Safety and efficacy of TRIplet combination of nivolumab (N) with dabrafenib (D) and trametinib (T) [TRIDeNT] in patients (pts) with BRAF-mutated metastatic melanoma (MM): A single center phase II study

Abstract Background Although targeted therapies (TT) and immunotherapies (IMT) have improved survival for pts with BRAF V600 mutated stage IV MM, many pts progress and will ultimately die from this disease. Preclinical data has shown that BRAF inhibition (BRAFi) in BRAF-mutated tumors is associated with increased T cell infiltration, supporting the rationale for a clinical combinatorial approach with IMT. Although there are multicentered trials ongoing evaluating this combinatorial approach for pts with untreated MM, there are no approved therapies for pts after TT and IMT failure. Notably, patients with untreated brain metastases (BM) are often excluded from such trials. We hypothesized that N in combination with DT is safe and will demonstrate clinical activity in BRAF-mutated pts refractory to PD1 therapy and in pts with BM. Methods We report a single arm phase II study (NCT02910700) of NDT in pts with BRAF-mutated, unresectable stage III or stage IV MM. Prior IMT is allowed, but pts who have received BRAF/MEKi are ineligible. Pts with untreated BM and asymptomatic or mildly symptomatic/requiring stable or decreasing steroids (up to PO dexamethasone of 8 mg or equivalent) are also allowed. Pts received 3mg/kg Q2wks of N (later amended to 480 mg q4wks), 150mg BID of D and 2mg QD of T, all starting on Day 1. The primary objective of this study is to determine safety and efficacy (ORR by RECIST 1.1) of the NDT combination. This study is continuously monitored for safety and futility. Tissue and blood-based samples to assess for correlative studies are also collected. Results Following a 6 pts safety run-in which no DLTs were observed, 24 patients in total have received NDT – 18 of which were PD1 refractory. 6 pts have discontinued due to toxicities. 7 of the 18 PD1 refractory pts had untreated BM. Of the 19 total evaluable pts, 15 achieved PR and 2 CR (ORR 89%). 12 PD1 refractory were evaluable for response; 2 achieved CR and 10 PR (ORR 67%). Conclusions NDT is well-tolerated and shows promising clinical activity in pts with IMT refractory disease and with BM. Further investigation into the correlatives and mechanisms of action is warranted. Clinical trial identification NCT02910700. Legal entity responsible for the study The University of Texas, MD Anderson Cancer Center. Funding Bristol-Myers Squibb. Disclosure R.N. Amaria: Research grant / Funding (institution): Merck. J. Wargo: Honoraria (self): BMS; Honoraria (self): Illumina; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca. M.A. Davies: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Advisory / Consultancy: Vaccinex. H.A. Tawbi: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Celegene. All other authors have declared no conflicts of interest.