Abstract 3925
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.