MA09.09 Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18-Month Follow-Up

In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up. Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955). Low recruitment halted full enrolment with 55 of 156 planned patients enrolled. As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles. Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]). Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients. Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.TableSummary of efficacy dataPopulationTepotinib + gefitinibChemotherapyHR/OR (90% CI)Overall MET+*Patients, n3124mPFS, months (90% CI)4.9 (3.9, 6.9)4.4 (4.2, 6.8)0.67 (0.35, 1.28)mOS, months (90% CI)17.3 (12.1, 37.3)18.7 (15.9, 20.7)0.67 (0.33, 1.37)ORR, n (%) [90% CI]14 (45.2) [29.7, 61.3]8 (33.3) [17.8, 52.1]1.99 (0.56, 6.87)MET IHC3+Patients, n1915mPFS, months (90% CI)8.3 (4.1, 21.2)4.4 (4.1, 6.8)0.35 (0.17, 0.74)mOS, months (90% CI)37.3 (24.2, 37.3)17.9 (12.0, 20.7)0.32 (0.14, 0.78)ORR, n (%) [90% CI]13 (68.4) [47.0, 85.3]5 (33.3) [14.2, 57.7]4.33 (1.03, 18.33)MET amplification†Patients, n127mPFS, months (90% CI)21.2 (8.3, NE)4.2 (1.4, 7.0)0.13 (0.04, 0.43)mOS, months (90% CI)37.3 (NE, NE)13.1 (3.3, NE)0.08 (0.01, 0.51)ORR, n (%) [90% CI]8 (66.7) [39.1, 87.7]3 (42.9) [12.9, 77.5]2.67 (0.37, 19.56)CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival All efficacy outcomes are investigator-assessed by RECIST v1.1. *IHC2+/IHC3+/gene amplification. †MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+). Open table in a new tab