BACKGROUND Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1–1b part of the KRYSTAL-1 phase 1–2 study. METHODS In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS As of October 15, 2021, a total of 116 patients with KRASG12C-mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients — grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) — and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS In patients with previously treated KRASG12C-mutated NSCLC, adagrasib showed clinical efficacy without new safety signals.
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