Prognostic Impact of KRAS and SMARCA4 Mutations and Co-Mutations on Survival in Non-Small Cell Lung Cancer: Insights from the AACR GENIE BPC Dataset

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Background/Objectives: KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), with their impact on survival influenced by co-mutations. SMARCA4 mutations are increasingly associated with poor prognosis and can be classified as class 1 or class 2 mutations. This study evaluates the prognostic implications of KRAS and SMARCA4 mutations, including their co-mutations and their impact on NSCLC patients by utilizing real-world evidence. Methods: A retrospective analysis was conducted using the AACR GENIE Biopharma Collaborative (BPC) NSCLC 2.0 dataset. NSCLC patients with KRAS mutations, SMARCA4 mutations, or KRAS/SMARCA4 co-mutations were identified. Survival outcomes were assessed using univariate and multivariate Cox proportional hazards models, incorporating key clinical variables such as sex, race, smoking history, and stage. Results: Among 659 NSCLC patients with KRAS or SMARCA4 mutations analyzed, KRAS mutations were the most prevalent (79%, n = 518). SMARCA4 mutations were identified in 14% of cases (n = 95) across two classes. Six percent (n = 41) with class 1 mutations and 8% (n = 54) with class 2. Neither SMARCA4 class was associated with worse survival outcomes compared to KRAS-mutated patients (p = 0.438 & 0.720). Patients harboring KRAS/SMARCA4 class 1 co-mutations (3%, n = 18) had significantly worse overall survival compared to those with KRAS mutations alone (hazard ratio [HR] = 3.23, p < 0.001). In contrast, KRAS/SMARCA4 class 2 co-mutations (4%, n = 28) did not significantly impact survival compared to KRAS-mutated patients (HR = 1.34, p = 0.205). Conclusions: KRAS/SMARCA4 class 1 co-mutations are associated with significantly worse overall survival compared to KRAS-mutated NSCLC patients. Our multivariate analysis demonstrates the critical need to incorporate routine next-generation sequencing (NGS) testing in managing NSCLC patients at the time of metastatic diagnosis, with particular emphasis on identifying SMARCA4 mutation class as a potential prognostic biomarker in those with KRAS co-mutations.

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