eMR) was defined as undetectable METamp 6–8 weeks on treatment. Results: 24 pts were enrolled (median age: 63.4 years [yrs]; smokers: 88%; ECOG PS 1: 88%; adenocarcinoma: 67%). Treatment duration was ≥1 yr in five pts and ≥2 yrs in two pts (both ongoing). Overall, objective response rate (ORR) was 41.7% (95% CI: 22.1, 63.4). Treatment-naïve pts (n=7) had an ORR of 71.4% (29.0, 96.3), median (m) DOR was 14.3 months (2.8, not estimable [ne]), and mPFS was 15.6 months (1.4, ne). BL biomarker analyses according to clinical benefit (CR/PR/SD [n=11] vs PD/NE [n=13]) showed association with better outcomes in pts with focal METamp, or without MYCamp or RB1 mutation (Table). MYCamp/ RB1 mutation was detected in 4/7 pts with neuroendocrine/not otherwise specified histology; MYCamp in 2/3 pts with neuroendocrine histology. Low BL ctDNA mutant allele frequency (MAF) was associated with better outcomes. 14 pts had eMRs (ORR 71.4%); persistent METamp (n=4) was associated with lack of clinical response. 2/9 pts with EOT biomarker profiles had emerging resistance mechanisms (MET kinase domain mutations Y1230 and D1228); both had METamp re-emergence. Treatment-related adverse events included edema (composite term; any grade: 46%; Grade 3: 13%) and constipation (any grade: 17%; Grade ≥3: 0%). Conclusions: Tepotinib showed meaningful activity, especially in first line, in the first trial of a MET inhibitor in EGFR WT NSCLC with high-level METamp to enroll based on a convenient LBx assay. BL biomarker analyses indicated focal METamp, MYC/RB1 WT, and low ctDNA MAF were associated with improved outcomes. Serial LBx could monitor molecular response and evaluate resistance. Clinical trial information: NCT02864992. [Table: see text]

9120 Background: Tepotinib is a highly selective, potent MET inhibitor approved in several Asian countries for the treatment of advanced METex14 skipping NSCLC. In VISION (n=275; data cut-off: Feb 1, 2021), tepotinib had an objective response rate (ORR) of 49.1% (95% CI: 43.0, 55.2) by independent review (IRC), with a median (m) DOR of 13.8 months (9.9, 19.4) across treatment lines. Here, we report outcomes in Asian pts. Methods: Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC. Efficacy was assessed in 79 Asian pts with ≥3 months’ follow-up, and safety was assessed in 88 Asian pts who received tepotinib by data cut-off (Feb 1, 2021). Only pts enrolled in Asia were assessed for HRQoL. Results: In 79 Asian pts assessed for efficacy (38% female, 42% smoking history, 34% treatment-naïve [1L] and 82% adenocarcinoma), ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne). ORR was 66.7% (46.0, 83.5) in 1L pts (n=27), and 48.1% (34.0, 62.4) in previously treated pts (n=52). Meaningful activity was observed irrespective of METex14 skipping detection method (Table). In pts analyzed for HRQoL (n=73), mean change from baseline for EORTC QLQ-C30 GHS (3.94), EQ-5D-5L VAS (0.83), and EORTC QLQ-LC13 for cough (-6.59), dyspnea (-1.26), and chest pain (-6.14) symptom scores, demonstrated stability in QoL. In 88 Asian pts analyzed for safety, the most common adverse events (AEs) were peripheral edema, increased blood creatinine, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reductions in 29.5%, temporary interruption in 43.2%, and permanent discontinuation in 14.8% of pts. Conclusions: In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC. TRAEs were manageable, with few leading to treatment discontinuation. Currently, VISION has enrolled 106 Asian pts with METex14 skipping NSCLC; analysis in this population is ongoing. Clinical trial information: NCT02864992. [Table: see text]

Background Brain metastases (BMs) are reported in 20–40% patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, has demonstrated an objective response rate (ORR) of 45% and median duration of response (mDOR) of 11.1 months, in METex14 skipping NSCLC patients in Cohort A of the Phase II VISION study. Here, we report the intracranial activity of tepotinib in Cohort A. Methods Patients received oral tepotinib 500 mg QD. Study eligibility allowed for patients with BM (asymptomatic and symptomatic/stable). Primary endpoint: systemic objective response (RECIST v1.1); subgroup analysis in patients with BM (RECIST v1.1) was predefined. An ad hoc retrospective analysis of brain lesions (by CT/MRI) was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For non-measurable lesions (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020. Results Twenty-three patients had baseline BM. Systemic efficacy in patients with BM (ORR 47.8% [95% CI: 26.8, 69.4]; mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population. Fifteen patients were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and progressive disease (PD; n=3). Of seven patients with measurable CNS disease (all of whom received prior radiotherapy), intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. Conclusions Tepotinib demonstrated intracranial activity in patients with METex14 skipping NSCLC with BM. Prospective evaluation of intracranial activity in VISION Cohort C is ongoing.

Background This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). Results In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P Conclusions Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression. Trial Registration ClinicalTrials.gov: NCT02115373.

Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D). Patients and Methods: Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects. Results: One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression. Conclusions: Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

9084 Background: Brain metastases (BMs) are reported in 20–40% of pts with METex14 skipping NSCLC and present a high unmet need with poor prognosis. Tepotinib is a highly selective MET inhibitor that has demonstrated intracranial activity in preclinical MET-driven lung cancer orthotopic BM models, and has high binding in brain tissue with 25% of free tepotinib levels in brain, relative to plasma. In VISION Cohort A (N = 152), tepotinib had robust and durable clinical activity in pts with METex14 skipping NSCLC, with an objective response rate (ORR) of 45% and a median duration of response (mDOR) of 11.1 months. Here, we report the intracranial activity of tepotinib. Methods: In the Phase II VISION study, pts with METex14 skipping NSCLC received 500 mg QD (450 mg active moiety) oral tepotinib. Study eligibility allowed for pts with BM (neurologically stable on symptomatic therapy with stable steroids, and pts with asymptomatic BM). Primary endpoint: systemic OR per RECIST v1.1; subgroup analysis in pts with BM (determined by RECIST v1.1) was predefined. An ad hoc retrospective analysis of brain lesions determined by CT/MRI was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, which accounts for pts’ clinical status and steroid use. Responses were determined in pts with ≥1 evaluable post-baseline tumor assessment (due to the retrospective nature and resulting incomplete data, confirmation was not required). For pts with non-measurable lesions per RANO-BM (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020. Results: Based on RECIST v1.1, 23 pts in Cohort A had BM at baseline. Systemic efficacy in pts with BM (ORR 47.8% [95% CI: 26.8, 69.4], mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population. 15 pts were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before tepotinib initiation [range 2.6–44]). Systemic best objective responses (BORs) were partial response (PR, n = 9), stable disease (SD, n = 3), and progressive disease (PD; n = 3). Of 7 pts with measurable CNS disease per RANO-BM (all of whom received prior radiotherapy), intracranial BORs were PR (n = 5; including 3 with complete disappearance of target lesions), SD (n = 1) and PD (n = 1). Of 8 pts with NTL only, 7 achieved intracranial disease control and 1 had PD. Of the 7 pts with disease control, 3 had CR of the enhancing NTL. Conclusions: Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC with BM; this is complemented by intracranial activity in an ad hoc analysis using RANO-BM. Small pt numbers, a large proportion of pts with prior radiotherapy for BM, and the retrospective nature of analysis should be considered. Prospective evaluation of intracranial activity data from VISION Cohort C is ongoing. Clinical trial information: NCT02864992.

9021 Background: METamp is an oncogenic driver occurring in 1–5% of NSCLCs that confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in NSCLC with MET exon 14 ( METex14) skipping in Cohort A of the Phase II VISION trial (NCT02864992). VISION Cohort B evaluated tepotinib in pts with advanced NSCLC and METamp, as detected by a convenient and minimally invasive liquid biopsy assay, in the absence of METex14 skipping. Methods: Pts with locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, 0–2 prior lines of therapy, EGFR/ ALK wild-type status, no METex14 skipping, and METamp by liquid biopsy (Guardant360®; MET gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). The primary endpoint was objective response (RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. The data cut-off was July 1, 2020. Results: Among 24 enrolled pts, median age was 63.4 years (range: 38–73), 21 pts (88%) were male, 21 (88%) had ECOG PS 1 and 21 (88%) were smokers. Tepotinib was given to 7 pts (29%) in first line (1L), 10 pts (42%) in second line (2L) and 7 pts (29%) in third line (3L). As of November 2020, treatment was ongoing for > 1 year in 5 pts (1L, n = 2; 2L, n = 2; 3L, n = 1). Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L (Table). Median DOR by IRC was not estimable (NE; 95% confidence interval [CI]: 2.8 months–NE). Investigator-assessed outcomes were similar. Five pts (20.8%) discontinued due to adverse events (AEs), which were considered unrelated to tepotinib. Treatment-related AEs were reported in 16 pts (67%; Grade 3/4, 7 pts [29%]) and included peripheral edema (9 pts [38%]; Grade 3/4, 2 pts [8%]), generalized edema (4 pts [17%]; Grade 3/4, 2 pts [8%]) and constipation (4 pts [17%]; Grade 3/4, 0 pts). Conclusions: In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in NSCLC with METamp. Clinical trial information: NCT02864992. [Table: see text]

Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-αv integrin inhibitor abituzumab in chemotherapy-naïve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS). Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR = 0.89; 95% confidence interval (CI), 0.57–1.39; abituzumab 1,500 mg, 4.3 months, HR = 0.81; 95% CI, 0.52–1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms. Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancer–associated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192–200. ©2016 AACR.

9575 Background: In the phase II VISION study (NCT02864992) tepotinib had promising efficacy (response rate of 40–50% & median duration of response >1 y) and tolerable safety in pts with advanced NSCLC with METex14 skipping (3–4% of NSCLC), who are typically elderly with poor prognosis. Pt reported outcomes (PROs) of HRQoL are described here. Methods: Pts with advanced NSCLC positive for METex14 skipping by tissue or liquid biopsy received oral tepotinib 500 mg once daily; PROs were assessed using QLQ-LC13 (lung cancer symptoms), EORTC QLQ-C30 (Global health status [GHS] & 5 functional scales), and EQ-5D-5L (VAS). Questionnaires were completed at baseline (BL) and every 6 weeks (Wk); results were scored from 0–100 (minimal clinically important difference [MCID] ≥10 points). Mean change from BL was analyzed at Wk 12 (predefined analyses). Results: By 19 Jul 19 cut-off, 130 pts across treatment lines were enrolled (median age 74.2 y), with PROs available for 129. Questionnaire completion rates were 90.1% at Wk 12. Symptom burden at BL was moderate for advanced NSCLC; mean change from BL for PROs are shown in the table (better functioning: lower QLQ-LC13 or higher QLQ-C30 scores). For the QLQ-LC13 symptoms, mean changes from BL indicated a meaningful improvement in coughing, with a median time to improvement (2.8 months) paralleling the onset of objective response (within first 3 months), and a numerical improvement in dyspnea (–2.3 at Wk 12) and chest pain (–4.2 at Wk 12). QLQ-C30 values remained stable over treatment as did EQ-5D-5L scores (higher=better): mean (standard deviation, SD) change from BL score (60 [20.4]) was 6 (18.6) at Wk 6 and 5 (20.9) at Wk 12. Conclusions: In this first analysis of PROs in pts with advanced NSCLC with METex14 skipping with a moderate symptom burden, treatment with tepotinib led to a clinically meaningful improvement in coughing symptoms, while maintaining HRQoL. Coupled with the efficacy and safety profile, the predefined HRQoL analysis from the VISION study supports tepotinib as a promising treatment option for this elderly population with METex14+ NSCLC. Clinical trial information: NCT02864992 . [Table: see text]

9556 Background: Preliminary tepotinib data showed durable activity in pts with NSCLC with METex14 skipping prospectively identified by liquid (L+) or tissue (T+) biopsy. Having met target enrollment of ≥60 L+ pts & ≥60 T+ pts, we report primary data. Methods: VISION Cohort A enrolled pts with advanced EGFR/ALK wt, METex14 skipping NSCLC (asymptomatic brain metastases [BM] allowed), who received oral tepotinib 500 mg QD. On-study treatment decisions were based on investigator assessment (INV) of response. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) analyzed in 3 primary ITT sets: L+ and/or T+, L+, T+. 2ary endpoints included ORR by INV, duration of response (DOR), disease control rate (DCR), PFS, OS, & safety. Preplanned analyses were performed in pts with BM at baseline (BL). BL/on-treatment ctDNA plasma samples (L+) were analyzed using a 73-gene NGS panel (Guardant360). Deep molecular responses (MR), defined as > 75% depletion of METex14, were compared with objective responses (OR). Results: By data cut-off (1 Oct 19) 151 pts received tepotinib (safety set); 99 L+/T+, 66 L+, 60 T+ pts comprised the 3 ITT sets with ≥6-month [m] follow-up. Across treatment lines (n = 44 1L, n = 55 ≥2L), primary ORR & mPFS [95% CI] in 99 L+/T+ pts were 43% [34–54] & 8.6 m [6.9–11.0] by IRC and 56% [45–66] & 9.5 m [6.7–13.5] by INV. ORR was similar in L+ or T+ pts (table) or in T+L− pts (n = 25): 40% [21–61] by IRC and 48% [28–69] by INV. Only 2 pts were T−L+. Outcomes were also comparable in pts with BM (n = 11): IRC ORR 55% [23–83] & mPFS 10.9 m [8.0–ne]. 34/51 pts (67%) with matched BL/on-treatment L+ samples had deep MR strongly associated with clinical response: 32/34 pts (94%) with MR had disease control (INV), including 29/34 pts (85%) with OR; 2/34 pts had progressive disease. Further biomarker data will be presented. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 37/151 pts (25%). 13 pts (9%) discontinued due to TRAEs. Conclusions: Tepotinib is a promising targeted therapy with durable clinical activity and manageable toxicity in pts with METex14 skipping NSCLC L+ or T+, including pts with BM. High ORR & DCR in pts with ctDNA molecular responses support that MET inhibition in METex14+ tumor cells can lead to clinical benefit. Clinical trial information: NCT02864992 . [Table: see text]

Background MET exon 14 skipping (METex14), reported in 3–4% of NSCLC patients (pts), is sensitive to MET inhibition. We report interim data from Cohort A of the phase II VISION study (NCT02864992) of tepotinib, an oral potent highly selective MET inhibitor in NSCLC pts with METex14 skipping. Methods Pts with advanced wt EGFR/ALK NSCLC and METex14 skipping identified by liquid (L+) or tumor (T+) biopsy enrolled at 124 sites in 11 countries (35 in Asia: Japan [from Dec 2016], Republic of Korea, Taiwan [from Oct 2018]) received tepotinib 500 mg once daily until progression, intolerable toxicity or withdrawal. Primary endpoint is objective response rate (ORR) by independent review (IRC). Secondary endpoints include investigator-assessed ORR (INV), duration of response (DOR), PFS and safety (CTCAE 4.0). Pts evaluable for ORR have ≥2 post-baseline assessments or have discontinued for any reason. Predefined analysis sets include pts who are L+ or T+. Results As of 14 June 2019, 1071 of 5102 prescreened pts were from Asia, 28 had been enrolled (17 Japan, 8 Korea, 3 Taiwan). At data cutoff (18 Feb 19) for efficacy and safety analyses, 87 pts had received tepotinib, treatment was ongoing in 47. In evaluable pts, ORR was 45–55% (Table). mDOR was >1 year in all groups (12.4–17.1 months) and >50% of pts were event free at 12 months (55–70%). mPFS was 9.5–12.2 months. 14 pts were from Asia (all from Japan), treatment was ongoing in 8. Of 11 evaluable pts from Japan, 6 were L+, 9 were T + (with overlap). In L+ pts, confirmed ORR (95% CI) was 66.7% (22.3, 95.7) by IRC and 83.3% (35.9, 99.6) by INV. In T+ pts, it was 33.3% (7.5, 70.1) by IRC, 55.6% (21.2, 86.3) by INV. Any/grade 3 treatment-related adverse events (TRAEs) reported by ≥ 15% of 87 treated pts were peripheral edema (48.3/8.0%), nausea (23.0/0%), diarrhea (20.7/1.1%). No TRAEs were grade 4/5. The safety profile was similar in pts from Japan.Table62OTableL +T +IRCInv n = 47IRC n = 51Inv n = 51n = 48ORR,* n (%)24 (50.0)26 (55.3)23 (45.1)28 (54.9)95% CI35.2, 64.840.1, 69.831.1, 59.740.3, 68.9mDOR, months 95% CI12.417.115.714.35.8, ne7.1, ne9.0, ne5.7, ne12-month event-free rate 95% CI58%55%70%59%30, 7828, 7640, 8732, 79n = 57n = 58PFS events22242322mPFS, months 95% CI9.59.510.812.26.7, ne5.3, 21.16.9, ne6.3, ne12-month event-free rate39%42%49%55%95% CI21, 5625, 5831, 6439, 69CI, confidence interval; ne, not estimable.*ORR: confirmed complete response/partial response. Patients evaluable for ORR have ≥2 post-baseline assessments or have discontinued for any reason. Conclusions Tepotinib has durable clinical activity and an acceptable safety profile in NSCLC pts with METex14 skipping detected by liquid or tissue biopsy. Clinical trial identification NCT02864992. Editorial acknowledgement Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Matthew deSchoolmeester, PhD of Bioscript Science (Macclesfield, UK). Legal entity responsible for the study Merck KGaA. Funding Merck KGaA. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blueprint Medicines; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Celgene, Guardant Health; Speaker Bureau / Expert testimony: MSD, Novartis, Pfizer, Roche, Takeda. R. Veillon: Research grant / Funding (institution): Takeda, AbbVie, Merck KGaA, BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony: DMS; Advisory / Consultancy: Pfizer, Novartis. A. Cortot: Research grant / Funding (institution): Merck KGaA; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda. J. Mazieres: Advisory / Consultancy: Roche, BMS, MSD, AstraZeneca, Pfizer, Novartis. H. Sakai: Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS, Ono, Chugai, MSD, Lilly, AstraZeneca; Research grant / Funding (institution): Merck KGaA, Regeneron, Taiho. N. Reinmuth: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer. J-Y. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Research grant / Funding (institution): ONO. M. Morise: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Chugai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho, Boehringer Ingelheim, Novartis, EMD, Kissei. T. Tokito: Honoraria (self): MSD, Chu-gai, Ono, Boehringer Ingelheim, Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca. R. Bruns: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. X. Le: Advisory / Consultancy: AstraZeneca, Lilly. P.K. Paik: Research grant / Funding (self), Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: AbbVie, BMS, Lilly, Takeda. All other authors have declared no conflicts of interest.

Background Activating MET exon 14 skipping (METex14) mutations can be detected by liquid biopsy (LBx) or tumor biopsy (TBx) and are sensitive to MET inhibition. We report interim data from the phase II VISION study of tepotinib, a highly selective MET inhibitor, in NSCLC patients with METex14 mutations (NCT02864992). Methods Patients (pts) with advanced EGFR/ALK wild-type NSCLC harboring METex14 mutation identified by RNA-based testing with LBx or TBx (both ≥60 pts; overlap of LBx/TBx anticipated), enrolled at 113 sites in 8 countries (13 sites in Japan), receive tepotinib 500mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint is ORR by independent review committee (IRC); secondary endpoints include investigator assessed ORR (INV) and safety. Results To date, 90 pts are enrolled, 15 are from Japan. At data cut-off (16/10/2018), in 35 evaluable LBx pts ORR (95% CI) was 51.4% (34.0, 68.6) by IRC with a median duration of response (mDoR) (range) of 9.8 months (1.1, 18.0) and 63.9% (46.2, 79.2) by INV with a mDOR of 17.1 months (1.3, 21.5). In 41 evaluable TBx pts, ORR was 41.5% (26.3, 57.9) by IRC and 58.5% (42.1, 73.7) by INV; mDoR was 12.4 months (1.1, 18.0; IRC) and 14.3 months (1.3, 21.5; INV). Of 11 evaluable Japanese pts, 6 were METex14 positive by LBx and 9 by TBx (overlap occurred). Confirmed responses were reported in 4/6 LBx pts and 3/9 TBx pts by IRC and in 4/6 LBx pts and 4/9 TBx pts by INV. Safety was evaluable in 69 pts. Main treatment-related adverse events (TRAEs; ≥15%) of any grade were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%). The safety profile was similar in Japanese pts. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). No TRAEs led to death. Conclusion In NSCLC pts with METex14 mutations, tepotinib had promising clinical efficacy. Similar activity was observed in Japanese pts. The safety profile was favorable. Recruitment, including a MET amplification cohort, is ongoing.

Background Promising clinical activity has been reported in patients with MET-altered NSCLC treated with tepotinib, an oral, selective, potent MET tyrosine kinase inhibitor. To support clinical development, we aimed to further characterize the safety profile of tepotinib in patients with cancer. Methods In this analysis from 5 phase I and II studies of tepotinib administered 500 mg once daily, adverse events (AEs), graded by NCI CTCAE v4.03, were pooled and summarized for all patients and for the subgroup of Asian patients. Results As of 28 Sep 2018, 228 patients (81 [35.5%] Asian, 59 [25.9%] NSCLC, 121 [53.1%] HCC) had received tepotinib 500 mg/day for a median of 2.7 months (range 0–21.5); in the ongoing phase II VISION study (NCT02864992), median was 4.1 months. The most common treatment-related AE of any grade was peripheral edema occurring in 33.8% of patients overall and in 24.7% of Asian patients. Other common treatment-related AEs were diarrhea, fatigue, and nausea (Table). Dose reduction due to an AE regardless of causality occurred in 33 (14.5%) patients and discontinuation in 49 (21.5%) patients; peripheral edema led to a dose reduction in 12 (5.3%) patients and discontinuation in 7 (3.1%) patients. In the Asian population, 13 (16.0%) patients had a dose reduction and 13 (16.0%) patients discontinued due to an AE; peripheral edema led to a dose reduction in 4 (4.9%) Asian patients and to no discontinuations. Two AEs leading to death were considered by the investigator to be potentially treatment-related and occurred in patients with HCC (upper gastrointestinal hemorrhage [in an Asian patient] and hypoglycemic coma).Table67PTableAll patients (N = 228)Asian patients (N = 81)Any GradeGrade ≥3Any GradeGrade ≥3Treatment-related AE (≥10%), n (%)172 (75.4)52 (22.8)64 (79.0)26 (32.1)Peripheral edema77 (33.8)8 (3.5)20 (24.7)0Diarrhea45 (19.7)4 (1.8)27 (33.3)4 (4.9)Fatigue34 (14.9)3 (1.3)14 (17.3)3 (3.7)Nausea29 (12.7)09 (11.1)0Decreased appetite27 (11.8)012 (14.8)0Blood creatinine increased18 (7.9)1 (0.4)11 (13.6)0Hypoalbuminemia16 (7.0)1 (0.4)10 (12.3)0Amylase increased13 (5.7)4 (1.8)9 (11.1)2 (2.5) Conclusions Tepotinib demonstrated an acceptable safety profile in patients with advanced cancer, with a similar profile in Asian patients and in the overall population. Further characterization of the clinical relevance of peripheral edema is ongoing. Clinical trial identification NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992. Editorial acknowledgement Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Jen Lewis, PhD of Bioscript Science (Macclesfield, UK). Legal entity responsible for the study Merck KGaA. Funding Merck KGaA. Disclosure K. Yamazaki: Honoraria (self): Chugai; Honoraria (self): Takeda; Honoraria (self): Yakult; Honoraria (self): Daiichi‐Sankyo; Honoraria (self): Merck Serono; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Honoraria (self): Taiho; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. P.K. Paik: Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Honoraria (self): Takeda. R. Veillon: Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Merck. T. Decaens: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Travel / Accommodation / Expenses: Gilead; Honoraria (self), Travel / Accommodation / Expenses: AbbVie; Honoraria (self): Sanofi; Advisory / Consultancy: BTG; Advisory / Consultancy: Sirtex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Genoscience Pharma. S. Faivre: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. G.S. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Travel / Accommodation / Expenses: Fujifilm; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): American Society of Clinical Oncology; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, No. J. Scheele: Full / Part-time employment: Merck KGaA. R. Bruns: Full / Part-time employment: Merck KGaA. K. Berghoff: Full / Part-time employment: Merck KGaA. All other authors have declared no conflicts of interest.

Background In patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. Methods Patients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. Results From 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). Conclusions TEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identification NCT01982955. Editorial acknowledgement Medical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

Background MET amplification (amp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). Tepotinib (TEP), an oral, selective MET TKI, has shown promising antitumor activity in combination with gefitinib (GEF) in patients with MET+ EGFR-mutant NSCLC and acquired resistance to 1st-line EGFR TKIs in a phase 1b/2 study (NCT01982955). In the phase 1b part of the study, 4/6 patients with METamp had an objective response with TEP+GEF (67%). Methods In the phase 2 part of the study, Asian patients with advanced MET+ (MET2+ or 3+ by immunohistochemistry and/or METamp by in-situ hybridization) EGFR-mutant T790M- NSCLC and acquired resistance to 1st-line EGFR TKIs were randomized to receive oral TEP 500 mg + GEF 250 mg once daily or platinum + pemetrexed chemotherapy (CTx). The primary endpoint was investigator-assessed PFS. Secondary endpoints included PFS by independent review committee (IRC), overall response rate (ORR), and safety. Data from a minimum follow-up of 6-months are presented (cut-off 26 Mar 2018) for the pre-planned analysis of patients with METamp, defined as gene copy number (GCN) ≥5 and/or MET/CEP7 ratio ≥2. Results Low recruitment halted enrolment into phase 2. From 24 Apr 2015 to 12 Jun 2017, 55/156 planned patients were enrolled; 19 had METamp (TEP+GEF, 12; CTx, 7) and are included in this analysis. Median age of METamp patients was 60.4 years (range 42-74), 6 were men, 13 were never smokers, 5 had ECOG PS 0 and 14 had PS 1. Median GCN was 8.8 (range 4.8-29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. Median TEP+GEF treatment duration was 37 weeks (range 4.6-91.9) and 4 patients are still receiving treatment, ongoing for ≥18 months. Investigator-assessed PFS improved with TEP+GEF vs CTx (mPFS 21.2 vs 4.2 months; HR 0.17 [90% CI 0.05, 0.57]), as well as IRC-assessed PFS (19.8 vs 5.5 months; HR 0.25 [90% CI 0.07, 0.85]). ORR also improved with TEP+GEF (investigator: 66.7% vs 42.9%; OR 2.67 [90% CI 0.37, 19.56] and IRC: 75.0% vs 42.9%; OR 4.00 [90% CI 0.51, 31.38]). Disease control was achieved in 11 (91.7%) patients receiving TEP+GEF vs 5 (71.4%) patients receiving CTx. Related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 6 (50.0%) patients receiving TEP+GEF and 5 (71.4%) patients receiving CTx. The most common related TEAEs in the TEP+GEF arm were diarrhea (TEP+GEF 50.0% vs CTx 14.3%) and amylase increased (TEP+GEF 41.7% vs CTx 0%) and in the CTx arm were anemia (TEP+GEF 0% vs CTx 57.1%), white blood cell count decreased (TEP+GEF 8.3% vs CTx 57.1%), neutrophil count decreased (TEP+GEF 0% vs CTx 57.1%), and nausea (TEP+GEF 8.3% vs CTx 42.9%). Conclusions Promising antitumor activity with TEP+GEF was reported in patients with METamp, EGFR-mutant T790M- NSCLC and acquired resistance to 1st-line EGFR TKIs. No new safety signals were observed. METamp can be considered a biomarker for tepotinib that should be further explored. Citation Format: James Chih-Hsin Yang, Jianying Zhou, Dong-Wan Kim, Azura Rozila Ahmad, Ross Andrew Soo, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, Keunchil Park, Yi-Long Wu. Tepotinib + gefitinib vs chemotherapy in MET-amplified EGFR-mutant non-small cell lung cancer (NSCLC): Predefined subgroup analysis of a Phase Ib/II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT193.