8MO Adagrasib (MRTX849) in patients with advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC): Preliminary analysis of mutation allele frequency

KRASG12C mutations occur in ~14% of NSCLC adenocarcinomas. Adagrasib (ada), a inhibitor, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. In the KRYSTAL-1 registrational phase II Cohort A, ada showed clinical activity with manageable tolerability patients (pts) previously treated KRASG12C-mutated NSCLC. Pts received 600 mg orally BID. Study objectives included objective response rate [ORR], progression-free survival [PFS], overall [OS], safety exploratory correlative analyses. An analysis pts detectable circulating tumor (ct) DNA at baseline, cycle 2 day 1, 4 1 (C4D1), who comprise mutation allele frequency clearance (MAFC)-evaluable population, also performed; ctDNA assessed by digital droplet polymerase chain reaction. At data cutoff, 15 Oct 2021, A 116 (median follow-up 12.9 months): median age 64 years, 56% female, prior systemic therapies. ORR blinded independent review (BICR) 42.9%, disease control 79.5%, PFS 6.5 months (95% CI 4.7–8.4) and, longer (cutoff Jan 2022), OS 12.6 9.2–19.2). Any grade treatment-related adverse events (TRAEs) occurred 97% (most commonly [>40%] diarrhea [63%], nausea [62%], vomiting [47%], fatigue [41%]), Grade 3–4 TRAEs 43% [≥5%] serum lipase increase [6%] anemia [5%]). Two 5 occurred; 8 (7%) led to discontinuation. MAFC-evaluable (n = 35), BICR 60% (21/35) all responses correlated MAFC >90% C4D1. Ada promising efficacy Additional analyses are needed further evaluate whether correlates ctDNA. III trial evaluating monotherapy vs docetaxel is ongoing (NCT04685135).