MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial

Abstract Background: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients 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. Methods: SQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625). Results: 45 patients were included in the NI arm and 46 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. 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 (PFS) (p=0.03) and OS (p<0.001). A higher density of CD8+PD1+ T cells (p=0.04) among MAPK-altered tumors versus wild-type, together with an increased CD8+PD1+/FOXP3 ratio (p=0.047) were observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK13 mutant and wild-type LSCC. Conclusion: We showed for the first time that MAPK pathway activating alteration influences the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.