Adagrasib in Advanced KRAS G12C–Mutant Solid Tumors

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In a first-in-human phase I/Ib study (KRYSTAL-1) reported in the Journal of Clinical Oncology, Ou et al identified the phase II dose of the oral small-molecule KRAS G12C inhibitor adagrasib and found that the agent was active in patients with advanced KRAS G12C–mutant solid tumors.

Study Details

The U.S. multicenter study enrolled 25 patients, including 18 with non–small cell lung cancer (NSCLC), 4 with colorectal cancer, 2 with mucinous appendiceal carcinoma, and 1 with duodenal adenocarcinoma. In the dose-finding phase, patients received adagrasib at 150 mg once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg twice daily. The recommended phase II dose was identified as 600 mg twice daily on the basis of safety, tolerability, and pharmacokinetics, with no maximum tolerated dose being defined.

Activity of the Agent

Assessment of activity included 20 patients who received adagrasib at 600 mg twice daily. Median follow-up was 19.6 months. Objective responses (all partial) were observed in 8 (53.3%, 95% confidence interval [CI] = 26.6%–78.7%) of 15 evaluable patients with NSCLC (1 patient was not evaluable). Median duration of response was 16.4 months (95% CI = 3.1 months–not estimable) and median progression-free survival was 11.1 months (95% CI = 2.6 months–not estimable).


  • The recommended phase II dose of adagrasib is 600 mg twice daily.
  • Objective response at 600 mg twice daily was observed in 8 of 15 patients with NSCLC and 1 of 2 with colorectal cancer.

Partial response was observed in one of two evaluable patients with colorectal cancer, with response duration of 4.2 months; progression-free survival was 3.3 and 5.5 months in the two patients, respectively. Stable disease was observed in two patients with mucinous appendiceal carcinoma; progression-free survival was 8.3 months and 24.8 months, respectively.


Among the 20 patients receiving 600 mg of adagrasib twice daily, the most common treatment-related adverse events of any grade were nausea (80%), diarrhea (70%), vomiting (50%), fatigue (45%), increased creatinine (35%), increased aspartate aminotransferase (AST, 35%), and decreased appetite (35%). The most common grade 3 or 4 treatment-related adverse event was fatigue (15.0%); increased AST, decreased appetite, anemia, increased alanine aminotransferase, hypokalemia, increased lipase, pneumonitis, increased amylase, and hyperglycemia occurring in one patient each. One patient with underlying pneumonitis associated with prior irradiation and systemic therapy died from treatment-related pneumonitis.

The investigators concluded, “Adagrasib at 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRAS G12C mutation.”

Sai-Hong Ignatius Ou, MD, PhD, of the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, is the corresponding author for the Journal of Clinical Oncology article.

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

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