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COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAFV600 mutant, metastatic melanoma (MM). Resistance develops in most pts, and oncogenic toxicities (e.g., cutaneous squamous carcinoma (cuSCC)) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects in the Phase I/II study of D+T v D (NCT01072175), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01584648) was conducted to confirm the superiority of D+T over D in pts with BRAFV600E/K mutant MM. Methods: Pts were randomized 1:1 to receive D (150 mg twice daily) + T (2 mg once daily) or D+ placebo (P) as first-line therapy. Eligible pts were ≥18 years and ECOG performance status ≤1, with histologically confirmed unresectable stage IIIC or IV, BRAFV600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59. Results: From May 2012 to Jan 2013, 423 pts were randomized (211 to D+T, 212 to D+P). Median follow up was 9 mo (0-16 mo). HR for investigator-assessed PFS was 0.75 (95% CI: 0.57, 0.99; p=0.035), in favor of D+T with a median PFS of 9.3 v 8.8 mo with D+P. The confirmed ORR was 67% (complete response [CR] 10%) for D+T and 51% (CR 9%) for D+P (p=0.0015). HR for interim OS was 0.63 (95% CI 0.42, 0.94; p=0.023), in favor of D+T (40 v 55 deaths). Rates of AEs were similar for both arms. More pts had AEs leading to dose modifications with D+T v D+P. Increased incidence (51% v 28%) and severity (grade 3, 6% v 2%) of pyrexia occurred with D+T v D+P. Fewer cutaneous hyperproliferative events occurred with D+T v D+P (CuSCC 2% v 9%; hyperkeratosis 3% v 32%). Conclusions: D+T demonstrated a significant improvement in PFS compared to D+P in pts with BRAFV600E/K mutant MM. Clinical trial information: NCT01072175.
Abstracts by Georgina V. Long:
A multicenter, open-label trial of talimogene laherparepvec (T-VEC) plus pembrolizumab vs pembrolizumab monotherapy in previously untreated, unresected, stage IIIB-IV melanoma.Meeting: 2015 ASCO Annual Meeting | Abstract No: TPS9081
BRAF inhibitor acquired resistance: A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms.Meeting: 2015 ASCO Annual Meeting | Abstract No: 9008
Effect of nivolumab (NIVO) on quality of life (QoL) in patients (pts) with treatment-naïve advanced melanoma (MEL): Results of a phase III study (CheckMate 066).Meeting: 2015 ASCO Annual Meeting | Abstract No: 9027