TY - JOUR
T1 - Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation
AU - Jänne, Pasi A.
AU - Riely, Gregory J.
AU - Gadgeel, Shirish M.
AU - Heist, Rebecca S.
AU - Ou, Sai Hong I.
AU - Pacheco, Jose M.
AU - Johnson, Melissa L.
AU - Sabari, Joshua K.
AU - Leventakos, Konstantinos
AU - Yau, Edwin
AU - Bazhenova, Lyudmila
AU - Negrao, Marcelo V.
AU - Pennell, Nathan A.
AU - Zhang, Jun
AU - Anderes, Kenna
AU - Der-Torossian, Hirak
AU - Kheoh, Thian
AU - Velastegui, Karen
AU - Yan, Xiaohong
AU - Christensen, James G.
AU - Chao, Richard C.
AU - Spira, Alexander I.
N1 - Publisher Copyright:
Copyright © 2022 Massachusetts Medical Society.
PY - 2022/7/14
Y1 - 2022/7/14
N2 - 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.
AB - 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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U2 - 10.1056/NEJMoa2204619
DO - 10.1056/NEJMoa2204619
M3 - Article
C2 - 35658005
AN - SCOPUS:85132116608
SN - 0028-4793
VL - 387
SP - 120
EP - 131
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 2
ER -