Real world efficacy of dose-reduced capmatinib and tepotinib for advanced MET exon 14–skipping+ NSCLC.

e20671 Background: First-line capmatinib (cap) and tepotinib (tep) have improved outcomes for patients with advanced MET Exon 14 Skipping+ NSCLC (METex14+), but in practice can be difficult to tolerate due to anasarca and hepatorenal dysfunction. We describe here our multi-institutional experience with dose-reduced cap/tep. Methods: All cases of METex14+ treated in our network with first-line cap/tep between 9/2020 and 12/2024 were identified and retrospectively reviewed for dose-reductions. For dose-reduced cases, in addition to dosage data, we assessed number of interruptions and cumulative dose-interruption time during the treatment period. Radiographic responses were clinically assessed via chart review of scan reports. Kaplan-Meier analysis was used for time-to-event endpoints. Event endpoints (mTTD, mPFS, mOS) were calculated as time from cap/tep start to discontinuation, progression, or death, respectively. Outcomes data were censored at last known follow-up date. Results: Among 17 pts (median age 76; 53% male) with METex14+ treated with cap (11) or tep (6), 14 (82%) were dose-reduced within median 83 days of starting cap/tep (including 3/14 reduced from treatment initiation, all 3 of whom were later further reduced). The most common dose level was a 50% reduction (50% reduction - 9/14 patients; 25% reduction - 3/14; other - 2/14). 11 pts experienced a single dose-interruption, while 1 and 2 pts each experienced two or more interruptions (max of 5; one pt treated with a week on/week off schedule). Mean cumulative dose-interruption time was 140 days. Despite dose-reductions and interruptions, outcomes among the dose-reduced cohort were encouraging: mTTD of 22.1, mPFS of 19.6 and mOS of 33.3 mos. 3/14 dose-reduced pts experienced primary progressive disease (PD) (one of whom treated with initial 50% reduction). Only one pt developed CNS PD while on dose-reduced cap/tep having been treated initially with cap 300 mg BID and reduced to 150 mg BID after 96 days. Common reasons for reduction were peripheral edema (8), fatigue (3), AKI (3), elevated LFTs (3). Conclusions: In this real-world cohort of METex14+ treated with dose-reduced cap/tep, clinical outcomes were encouraging. Dose-reduction and, in some cases, unorthodox dosing schedules allowed for mitigation of toxicity and continuation of therapy. Low rates of CNS-only PD in the dose-reduced cohort suggest encouraging CNS penetrance. These data support further study of cap/tep dose-reduction or alternative schedules, which may be a viable strategy to improve QOL while retaining disease control. Demographics and clinical outcomes (n=17). Age at diagnosis (median, y) 76 Sex (F/M) 8F, 9M ECOG PS at diagnosis (0-1; 2+) 6, 11 Treated with capmatinib/tepotinib 11C, 6T Dose reduced (n, %) 14/17 (82%) Median dose reduction 50% Clinical outcomes dose reduced cohort, months (n=14) mTTD (95% CI) 22.1 (2.3 - NR) mPFS (95% CI) 19.6 (2.5 - NR) mOS (95% CI) 33.3 (8.2 - NR)