Abstract CT538: Tepotinib + gefitinib in patients with EGFR-mutant NSCLC with MET amplification: Final analysis of INSIGHT

Abstract

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.

Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments

“…Inhibition of MET signaling is being investigated as a promising therapeutic strategy in patients with MET amp NSCLC; a total of 16 publications providing information on clinical trial evidence in MET amp NSCLC were identified. Several agents alone or in combination with EGFR-TKIs are currently under investigation for the treatment of MET amp NSCLC, including small molecule MET receptor inhibitors (e.g., crizotinib ( 30 , 55 ), savolitinib ( 57 , 76 , 77 ), tepotinib ( 61 , 62 , 78 , 79 ), and capmatinib ( 56 , 60 )), monoclonal or bispecific antibodies that can block MET activity (e.g., amivantamab ( 80 )), and an anti-MET antibody–drug conjugate (e.g., telisotuzumab vedotin ( 81 )).…”

“…There are two types of MET-TKIs, including type I MET-TKIs that bind to an active form of MET (e.g., tepotinib, capmatinib, crizotinib, savolitinib, and bozitinib), and type II MET-TKIs that bind to an inactive form of MET (e.g., cabozantinib and glesatinib). The majority of MET-TKIs are orally administered (e.g., tepotinib, capmatinib, savolitinib, crizotinib) ( 30 , 55 – 57 , 60 – 62 , 76 , 78 , 79 ).…”

“…A total of 19 patients with EGFR -mutated, MET amp advanced NSCLC who progressed on an EGFR-TKI were enrolled in a Phase Ib/II trial (INSIGHT) ( 61 , 78 ). In this study evaluating tepotinib plus gefitinib (n=12) and chemotherapy (n=7), median (90% CI) progression-free survival was 16.6 (8.3, 22.1) and 4.2 (1.4, 7.0) months (hazard ratio: 0.13; 90% CI: 0.04, 0.43), and median (90% CI) overall survival was 37.3 (21.1, 52.1) and 13.1 (3.3, 22.6) months (hazard ratio: 0.10; 90% CI: 0.02, 0.36).…”

Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3

“…Eight additional RCTs were identified in the latest literature search that spanned from February 6 to October 30, 2023. [14][15][16][17][18][19][20][21] The randomized trials compared different therapies. Results from these studies either necessitated some modifications to the recommendations, or the quality of evidence rating in some recommendations.…”

Speeding up Antibody-Drug Conjugate Development in Pretreated EGFR-Mutant Non–Small-Cell Lung Cancer

“…Although certain trials have suggested that a personalized treatment approach on EGFR TKI progression yields better outcomes compared with PBC, 20 not all physicians have access to genomic profiling. Furthermore, even when a potential targetable resistance mechanism is identified, a specific clinical trial might not always be available.…”