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Purpose

With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non–small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice.

Materials and Methods

We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity.

Results

Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR] 3.19, P=0.004, OS HR 4.10, P=0.003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR 1.10, P=0.731, OS HR 1.19, P=0.631) or STK11 (rwPFS HR 1.66, P=0.098, OS HR 1.73, P=0.168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti–PD-(L)1 therapy. Among these patients, anti–PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs (P<0.001) and TRAE-related sotorasib discontinuation (P=0.014). Twenty-eight percent of patients with recent anti–PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity.

Conclusion

Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti–PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.

Read a Q&A related to the study here and expert commentary about it here.