• Among KRAS G12C NSCLC patients, a never or light smoking history of less than 10 pack-year is associated with worse clinical outcomes on KRAS inhibitors. • High performance status at initiation of KRAS inhibitors is linked to improved clinical outcomes. • The presence of tumoral co-mutation in KEAP1 predisposes patients to inferior clinical outcomes on KRAS inhibition. The oral KRAS G12C inhibitors, sotorasib and adagrasib, were approved for advanced non-small cell lung cancer (NSCLC) in the later-line setting in 2021 and 2022, respectively. However, data are still emerging regarding how clinical and molecular variables impact outcomes. Patients with advanced KRAS G12C-mutant NSCLC who were treated at a matrix cancer center with an oral KRAS G12C inhibitor between May 2021 and August 2024 had their clinical and outcome data collected and analyzed. A total of 38 patients who met the inclusion criteria were identified. The overall median progression-free survival (PFS) of the cohort was 3.5 (95% confidence interval (CI) 2.7-6.1) months, and median overall survival (OS), 7.8 (4.8-11.0) months. Patients with a never or light smoking history (defined by a cutoff of ≤10 pack-years), worse Eastern Cooperative Oncology Group (ECOG) performance status (≥2), and tumors harboring a concurrent pathogenic KEAP1 mutation were shown to be associated with shorter median PFS and OS. Other variables such as age, presence of brain metastasis, the presence of STK11 , and TP53 mutations did not have a significant impact on clinical outcomes. In this single-center, real-world, retrospective analysis, among the 38 patients with advanced NSCLC receiving KRAS G12C inhibitors, a never or light smoking history, poor performance status, and the presence of tumor pathogenic KEAP1 mutations were associated with worse clinical outcomes. Within the limitations of the study, clinicians should consider these variables when formulating treatment for KRAS G12C-mutant NSCLC.
Xu et al. (Wed,) studied this question.