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A Phase 1/1B Trial of Pembrolizumab and Trametinib in Advanced NSCLC Enriched for KRAS Mutations
Jonathan W Riess1, Matthew S Lara1, Guillaume Luxardi1
1University of California Davis Comprehensive Cancer Center, Sacramento, California.
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.
Insights
Combining MEK inhibitors (MEKi) with immune checkpoint inhibitors (ICI) showed modest activity in NSCLC. Lead-in MEKi with trametinib and pembrolizumab altered immune cells but increased toxicity, suggesting careful sequencing is needed.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Combination of MEK inhibitors (MEKi) and immune checkpoint inhibitors (ICI) can modulate the tumor immune microenvironment.
- Understanding optimal sequencing of MEKi and ICI is crucial for improving efficacy in non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To evaluate different sequencing strategies of trametinib (MEKi) and pembrolizumab (ICI) in patients with advanced NSCLC.
- To assess the safety, tolerability, and preliminary efficacy of combined MEKi and ICI therapy.
Main Methods:
- A Phase 1, 3+3 dose escalation study.
- Patients received either lead-in trametinib or lead-in pembrolizumab, followed by combination therapy.
- Tumor tissue and blood samples were analyzed for immune cell alterations; adverse events and efficacy were assessed.
Main Results:
- Fifteen patients were enrolled, with a high prevalence of KRAS mutations (86%) and prior ICI exposure (66%).
- Two patients (14%) achieved a partial response; 33% experienced grade >= 3 treatment-related adverse events.
- Lead-in trametinib was associated with decreased T-regulatory cells and myeloid-derived suppressor cells.
Conclusions:
- The combination of trametinib and pembrolizumab demonstrated modest clinical activity in NSCLC with increased toxicity.
- The recommended Phase 2 dose is 2 mg oral trametinib (days 1-10) and 200 mg IV pembrolizumab every 21 days, with trametinib lead-in.
- While clinical activity was limited, lead-in MEKi may induce favorable changes in immune cell populations.
