MAPK Pathway–Activating Alteration and Immunotherapy Efficacy in Squamous Cell Lung Carcinoma: Results from the Randomized, Prospective SQUINT Trial

Abstract Purpose: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in patients with lung squamous cell carcinoma (LSCC) is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC. Patients and Methods: SQUINT was an open-label, randomized, parallel, noncomparative, phase II trial of NI versus N-CT in chemo-naïve adult patients with metastatic or recurrent LSCC. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625). Results: Forty-five patients were included in the NI arm and 46 patients in the N-CT arm. At 12 months, the overall survival (OS) rate was 62% in the NI arm and 50% in the N-CT arm. In total, 74 patients were included in the analyses for individual biomarkers. In patients with mutations or copy-number variations of genes involved in the MAPK pathway, we observed higher response to immunotherapy (43% vs. 15%), longer progression-free survival (P = 0.03), and OS (P < 0.001). A higher density of CD8+PD1+ T cells (P = 0.04) among MAPK-altered tumors versus that in wild-type tumors, together with an increased CD8+PD1+/FOXP3 ratio (P = 0.047), was observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK1/3-mutant and wild-type LSCC. Conclusions: We showed for the first time that MAPK pathway–activating alterations influence the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.