Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation

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The New England journal of medicine


BACKGROUND: Adagrasib, a KRAS(G12C) inhibitor, irreversibly and selectively binds KRAS(G12C), 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 KRAS(G12C) -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 KRAS(G12C) -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 KRAS(G12C) -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals.


Funded by Mirati Therapeutics; number, NCT03785249.

Medical Subject Headings

Acetonitriles; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyrimidines

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ePub ahead of print





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