A Phase II, Randomised, Open Label Study of Neoadjuvant Pembrolizumab with/without Dabrafenib and Trametinib (D+T) in BRAF V600 Mutant Resectable Stage IIIB/C/D Melanoma (NeoTrio Trial)

Abstract

Background: BRAF targeted and CTLA-4/PD-1 immunotherapies have high response rates and improve survival for patients (pts) with metastatic melanoma, however, most still die of this disease. It is hypothesised the activated cytotoxic T cell infiltrate that occurs early during treatment with BRAF/MEK inhibitors is potentiated by adding checkpoint inhibitors, resulting in improved response and survival. While trials combining BRAF/MEK inhibitors and anti-PD-1/L1 antibodies are underway in the metastatic setting, the neoadjuvant setting provides an opportunity to test different treatment schedules in small cohorts of pts. Tissue and blood biomarkers can be drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response, biomarkers of efficacy, and to select the best schedules to take forward to larger-scale trials. Trial design: Eligible pts with BRAF V600 mutant, stage IIIB/C/D, resectable and measurable (RECIST 1.1) metastatic melanoma are evenly assigned to 3 cohorts (n=60). All pts undergo complete macroscopic resection (RES) at week 12 and receive neoadjuvant therapy for 12 weeks preceding RES, followed by 40 weeks of adjuvant therapy. Cohort 1 receive sequential therapy with D+T for 2 weeks, followed by 4 pembrolizumab (pembro) doses until week 12, and 3 weekly pembro after RES. Cohort 2 receive concurrent D+T and 3 weekly pembro before and after RES. Cohort 3 receive 3 weekly pembro for the entire treatment course. Pembro is given at a flat dose of 200mg. Ultrasound surveillance of known disease areas is undertaken during the neoadjuvant period. Serial CT and FDG PET/CT are used to measure response and exclude progression in the neoadjuvant phase, and to monitor for recurrence during adjuvant and post treatment phases. Blood and tumour samples are collected at baseline, week 1, 4 and 12. The primary endpoint is the complete pathological response rate at RES following 12 weeks of therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, as well as biomarker analysis.