Pooled analysis of factors to predict durable clinical outcomes with combination dabrafenib (D) and trametinib (T) across registration trials

Date

09 Oct 2016

Session

Poster display

Presenters

Michael Davies

Citation

Annals of Oncology (2016) 27 (6): 379-400. 10.1093/annonc/mdw379

Authors

M. Davies1, J.J. Grob2, G.V. Long3, K. Flaherty4, P. Nathan5, A. Ribas6, D. Schadendorf7, B. Mookerjee8, J.J. Legos8, S. Lane8, C. Robert9

Author affiliations

  • 1 Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 2 Service De Dermatologie Et Cancérologie Cutanée, Aix Marseille University, 13885 Marseille CEDEX 05 - Marseille/FR
  • 3 Medical Oncology, Melanoma Institute of Australia and The University of Sydney, 2060 - Sydney/AU
  • 4 Melanoma, Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, 02114 - Boston/US
  • 5 Department Of Medical Oncology, Mount Vernon Cancer Centre, HA6 2RN - Northwood/GB
  • 6 Medicine, Hematology & Oncology, UCLA and the Jonsson Comprehensive Cancer Center, 90095 - Los Angeles/US
  • 7 Department Of Dermatology, University Hospital of Essen, 45147 - Essen/DE
  • 8 Global Oncology, Novartis Pharmaceuticals Corporation, 07936 - East Hanover/US
  • 9 Dermatology, Gustave Roussy Comprehensive Cancer Center, 94805 - Villejuif/FR
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Background

Phase 2 (BRF113220 [NCT01072175]) and phase 3 (COMBI-d [NCT01584648], COMBI-v [NCT01597908]) trials provide a large dataset for evaluating D + T in patients (pts) with BRAF V600E/K–mutant melanoma. Pooled analyses showed that D + T efficacy across studies (N = 617) is consistent with that in individual trials (response, 67%; median progression-free survival [PFS], 11.1 mo [95% CI, 9.7-12.9]; median overall survival [OS], 25.6 mo [95% CI, 23.1-34.3]) and identified factors associated with these outcomes. Here we describe additional analyses to determine factors that predict durable outcomes (≥ 24 mo) in the pooled D + T population.

Methods

The pooled population included randomized pts treated with D 150 mg twice daily + T 2 mg once daily in BRF113220 (Part C; cutoff Jan 2015), COMBI-d (cutoff Jan 2015), and COMBI-v (cutoff Mar 2015). Baseline factors (Table) were analyzed by regression tree analyses to identify predictors of D + T treatment (Tx), PFS, or OS lasting ≥ 24 mo.

Results

Of 617 pts treated with D + T in BRF113220 (n = 54), COMBI-d (n = 211), and COMBI-v (n = 352), 165 (27%) received it for ≥ 24 mo. Long-term PFS (n = 472) and OS (n = 456) analyses excluded pts censored prior to 24 mo. A total of 85 pts (18%) had PFS ≥ 24 mo and 186 (41%) had OS ≥ 24 mo (Table). Regression tree analyses identified baseline lactate dehydrogenase (LDH) as the most predictive factor for durable benefit. Pts with normal vs elevated LDH had improved PFS (median: 12.1 vs 5.5 mo; 2-y rate: 26% vs 5%) and OS (median: 31.6 vs 10.8 mo; 2-y rate: 56% vs 15%). At data cutoff, 172 pts (28%) remained on D + T, including 140 (81%) with Tx ≥ 24 mo and 69 (40%) with PFS ≥ 24 mo.

Characteristic PFS 

Conclusions

Long-term Tx and durable PFS and OS were achieved in a subset of pts with BRAF V600–mutant melanoma receiving D + T. Baseline LDH was the strongest predictor for PFS and OS ≥ 24 months. Additional follow-up/analyses are needed to further define the durability of PFS and OS achievable with D + T.

Clinical trial identification

NCT01597908; first received by CT.gov on May 10, 2012 and NCT01584648; first received by CT.gov on April 23, 2012 and NCT01072175; first received by CT.gov on February 12, 2010

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

M. Davies: Research funding: Genentech/Roche, GlaxoSmithKline, AstraZeneca, Sanofi-Aventis, Merck Membership on board of directors or advisory committees: Novartis, Genentech/Roche, GlaxoSmithKline, Sanofi-Aventis, Vaccinex. J.J. Grob: Consultancy: Novartis, GlaxoSmithKline, Roche, Merck, Bristol-Myers Squibb, Amgen. G.V. Long: Consultancy: Roche, Bristol-Myers Squibb, Merck, Amgen, Novartis Honoraria: Bristol-Myers Squibb, Merck, Novartis. 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 committees: Novartis. A. Ribas: Consultancy: Novartis, Merck, Pfizer, Roche Equity Ownership: Kite Pharma Honoraria: Novartis. D. Schadendorf: Consultancy, Honoraria, Speakers Bureau: Amgen, Novartis, Roche, BMS, MSD/Merck, Pfizer Research Funding: BMS, MSD/Merck Membership on board of directors: Amgen, Novartis, Roche, BMS, MSD/Merck, Pfizer, Array. B. Mookerjee: Employment: Novartis Equity Ownership: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. J.J. Legos: Employment: Novartis Own company stock: Novartis. S. Lane: Employment: Novartis. C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria: Novartis, Amgen, BMS, Merck, Roche.

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