Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced, Unresectable KRAS-mutated Non-Small Cell Lung Cancer.

Background: Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes.

Methods: We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression.

Results: Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015).

Conclusion: Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.