Adagrasib in Previously Treated Patients With KRAS G12C–Mutated Advanced NSCLC

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As reported in The New England Journal of Medicine by Pasi A. Jänne, MD, PhD, and colleagues, findings in a phase II cohort of the multicohort KRYSTAL-1 phase I/II study indicate that the KRAS G12C inhibitor adagrasib showed activity in previously treated patients with unresectable or metastatic non–small cell lung cancer (NSCLC) and a KRAS G12C mutation.

Pasi A. Jänne, MD, PhD

Pasi A. Jänne, MD, PhD

Study Details

A total of 112 patients with measurable disease at baseline who had previously received platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy were enrolled in the U.S. multicenter trial between January 2020 and December 2020. Patients were treated with 600 mg of adagrasib twice daily. The primary endpoint was objective response on blinded independent central review.


Median follow-up was 12.9 months. Objective response was observed in 48 (42.9%, 95% confidence interval [CI] = 33.5%–52.6%) of 112 patients, with complete response observed in 1 patient. An additional 41 patients (36.6%) had stable disease. Median duration of response was 8.5 months (95% CI = 6.2–13.8 months).

Among 33 patients with previously treated stable central nervous system metastases, intracranial objective response was observed in 11 (33.3%, 95% CI = 18.0%–51.8%). Median duration of response was 11.2 months (95% CI = 2.99 months–not evaluable).

Median progression-free survival was 6.5 months (95% CI = 4.7–8.4 months). At a median follow-up of 15.6 months, median overall survival was 12.6 months (95% CI = 9.2–19.2 months).


  • Adagrasib produced objective responses in 43% of patients.
  • Median duration of response was 8.5 months.

Adverse Events

The most common treatment-related adverse events of any grade were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), increased alanine aminotransferase (ALT; 27.6%), increased creatinine (25.9%), and increased aspartate aminotransferase (AST; 25.0%).

Treatment-related grade ≥ 3 adverse events occurred in 44.8% of patients, most commonly fatigue, nausea, and increased ALT (4.3% each) and increased AST (3.4%). Treatment-related death occurred in two patients (1.7%), due to cardiac failure and pulmonary hemorrhage.

The investigators concluded, “In [previously treated] patients with KRAS G12C–mutated NSCLC, adagrasib showed clinical efficacy without new safety signals.”

Dr. Jänne, of Dana-Farber Cancer Institute, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Mirati Therapeutics. For full disclosures of the study authors, visit

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