Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma

Background

Prior comparative analyses of COMBI-v (NCT01597908) at a planned interim cutoff and again after 2 y of follow-up (f/u) showed significantly improved outcomes favoring D + T vs vemurafenib (Vem). Durable benefit and sustained tolerability was also seen in some pts receiving D + T (COMBI-v: 2-y OS, 51%; COMBI-d: 2-y OS, 52%; 3-y OS, 44%). Although these results support use of first-line D + T for BRAF V600–mutant melanoma, continued monitoring of these pts for long-term efficacy (eg, OS) is needed to determine the full impact of this regimen.

Methods

In this phase 3, randomized, double-blind study, pts with histologically confirmed unresectable stage IIIC or IV BRAF V600E/K–mutant melanoma were randomized 1:1 to receive first-line D 150 mg BID + T 2 mg QD or Vem 960 mg BID. Based on the OS benefit with D + T at interim analysis, crossover from Vem to D + T was permitted. The primary endpoint is OS; secondary endpoints are PFS, ORR, DOR, and safety.

Results

From Jun 2012 to Oct 2013, 704 pts were enrolled (D + T, n = 352; Vem, n = 352). This updated analysis (cutoff: Jul 2016) occurred after 411 deaths and 16 mo of additional f/u since the 2-y data cutoff (Robert, et al. ECC 2015). A total of 33 Vem pts (9%) crossed over to D + T. Pts in the D + T arm continued to achieve durable OS (D + T vs Vem: 3-y OS, 45% [95% CI, 39-50] vs 32% [95% CI, 27-37]) and PFS (3-y PFS, 25% [95% CI, 20-30] vs 11% [95% CI, 7-16]), with the greatest OS benefit in pts with baseline LDH ≤ ULN and < 3 organ sites with metastasis (D + T vs Vem: 3-y OS, 70% [95% CI, 62-77] vs 46% [95% CI, 38-54]). For OS, 68 D + T pts (19%) and 47 Vem pts (13%) were censored with f/u ongoing. ORR and DOR remained improved with D + T (D + T vs Vem: ORR, 67% [95% CI, 62-72] vs 53% [95% CI, 48-59]; median DOR, 13.8 mo [95% CI, 11.3-17.6] vs 7.6 mo [95% CI, 7.4-9.3]). D + T safety and tolerability continued to remain acceptable with additional f/u; there were no new toxicities or clinically significant changes in previously reported AEs. Of pts in the D + T arm alive at 3 y, 58% remained on D + T.

Conclusions

This updated 3-y efficacy and safety analysis further supports long-term use of D + T in BRAF V600–mutant melanoma.

Clinical trial identification

NCT01597908; first received by clinicaltrials.gov on May 10, 2012.

Legal entity responsible for the study

Study is/remains sponsored by GlaxoSmithKline, however, as of 2 March 2015, dabrafenib and trametinib became assets of Novartis AG.

Funding

Study is/remains sponsored by GlaxoSmithKline, however, as of 2 March 2015, dabrafenib and trametinib became assets of Novartis AG.

Disclosure

C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria: Novartis, Amgen, BMS, Merck, Roche. J. Schachter: Consultancy: BMS, MSD, Novartis Honoraria: BMS, MSD, Novartis Speakers Bureau: BMS, MSD, Novartis. P. Rutkowski: Honoraria: Novartis, GSK, Roche, MSD, BMS, Amgen Speakers Bureau: Novartis, MSD, BMS Membership on Board of Directors or Advisory Committee: Novartis, GSK, Roche, MSD, BMS. R. Dummer: Research Funding: Novartis, Merck Sharp & Dhome (MSD), BMS, Roche, GSK. Consultancy: Novartis, Merck Sharp & Dhome, BMS, Roche, GSK, Amgen Membership on Board of Directors or Advisory Committee: Novartis, Merck Sharp & Dhome, BMS, Roche, GSK, Amgen. L. Mortier: Consultancy: Roche, GSK, BMS, MSD Honoraria: Roche, GSK, BMS, MSD. V. Chiarion-Sileni: Consultancy: Novartis, BMS Speakers Bureau: GSK, Novartis Membership on Board of Directors or Advisory Committee: GSK, Novartis, Roche, BMS, MSD. I. Krajsová: Membership on Board of Directors or Advisory Committee: BMS, Roche, Novartis, MSD A. Hauschild: Consultancy/Honoraria: Amgen, BMS, MedImmune, MSD/Merck, Nektar Therapeutics, Novartis, Oncosec, Philogen, Provectus, Regeneron, Roche Other: Amgen, BMS, Celgene, Eisai, GSK, Merck Serono, MSD/Merck, Novartis, Roche (trial grants). B. Mookerjee: Employment: Novartis Equity Ownership: Novartis, GSK, Incyte, AstraZeneca. J.J. Legos: Employment: Novartis Pharmaceuticals Corporation Other: Own company stock. Y. Zhang, S. Lane: Employment: Novartis. D. Schadendorf: Consultancy/Honoraria/Speakers Bureau: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer Research Funding: BMS, MSD Merck Membership on Board of Directors or Advisory Committee: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer, Array. All other authors have declared no conflicts of interest.