1137P - Health-related quality-of-life (HRQOL) impact of dabrafenib (D) and trametinib (T) vs BRAF inhibitor (BRAFi) monotherapy by lactate dehydrogenase (...

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Melanoma and other Skin Tumours
Presenter Jean Jacques Grob
Citation Annals of Oncology (2016) 27 (6): 379-400. 10.1093/annonc/mdw379
Authors J.J. Grob1, C. Robert2, G.V. Long3, D. Stroyakovskiy4, E. Levchenko5, V. Chiarion-Sileni6, K. Flaherty7, P. Nathan8, A. Ribas9, M. Davies10, J. Zhang11, L. Chen11, B. Mookerjee12, S. Redhu11, D. Schadendorf13
  • 1Service De Dermatologie Et Cancérologie Cutanée, Aix Marseille University, 13885 Marseille CEDEX 05 - Marseille/FR
  • 2Dermatology, Gustave Roussy Comprehensive Cancer Center, Villejuif/FR
  • 3Medical Oncology, Melanoma Institute of Australia and The University of Sydney, 2006 - Sydney/AU
  • 4Chemotherapy Department, Moscow City Oncology Hospital No. 62, Moscow/RU
  • 5Oncology, N. N. Petrov Research Institute of Oncology, St-Petersburg/RU
  • 6Melanoma And Skin Cancer Unit, Veneto Oncology Institute, Padova/IT
  • 7Melanoma, Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, 02114 - Boston/US
  • 8Department Of Medical Oncology, Mount Vernon Cancer Centre, HA6 2RN - Northwood/GB
  • 9Medicine, Hematology & Oncology, UCLA Jonsson Comprehensive Cancer Center, 90095 - Los Angeles/US
  • 10Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 11Global Oncology, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 12Global Oncology, Novartis Pharmaceuticals Corporation, 07936 - East Hanover/US
  • 13Department Of Dermatology, University Hospital of Essen, 45147 - Essen/DE

Abstract

Background

D + T improved outcomes and HRQOL in pts with BRAF V600–mutant melanoma vs BRAFi alone in COMBI-d (NCT01584648) and COMBI-v (NCT01597908). Although pooled analysis of melanoma clinical/prognostic characteristics across D + T registration trials identified baseline (BL) LDH as the most influential covariate on outcomes, D + T improved response, PFS, and OS vs BRAFi alone in both normal and elevated-LDH groups. This retrospective analysis of COMBI-d and COMBI-v patient-reported outcomes (PROs) assessed whether HRQOL was consistently improved across LDH groups.

Methods

COMBI-d and COMBI-v are phase 3, randomized, double-blind studies of first-line D + T vs D + placebo (Pbo) or vemurafenib (V), respectively, in pts with unresectable stage IIIC or IV BRAF V600–mutant melanoma. HRQOL was evaluated in COMBI-d and COMBI-v by EORTC QLQ-C30 (global QOL, functional, and symptom domains) at BL, during treatment (Tx), and at disease progression (PD). PROs were analyzed by LDH (≤ and > ULN). ANCOVA adjusted for BL score using mixed-model repeated measures was carried out.

Results

Across COMBI-d (D + T, n = 211 [77 with LDH > ULN]; D + Pbo, n = 212 [71 with LDH > ULN]) and COMBI-v (D + T, n = 352 [118 with LDH > ULN]; V, n = 352 [114 with LDH > ULN]), EORTC QLQ-C30 completion rates were > 85% through wk 40 and ≥ 70% at PD. Clinically meaningful differences in mean scores between arms favoring D + T vs BRAFi alone were seen for most HRQOL domains for both LDH subgroups across time points, including at PD (Table). Results for D + T vs BRAFi alone by LDH in COMBI-d and COMBI-v for all EORTC QLQ-C3cl be presented.

EORTC QLQ-C30 Domain Change From Baseline at PD
COMBI-d COMBI-v
LDH ≤ ULN LDH > ULN LDH ≤ ULN LDH > ULN
Global health + +C +C* +C*
Functioning
Cognitive + + +C*
Emotional +C +* +C
Physical + + +* +C*
Role + +C +C* +C*
Social +C +C* +C*
Symptoms
Appetite loss +C* +C* +C*
Constipation +
Diarrhea + +C* +C*
Dyspnea + + +
Fatigue + +C + +C*
Insomnia + + +C* +C*
Nausea & vomiting Neither favored + +C*
Pain +C* +C* +C* +C*
Financial difficulties + +

+ favors D + T; – favors BRAFi alone; C clinically meaningful difference (≥ 5 points); * statistically significant (P 

Conclusions

D + T consistently improved HRQOL vs BRAFi alone for most EORTC QLQ-C30 domains, regardless of LDH, further supporting continued use of D + T in BRAF-mutant melanoma across LDH subgroups. HRQOL benefit with D + T may be greater in pts with LDH > ULN.

Clinical trial identification

NCT01597908; first received by clinicaltrials.gov on May 10, 2012 and NCT01584648; first received by clinicaltrials.gov on April 23, 2012.

Legal entity responsible for the study

Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015.

Funding

Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015.

Disclosure

J.J. Grob: Consultancy: Novartis, GSK, Roche, Merck, BMS, Amgen. C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria: Novartis, Amgen, BMS, Merck, Roche. G.V. Long: Consultancy: Roche, BMS, Merck, Amgen, Novartis Honoraria: BMS, Merck, Novartis. V. Chiarion-Sileni: Consultancy: Novartis, BMS Speakers Bureau: GSK, Novartis Membership on Board of Directors or Advisory Committee: GSK, Novartis, Roche, BMS, MSD. K. Flaherty: Consultancy: Novartis, Roche, Array, Lilly, Takeda Research Funding: Novartis. P. Nathan: Consultancy: Novartis Speakers Bureau: Novartis Membership on Board of Directors or Advisory Committee: Novartis. A. Ribas: Consultancy: Novartis, Merck, Pfizer, Roche Equity Ownership: Kite Pharma Honoraria: Novartis. M. Davies: Research Funding: Genentech/Roche, GSK, AstraZeneca, Sanofi-Aventis, Merck Membership on Board of Directors or Advisory Committee: Novartis, Genentech/Roche, GSK, Sanofi-Aventis, Vaccinex. J. Zhang, L. Chen: Employment: Novartis Equity Ownership: Novartis. B. Mookerjee: Employment: Novartis Equity Ownership: Novartis, GSK, Incyte, AstraZeneca. S. Redhu: Employment: Novartis. D. Schadendorf: Consultancy/Honoraria/Speakers Bureau/Board of Directors: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer Research Funding: BMS, MSD Merck Board of Directors: Array. All other authors have declared no conflicts of interest.