Introduction: Tepotinib (a MET tyrosine kinase inhibitor) + osimertinib has shown promising efficacy in patients (pts) with EGFR-mutant (EGFRm) MET amplification (METamp) non-small cell lung cancer (NSCLC), who have a high unmet need after progression on first-line (1L) osimertinib. We report the primary analysis of tepotinib + osimertinib from INSIGHT 2 (NCT03940703) in pts with ≥9 months’ follow-up (data-cut: March 28, 2023). Given the higher incidence of EGFRm NSCLC in Asia, outcomes among pts enrolled in Asia are also reported.   Methods: In this open-label Phase II study, pts with advanced EGFRm METamp NSCLC following progression on 1L osimertinib received tepotinib 500 mg (450 mg active moiety) + osimertinib 80 mg once daily.  METamp was centrally detected by tissue biopsy (TBx) FISH (MET gene copy number [GCN] ≥5 and/or MET/CEP7 ≥2) and/or by liquid biopsy (LBx) next generation sequencing (NGS; MET plasma GCN ≥2.3; Archer®).   Primary endpoint was objective response by IRC in pts with central FISH+ METamp. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety is reported for all pts who received ≥1 dose of the combination.

Results: Of 481 pts prescreened, 128 received tepotinib + osimertinib (median age 61 years [range 20–84], 57.8% female, 61.7% Asian, 67.2% never smoker, 72.7% ECOG PS 1).   In 98 pts with FISH+ METamp, objective response rate (ORR) was 50.0% (95% confidence interval [CI]: 39.7, 60.3). Median (m) DOR was 8.5 months (95% CI: 6.1, not evaluable [ne]) and mPFS was 5.6 months (95% CI: 4.2, 8.1).   76 pts receiving tepotinib + osimertinib were enrolled in Asia. In 52 pts with FISH+ METamp, ORR was 59.6% (95% CI: 45.1, 73.0), mDOR was 7.3 months (95% CI: 4.7, ne), and mPFS was 6.9 months (95% CI: 5.4, 8.4).   Outcomes were also meaningful in pts with LBx NGS+ METamp. In the overall population with LBx NGS+ METamp (n=31), ORR was 54.8% (95% CI: 36.0, 72.7), mDOR was 5.7 months (95% CI: 2.9, 15.4) and mPFS was 5.5 months (95% CI: 2.7, 7.2).   In pts enrolled in Asia with LBx NGS+ METamp (n=14), ORR was 71.4% (95% CI: 41.9, 91.6), mDOR was 5.6 months (95% CI: 2.9, ne) and mPFS was 5.5 months (95% CI: 4.2, 8.4).  In 128 pts treated with tepotinib + osimertinib, the most common treatment-related adverse events (TRAEs) were diarrhea in 63 (49.2%; Grade ≥3, 1 [0.8%]) and peripheral edema in 52 (40.6%; Grade ≥3, 6 [4.7%]) pts. Tepotinib dose was reduced in 27 (21.1%) and osimertinib in four (3.1%) pts. Thirteen pts (10.2%) discontinued treatment due to TRAEs, most often due to pneumonitis (6 [4.7%]). The safety profile of the combination was similar in pts enrolled in Asia.

Conclusions: Tepotinib + osimertinib demonstrated durable responses and a manageable safety profile in pts with EGFRm METamp NSCLC following 1L osimertinib, especially in Asian pts. Tepotinib + osimertinib provides a potential chemotherapy-sparing oral targeted therapy option in this population with high unmet need.

Citation Format: Xiuning Le, Tae Min Kim, Valentina Guarneri, Pei Jye Voon, Boon Khaw Lim, Jinji Yang, Marie Wislez, Cheng Huang, Chong Kim Liam, Julien Mazieres, Lye Mun Tho, Hidetoshi Hayashi, Nguyen Nhung, Puey Ling Chia, Fillippo De Marinis, Jo Raskin, Qinghua Zhou, Giovanna Finochhiaro, Daniel Tan, Sabine Brutlach, Aurora O'Brate, Svenja Adrian, Karin Berghoff, Barbara Ellers-Lenz, Niki Karachaliou, Yi-Long Wu. Tepotinib + osimertinib in EGFR-mutant NSCLC with MET amplification following first-line osimertinib: INSIGHT 2 primary analysis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR005.