Outcomes of first-line chemo-immunotherapy in advanced non-squamous NSCLC according to KRAS status: An Italian real-world study

Introduction: Chemo–immunotherapy is the standard frontline treatment of advanced non–squamous non–small cell lung cancer (nsq–NSCLC). Among oncogenic drivers, KRAS mutation accounts for approximately 25% of lung adenocarcinomas, with p.G12C being the most common variant. This study assessed clinical features and survival outcomes according to KRAS mutation in a real–life population of nsq–NSCLC patients treated with first–line platinum–pemetrexed–pembrolizumab. Methods: This is a retrospective–prospective study including patients with nsq–NSCLC who received first–line platinum–pemetrexed–pembrolizumab from 4 September 2018 in 33 Italian Centers. Results: Among the 765 patients included in this analysis, 121 (15.8%) had KRAS p.G12C mutation, 201 (26.3%) KRAS non–p.G12C mutation and 443 (57.9%) KRAS WT. KRAS–mutated patients had more frequently a history of smoking (90.6% vs 84.1%, p=0.012) and bone metastases (44.1% vs 35.9%; p=0.022) compared to KRAS WT. Median Overall Survival (OS) was similar between KRAS–mutated and KRAS WT patients (16.7 vs 18.2 months; adjusted Hazard Ratio [HR] 1.19, 95% Confidence Interval [CI] 0.95–1.50, p=0.132). No difference in OS was found between KRAS p.G12C and KRAS non–p.G12C (15.9 vs 17.0 months, HR 0.93, 95% CI: 0.66–1.31, p=0.676). Median progression–free survival was significantly shorter in KRAS–mutated compared to KRAS WT patients (8.8 vs 10.8 months; adjusted HR 1.29, 95% CI 1.04–1.59, p=0.018), with no differences between KRAS p.G12C and KRAS non–p.G12C (8.8 vs 8.8 months, HR 0.95, 95% CI: 0.70–1.30, p=0.756). Conclusions: KRAS mutation showed a potential negative predictive role in advanced nsq–NSCLC treated with first–line chemo–immunotherapy. The impact of co–mutations and post–progression outcomes warrants further investigation.