Clinical and translational study of p38 inhibitor pexmetinib plus nivolumab following anti–PD-1/L1 failure in advanced solid tumors.

2515 Background: Cancers resistant to immune checkpoint blockade typically harbor a non-T cell-inflamed phenotype, characterized by low type I/II interferon activity and limited CD8⁺ T-cell infiltration within the tumor microenvironment. We previously identified p38 MAPK activation as a tumor-intrinsic immune exclusion mechanism associated with resistance to immunotherapy across solid tumors. Based on these preclinical observations, we conducted a Phase II clinical trial (NCT04074967) combining pexmetinib, a p38 inhibitor, with nivolumab in advanced solid tumors. Here, we report safety, clinical activity, and translational results in patients with PD-1 refractory head and neck (HN) cancer and lung cancers. Methods: Patients received pexmetinib 200 mg orally once daily plus nivolumab 480 mg intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) assessed by RECIST v1.1. Translational analyses included pharmacodynamic assessment, plasma proteomics, single-cell RNA sequencing (scRNAseq), and computed tomography-based radiomic analyses. Results: Thirty-five patients were enrolled (HN cohort = 11 [31%; 100% squamous cell carcinoma]), lung cohort = 24 [69%; 63% adenocarcinoma]). Median age was 62 years; 60% were male and 89% had ECOG performance status 1. Twenty-nine patients were radiographically evaluable. Partial responses were observed in four patients (ORR 14%), and 13 patients (45%) experienced stable disease. Median duration of response was 11.1 months. Median progression-free survival (PFS) was 7.2 months and overall survival (OS) was 9.3 months. Treatment-related adverse events (TRAEs) of any grade occurred in 89% of patients; 47% experienced grade ≥3 TRAEs. No fatal TRAEs were reported. Plasma proteomic profiling identified on-treatment immune modulation relative to baseline, with increased T cell-associated cytokines/chemokines in patients with durable clinical benefit (PFS > 6 months). Among three patients with paired pre- and on-treatment tumor scRNAseq, an increase in intratumoral T-cell abundance was observed in one patient with tumor shrinkage but not in two patients with progressive disease. On-treatment increases in T-cell radiomic score relative to baseline were significantly greater in responders vs. non-responders, and were associated with improved PFS and OS ( P < 0.05). Conclusions: In patients with PD1-refractory HN cancer and lung cancers, pexmetinib plus nivolumab demonstrated an acceptable safety profile and durable clinical benefit. Multimodal translational profiling revealed increased inflammatory cytokine signaling and radiomic and molecular features consistent with enhanced CD8⁺ T-cell engagement in responders. These findings suggest that targeting tumor-intrinsic p38 MAPK may represent a mechanistically informed strategy to overcome immunotherapy resistance. Clinical trial information: NCT04074967 .