Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation

Pasi A. Jänne, Gregory J. Riely, Shirish M. Gadgeel, Rebecca S. Heist, Sai Hong I. Ou, Jose M. Pacheco, Melissa L. Johnson, Joshua K. Sabari, Konstantinos Leventakos, Edwin Yau, Lyudmila Bazhenova, Marcelo V. Negrao, Nathan A. Pennell, Jun Zhang, Kenna Anderes, Hirak Der-Torossian, Thian Kheoh, Karen Velastegui, Xiaohong Yan, James G. ChristensenRichard C. Chao, Alexander I. Spira

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)120-131
Number of pages12
JournalNew England Journal of Medicine
Volume387
Issue number2
DOIs
StatePublished - Jul 14 2022

ASJC Scopus subject areas

  • Medicine(all)

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