P15.04 A Phase I/IB Trial of Pembrolizumab and Trametinib Focused on Advanced KRAS Mutant Non-Small Cell Lung Cancer

Abstract

KRAS mutant NSCLC is heterogeneous with differential responses to MEK inhibition and immune checkpoint blockade that may be dependent on: KRAS amino acid substitution, associated co-mutations, smoking status, and tumor mutational burden. Preclinical models suggest sequencing of MEK inhibitor before or after PD-1 blockade differentially modulate the immune microenvironment, impacting anti-tumor activity of PD-1 blockade. This phase 1 study examined intercalated sequencing schemes of the MEK inhibitor trametinib and the PD-1 antibody pembrolizumab with planned dose expansion in KRAS mutant NSCLC. In this phase 1 dose escalation study, patients were treated with concurrent trametinib 1.5 to 2 mg PO daily D1-D10 and pembrolizumab 200 mg IV on a q21day cycle with either lead in trametinib alone for the first cycle (Cohort A) or lead in pembrolizumab alone for the first cycle (Cohort B). Key Eligibility: advanced non-squamous NSCLC with progression (PD) on prior platinum-based chemotherapy, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed at baseline and optional week 1-2 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1 and KRAS-mut, and changes in circulating immune cell subsets. T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex. Response was assessed by RECIST 1.1 and toxicity graded by CTCAE v5. Twelve patients enrolled thus far. Key clinical and molecular characteristics: 10 (83%) patients with KRAS mutation (5 p53 and 1 STK11 co-mutation), 1 pt with BRAF non-V600E/K mutation, 10 patients (83%) with smoking history, and 8 (66%) patients had prior immune checkpoint blockade. Baseline PD-L1 (22C3) TPS ranged from 0% to 100%. Five (42%) patients had ≥G3 AEs possibly, probably or definitely related to treatment (1 G5 pneumonitis, 1 G3 retinal detachment, 1 G3 diarrhea, 1 G3 anemia, 1 G3 mucositis). Six patients received trametinib 1.5 mg D1-10 (3 cohort A and 3 cohort B) and 6 patients at 2 mg D1-10 (3 Cohorts A and 3 Cohort B). There was 1 DLT in Cohort A at the 2 mg lead in trametinib dose (G3 mucositis). Eleven patients evaluable for response: (2 PR, 3 SD and 6 PD). One responding patient had progressed on prior nivolumab. 3/6 (50%) patients with lead in trametinib had PFS ≥6 months and 2 of these patients had prior PD-1 blockade. No patients with lead in pembrolizumab had PFS ≥6 months. The study continues to accrue patients at dose level 2 (trametinib 2 mg PO daily with both lead in schemes) with planned expansion cohort in KRAS mutant NSCLC. Results of tissue and blood correlative studies will be presented. Preliminary clinical activity has been observed thus far with trametinib and pembrolizumab, including in a patient with prior treatment on immune checkpoint blockade. The study is currently accruing patients at the highest planned dose levels and a dedicated expansion cohort at the MTD is planned in KRAS mutant NSCLC.