BackgroundMET 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.