Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers

Background Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed. Objective The purpose of this multicenter study was to evaluate the clinical activity of CIT according to oncogenic drivers, STK11 and TP53 mutations, and MET overexpression. Patients and methods Patients receiving CIT for advanced NSCLC with available comprehensive molecular profile were included. The primary endpoint was progression-free survival (PFS), adjusted on main confounding factors, and secondary endpoints were overall survival (OS) and objective response rate. Results Among the 195 patients included between September 2018 and October 2021, 88 (41%) had a KRAS mutation, 16 (8.2%) an EGFR mutation or an ALK , ROS1 , or RET rearrangement, 11 (5.6%) a BRAF mutation, 6 (3.1%) a MET exon 14 mutation or MET amplification, and 5 (2.6%) a HER2 mutation. Seventy-seven patients (39.5%) had none of these alterations. The median PFS was 6.4 months (95% CI 5.3–7.3). Per subgroup, the median PFS was 7.1 months (5.4–8.9) for KRAS , 5.5 months (2.5–15.3) for EGFR/ALK/ROS1/RET , 12.9 months (2.6–not reached [NR]) for BRAF , 1.5 months (0.6–NR) for MET , 3.9 months (2.6–NR) for HER2 , and 5.6 months (4.7–7.8) for patients without any oncogenic alteration. No difference in PFS was observed between the KRAS, BRAF, EGFR/ALK/ROS1/RET , and no-driver subgroups. STK11 mutations were associated with poor PFS (HR 1.59 [95% CI 1.01–2.51]) whereas TP53 mutations had no impact. MET overexpression was associated with longer PFS (HR 0.59 [95% CI 0.35–0.99]). Conclusion This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT.