Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: A phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial).

TPS9604 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 neo-adjuvant (neo-adj) 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. Methods: Eligible pts with BRAF V600 mut, stage IIIB/C/D, resectable and measurable (RECIST 1.1) melanoma are evenly assigned to 3 cohorts (n = 60). All pts undergo complete macroscopic resection (RES) at wk 12 and receive neo-adj therapy for 12 wks preceding RES, followed by 40 wks of adjuvant (adj) therapy. Cohort 1 receive sequential therapy with D+T for 2 wks, then 4 pembrolizumab (pembro) doses until wk 12, and 3 wkly pembro after RES. Cohort 2 receive concurrent D+T and 3 wkly pembro before and after RES. Cohort 3 receive 3 wkly pembro for the entire treatment course. Pembro is given at a flat dose of 200mg. Ultrasound of known disease areas is undertaken during the neo-adj period. CT and FDG PET/CT are used to measure response and exclude progression in the neo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, wk 1, 4 and 12. The primary endpoint is the complete pathological response rate at RES following 12 wks of therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analysis. First patient enrolled 29Nov2017. Clinical trial information: NCT02858921.