Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer

KRAS mutations are found in 20-30 % of non-small cell lung cancers (NSCLC) and were traditionally considered undruggable. KRAS^G12C mutation confers sensitivity to KRAS^G12C covalent inhibitors, however its prognostic impact remains unclear. This study assesses the frequency, clinical features, prevalence of brain metastases and outcomes in KRAS^G12C NSCLC in a real-world setting.

Patients enrolled in the prospective Thoracic Malignancies Cohort (TMC) between July 2012 to October 2019 with recurrent/metastatic non-squamous NSCLC, available KRAS results, and without EGFR/ALK/ROS1 gene aberrations, were selected. Data was extracted from TMC and patient records. Clinicopathologic features, treatment and overall survival (OS) was compared for KRAS wildtype (KRAS^WT) and KRAS mutated (KRAS^mut); and KRAS^G12C and other (KRAS^other) mutations.

Of 1386 NSCLC patients, 1040 were excluded: non-metastatic/recurrent (526); unknown KRAS status (356); ALK/EGFR/ROS1 positive (154); duplicate (4). Of 346 patients analysed, 144 (42 %) were KRAS^mut, of whom 65 (45 %) were KRAS^G12C. All patients with KRAS^G12C were active or ex-smokers, compared to 92 % of KRAS^other and 83 % of KRAS^WT. The prevalence of brain metastases during follow-up was similar between KRAS^mut and KRAS^WT (33 % vs 40 %, p = 0.17), and KRAS^G12C and KRAS^other (40 % vs 41 %, p = 0.74). The proportion of patients receiving one or multiple lines of systemic therapy was comparable. OS was similar between KRAS^mut and KRAS^WT (p = 0.54), and KRAS^G12C and KRAS^other (p = 0.39).

Patients with KRAS^mut and KRAS^WT, and KRAS^G12C and KRAS^other NSCLC have comparable clinical features, treatment and survival. While not prognostic, KRAS^G12C may be an important predictive biomarker as promising KRAS^G12C covalent inhibitors continue to be developed.