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Approximately 20% of lung adenocarcinomas harbor activating mutations at KRAS, an oncogene with the ability to alter the tumor immune microenvironment. In this retrospective study, we examined 103 patients with KRAS-mutant lung adenocarcinoma who were treated with immunotherapy-based regimens and we evaluated the clinical outcomes according to PD-L1 expression and the type of KRAS mutation. Among all patients included, 47% carried KRAS G12C mutation whereas 53% harbored KRAS non-G12C mutations. PD-L1 status was available for 77% of cases, with higher expression among KRAS G12C tumors (p = 0.01). Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of KRAS mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.

Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.