Phase II Study of TRIplet combination Nivolumab (N) with Dabrafenib (D) and Trametinib (T) (TRIDeNT) in patients (pts) with PD-1 naïve or refractory BRAF-mutated metastatic melanoma (MM) with or without active brain metastases.
Authors: Burton Elizabeth M. , Amaria Rodabe Navroze , Glitza Isabella Claudia , Milton Denai R. , Diab Adi , Patel Sapna Pradyuman , McQuade Jennifer Leigh , Honaker Virginia , Wong Michael K.K. , Hwu Patrick , Wargo Jennifer Ann , Davies Michael A. , Tawbi Hussein Abdul-Hassan 
Published: June 2021

9520 Background: Targeted therapies (TT) & immunotherapies (IMT) have improved survival for pts with BRAF V600 mutated stage IV MM, however many pts still progress and ultimately die from their disease. Preclinical data support the rationale for combining TT and IMT, but trials evaluating triplet combinations in IMT-naïve pts have reported mixed results. Notably, pts with untreated brain metastases (BM) were excluded from prior triplet trials and have a median PFS of 5.6 months when treated with TT. Further, there remains an unmet need for effective therapies for pts after IMT failure, as retrospective studies have reported short median PFS (5 mos) for TT in this setting. We hypothesized that N in combination with DT is safe and will demonstrate clinical activity in BRAF-mutated pts naïve or refractory to PD1 therapy and in pts with BM. Methods: We conducted a single arm phase II study (NCT02910700) of NDT in pts with BRAF-mutated, unresectable stg III or stg IV MM. Prior IMT was allowed, but prior BRAF/MEKi was not. Pts with untreated BM and asymptomatic or mildly symptomatic/requiring steroids were also allowed. Pts received 3mg/kg IV Q2wks of N (later amended to 480 mg IV Q4wks), 150mg PO BID of D and 2mg PO QD of T, all starting on Day 1. The primary objective was to determine safety and efficacy (ORR by RECIST 1.1). Monitoring for safety and futility using Bayesian stopping rules was performed. Longitudinal tissue and blood samples were collected to perform correlative analyses. Results: Following a 6 pt safety run-in with no observed DLTs, 27 pts were treated w NDT. 17 pts were PD1 refractory, 10 were PD-1 naïve. 10 of these 27 pts had a history or presence of BM, including active BM. Median follow up was 18.4 months (range 3.2-45.9). ORR in 26 evaluable pts was 92% (3 CR, 21 PR). Among the PD1 refractory pts evaluable for response (n = 16), ORR was 88% (2 CRs, 12 PR). All 10 evaluable PD-1 naïve pts achieved a response. 4 of 7 evaluable pts w BM achieved an intracranial response (57%), including 2 CRs. The median PFS for all pts was 8.5mos (8.5mos in PD1 naïve pts, 8.2mos in PD1 refractory pts). Median PFS for pts without BM was 8.5mos, 8.0 mos for those with BM. Median OS for all pts was not reached, and no statistically significantly difference in OS by PD1 exposure or presence of BM. 78% of pts experienced treatment related grade 3/4 AEs and 6 pts (22%) discontinued all 3 drugs due to toxicities. Conclusions: NDT at full doses of all 3 agents has a toxicity profile consistent with previously reported triplet combinations and shows promising clinical activity in pts with IMT refractory disease and with BM. There were no significant differences in outcomes between pts with and without BM. Translational studies to delineate predictors and mechanisms of response and resistance are ongoing. Clinical trial information: NCT02910700.