Reference Detail

Ref Type

PMID

Authors

Elizabeth M. Burton, Rodabe Navroze Amaria, Isabella Claudia Glitza, Denai R. Milton, Adi Diab, Sapna Pradyuman Patel, Jennifer Leigh McQuade, Virginia Honaker, Michael K.K. Wong, Patrick Hwu, Jennifer Ann Wargo, Michael A. Davies, Hussein Abdul-Hassan Tawbi

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	no. 15_suppl	May 20, 2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.9520

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600X	melanoma	predicted - sensitive	Dabrafenib + Nivolumab + Trametinib	Phase II	Actionable	In a Phase II trial, combination of Tafinlar (dabrafenib), Mekinist (trametinib), and Opdivo (nivolumab) resulted in an objective response rate (ORR) of 92% (24/27, 3 CR, 21 PR) in patients with MEK inhibitor-naive, BRAF V600-mutated melanoma, with a median progression-free survival of 8.5 mos, ORR was 88% (14/16) and 100% (10/10) in PD1 refractory or naive patients, 57% (4/7) of patients with brain metastasis achieved intracranial response (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 9520; NCT02910700).	detail...