A Phase 1/1B Trial of Pembrolizumab and Trametinib in Advanced NSCLC Enriched for KRAS Mutations.

INTRODUCTION: MEK inhibition (MEKi) combined with programmed death ligand 1 inhibition (immune checkpoint inhibitor [ICI]) modulates the tumor immune microenvironment. This phase 1 study evaluated sequencing schemes of MEKi and ICI with trametinib and pembrolizumab in NSCLC. METHODS: In this 3+3 dose escalation study, patients with advanced NSCLC were treated with lead-in trametinib (arm A) or lead-in pembrolizumab (arm B) for cycle 1, followed by a 1.5 to 2 mg oral daily dose of trametinib (d 1-10) with pembrolizumab 200 mg intravenously every 21 days. Eligible patients with progressive disease on or after platinum-based chemotherapy were enrolled. Prior ICI was allowed. Tumor tissue was analyzed with quantitative immunofluorescence. High-parameter flow cytometry was performed on blood. Adverse events were graded using the Common Terminology Criteria for Adverse Events version 4 and efficacy was evaluated by Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Fifteen patients enrolled (nine arm A and six arm B) with 13 (86%) harboring KRAS mutations and 10 (66%) receiving prior ICI. Five patients (33%) experienced at least one grade greater than or equal to 3 treatment-related adverse event including one dose-limiting toxicity (grade 3 esophagitis). Two patients had a partial response (ORR = 14%). Trametinib lead-in was associated with decreased T-regulatory cells and myeloid-derived suppressor cells (p = 0.002 and p = 0.05, respectively). CONCLUSIONS: The activity of trametinib and pembrolizumab is modest in NSCLC with increased toxicity compared with programmed death ligand 1 blockade alone. The recommended phase 2 dose for the combination is 2 mg of oral trametinib (d 1-10) and 200 mg of intravenous pembrolizumab every 21 days, with lead-in trametinib. Adverse events were comparable with other MEKi and ICI combination studies. Though limited clinical activity was observed, lead-in MEKi may induce favorable immune cell alterations.