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

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Conference Proceeding

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J Thorac Oncol


Background: KRASG12C mutations occur in ~14% of NSCLC adenocarcinomas. Adagrasib (ada), a KRASG12C 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 in patients (pts) with previously treated KRASG12C-mutated NSCLC.

Methods: Pts with previously treated KRASG12C-mutated NSCLC received ada 600 mg orally BID. Study objectives included objective response rate [ORR], progression-free survival [PFS], overall survival [OS], safety and exploratory correlative analyses. An exploratory analysis of clinical response for pts with detectable circulating tumor (ct) DNA at baseline, cycle 2 day 1, and cycle 4 day 1 (C4D1), who comprise the mutation allele frequency clearance (MAFC)-evaluable population, was also performed; KRASG12C ctDNA was assessed by digital droplet polymerase chain reaction.

Results: At data cutoff, 15 Oct 2021, Cohort A included 116 pts (median follow-up 12.9 months): median age 64 years, 56% female, median 2 prior systemic therapies. ORR by blinded independent central review (BICR) was 42.9%, disease control rate 79.5%, median PFS 6.5 months (95% CI 4.7–8.4) and, with longer follow-up (cutoff 15 Jan 2022), median OS 12.6 months (95% CI 9.2–19.2). Any grade treatment-related adverse events (TRAEs) occurred in 97% of pts (most commonly [>40%] diarrhea [63%], nausea [62%], vomiting [47%], and fatigue [41%]), and Grade 3–4 TRAEs in 43% (most commonly [≥5%] serum lipase increase [6%] and anemia [5%]). Two grade 5 TRAEs occurred; 8 (7%) TRAEs led to discontinuation. In MAFC-evaluable pts (n = 35), ORR by BICR was 60% (21/35) and all responses correlated with MAFC >90% by C4D1.

Conclusions: Ada showed promising efficacy and manageable tolerability in previously treated pts with KRASG12C-mutated NSCLC. Additional analyses are needed to further evaluate whether clinical response with ada correlates with MAFC in ctDNA. A phase III trial evaluating ada monotherapy vs docetaxel in previously treated pts with KRASG12C-mutated NSCLC is ongoing (NCT04685135). Clinical trial identification NCT03785249.





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