Is Adagrasib Active in KRAS G12C–Mutated NSCLC?

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The oral KRAS G12C inhibitor adagrasib may offer durable clinical activity, with a median overall survival of 14.1 months and a 2-year survival rate of about 33%, in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to findings presented by Gadgeel et al at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (Abstract MA06.04).


KRAS G12C mutations occur in approximately 14% of patients with NSCLC.

The U.S. Food and Drug Administration granted accelerated approval of adagrasib for patients with previously treated KRAS G12C–mutated advanced or metastatic NSCLC based on previous data from the KRYSTAL-1 study—which evaluated its efficacy as monotherapy or in combination therapy for patients with solid tumors. The European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are currently reviewing the agent.

Study Methods and Results

In a 2-year follow-up and pooled analysis of the multicohort phase I/Ib and phase II KRYSTAL-1 study, researchers assigned 132 patients (with a median age of 64 years) with KRAS G12C–mutated NSCLC who had received a median of two prior therapies (including platinum-based and checkpoint inhibitor therapies) to receive 600 mg of oral adagrasib twice daily. At baseline, 19.7% of patients had central nervous system metastases.

The researchers demonstrated that the patients who received the 600-mg doses of adagrasib experienced a favorable objective response rate of 43.0% and a median duration of response of 12.4 months. Further, the median progression-free survival was 6.9 months, and the median overall survival was 14.1 months. Of note, the 1-year and 2-year survival rates were 52.8% and 31.3%, respectively.

The researchers reported that the treatment-related adverse events were manageable, with grade ≥ 3 events occurring in 40.9% of patients. A total of 2.3% of patients experienced grade 5 treatment-related adverse events (including pneumonitis, cardiac failure, and pulmonary hemorrhage).


“The study data demonstrate promising results, providing hope for patients with this specific mutation,” highlighted lead study author Shirish Gadgeel, MD, of the Henry Ford Cancer Institute at the Henry Ford Health System. “Exploratory analyses indicated that the presence of comutations—such as KEAP1, STK11, or TP53—may impact the clinical benefit of adagrasib and warrants further investigation,” he emphasized.

The ongoing phase III trial is evaluating adagrasib monotherapy compared with docetaxel in previously treated patients with advanced KRAS G12C–mutated NSCLC. The study investigators believe this study may further establish adagrasib as a therapeutic option for patients with this specific mutation.

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