November 2017 VOL 8, NO 11

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Clinical Research

Pooled Analysis of Safety with Extended 3-Year Follow-up Across Combination Dabrafenib and Trametinib (D+T) Phase 3 Trials

Jean-Jacques Grob, MD, PhD1; Keith T. Flaherty, MD2; Georgina V. Long, MD, PhD3; Paul Nathan, MD4; Dirk Schadendorf, MD, PhD5; Antoni Ribas, MD, PhD6; Caroline Robert, MD7; Stephen Lane, MS8; Carmen Mak, PhD8; Bijoyesh Mookerjee, MD8; Michael A. Davies, MD, PhD9
1Aix-Marseille University, Marseille, France; 2Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, MA; 3Melanoma Institute of Australia and The University of Sydney, Sydney, NSW, Australia; 4Mount Vernon Cancer Centre, Northwood, UK; 5University Hospital of Essen, Essen, Germany; 6UCLA and the Jonsson Comprehensive Cancer Center, Los Angeles, CA; 7Gustave Roussy Comprehensive Cancer Center, Villejuif, Paris-Sud, France; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ; 9The University of Texas MD Anderson Cancer Center, Houston, TX 

Background: Significantly improved outcomes with D+T vs BRAF inhibitor (BRAFi) monotherapy have been demonstrated in phase 3 BRAF V600E/K–mutant mel­anoma trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]), supporting use of D+T as a treatment for this disease. Additionally, long-term survival and sustained tolerability have been observed in a significant number of patients (pts) with D+T in these trials. As pts achieve long-term benefits, understanding the safety profile of these agents with extended follow-up is important for optimizing pt management. A prior pooled analysis of safety data in D+T cohorts across registration trials (median follow-up, 20 mo) showed that the highest adverse event (AE) rates were observed within 6 mo of D+T initiation and that, although common with D+T, occurrence of pyrexia during treatment did not predict response or progression.

Objectives: The aim of this retrospective study was to evaluate pooled safety with extended follow-up in pts treated with D+T in COMBI-d and COMBI-v.

Methods: This is a 3-y pooled safety analysis of D+T pts across COMBI-d (n = 209; cutoff, February 2016) and COMBI-v (n = 350; cutoff, July 2016). AEs were graded per National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and assessed by time.

Results: Consistent with previous reports for D+T, the most frequent AEs across the pooled data set (N = 559) with extended follow-up were pyrexia (58%), nausea (36%), chills (33%), diarrhea (33%), fatigue (33%), vomiting (29%), and hypertension (29%). In pts receiving D+T for ≥36 mo (n = 50; 9%), AE incidence generally peaked within 6 mo of treatment initiation and declined thereafter (eg, pyrexia rate was 60% from 0-6 mo, 24% from 6-12 mo, 32% from 12-18 mo, 22% from 18-24 mo, 24% from 24-30 mo, and 12% from 30-36 mo).

Conclusions: These results confirm that long-term tolerability of D+T is achievable in some pts with BRAF-mutant melanoma who are still under treatment after 3 years. The frequency of AEs was highest in the initial 6 months of therapy and declined thereafter. Analyses of the impact of D+T dose reductions or discontinuation, as well as description of the ways that recurrent pyrexias were managed, will be presented.

Disclosures: The studies included in this pooled analysis were sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015.

This abstract was accepted and previously presented at the Thirteenth International Congress of the Society for Melanoma Research 2016. All rights reserved.

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