Sotorasib produced objective responses in 37.1% of patients for a median duration of 11.1 months.

  • Major Finding: Sotorasib produced objective responses in 37.1% of patients for a median duration of 11.1 months.

  • Concept: Activating KRAS mutations are common drivers of this cancer and are often associated with smoking.

  • Impact: A phase III trial evaluating sotorasib in KRASG12C-mutant non–small cell lung cancer is under way.

Activating mutations in KRAS, particularly G12C, are the most common genetic driver events in non–small cell lung cancer (NSCLC). Although mutant KRAS has long been thought to be inherently undruggable, the recent development of drugs targeting KRASG12C have challenged that notion. Following the phase I portion of the CodeBreaK100 trial, which revealed a favorable safety profile and established early evidence of anticancer activity for the irreversible KRASG12C inhibitor sotorasib in patients with KRASG12C-mutant advanced solid tumors, Skoulidis, Li, and colleagues embarked upon the phase II portion of the trial, which enrolled patients with previously treated KRASG12C-mutant NSCLC. Among the 124 patients whose disease was evaluable for response, 37.1% exhibited objective responses according to an independent central review, with 3.2% of patients having complete responses and 33.9% of patients having partial responses. The median duration of response was 11.1 months, and the median progression-free survival was 6.8 months. Additionally, stable disease was the best response in 43.5% of patients. Among all 126 sotorasib-treated patients, including two who were not included in the response analysis due to lack of measurable disease at baseline, the median overall survival was 12.5 months. The response rate observed in this trial is lower than that seen with tyrosine kinase inhibitors in patients with targetable mutations in receptor tyrosine kinases. This may be attributable to the molecular heterogeneity of KRAS-mutant tumors, which are often found in patients exposed to tobacco smoke (92.9% of patients in this trial currently or formerly smoked); further, cross-trial comparisons should be interpreted with caution. The safety profile for sotorasib was as expected based on the phase I results, with the most common treatment-related adverse events being gastrointestinal disturbances (particularly diarrhea, nausea, and vomiting), liver enzyme increases, and fatigue. The results of this trial supported the recent FDA approval of sotorasib for refractory KRASG12C-mutant locally advanced or metastatic NSCLC, and a phase III trial (CodeBreaK200) comparing sotorasib with docetaxel in this context is now under way.

Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:2371–81.

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