Encorafenib/Binimetinib Combo Continues to Show Survival Benefits in BRAF V600-Mutant Melanoma

Helen J. Gogas, MD, PhD

The combination of encorafenib (Braftovi) and binimetinib (Mektovi) demonstrated continuing benefit in overall survival (OS) and progression-free survival (PFS) for patients with BRAF V600—mutant melanoma, according to an updated analysis of the COLUMBUS (NCT01909453) trial during a poster presentation at the 2020 American Society of Clinical Oncology Virtual Scientific Program.¹

The 2-part, phase 3 trial compared the combination of encorafenib and binimetinib versus encorafenib or vemurafenib (Zelboraf) in 577 patients enrolled across 28 countries and from 162 hospitals between December 2013 and November 2015.

In part 1, patients with unresectable or locally advanced or metastatic melanoma who were treatment naïve or progressed after prior first-line immunotherapy with a BRAF V600 mutation were equally randomized into 3 arms: encorafenib (450 mg once daily) and binimetinib (45 mg twice a day); vemurafenib (960 mg twice a day); or encorafenib (300 mg once daily).2

Previous findings were published in the Lancet Oncology. The median follow up was 16.6 months (95% CI, 14.8-16.9) and median PFS for the combination was 14.9 months (95% CI, 11.0-18.5) compared with 7.3 months (95% CI, 5.6-8.2) for vemurafenib (HR, 0.54; 95% CI, 0.41-0.71; 2-sided P <.0001).2 A later analysis reviewed OS data and showed that after a median follow-up of 36.8 months (95% CI, 35.9-37.5), median OS favored the combination (33.6 months; 95% CI, 24.4-39.2) over vemurafenib (16.9 months; HR, 0.61; 95% CI, 0.47-0.79; 2-sided P <.0001).³

Baseline characteristics were well balanced between the treatment groups with a median age of 56 years, about 60% were men, and nearly 90% of patients had the BRAF V600 mutation.

The current 4-year follow-up of COLUMBUS provided landmark analyses of PFS and OS, in addition to other prognostic subgroups, according to lead author Helen J. Gogas, MD, PhD, associate professor of medical oncology, First Department of Medicine, University of Athens, Greece.¹

At the data cut off in November 2019, investigators reported that OS events occurred in 65%, 59%, and 75% for the combination, encorafenib, and vemurafenib arms, respectively. Also, PFS events occurred in 62%, 60%, and 62% of patients in these groups, respectively.

Median follow-up for OS across all arms was 60.6 months. For the combination arm, the median OS was 33.6 months (95% CI, 24.4-39.2), for the encorafenib arm, median OS was 23.5 months (95% CI, 19.6-33.6), and for the vemurafenib arm, the OS was 16.9 months (95% CI, 14.0-24.5). Patients in the combination group had a decreased risk of death by 39% compared with vemurafenib (HR, 0.61; 95% CI, 0.48-0.78).

Four-year OS rates favored the combination arm at 39% (95% CI, 32%-46%) compared with the encorafenib arm (37%; 95% CI, 30%-44%), and the vemurafenib arm (26%; 95% CI, 19%-32%). Similarly, PFS rates favored the combination arm at 26% (95% CI, 19%-33%), compared with encorafenib at 22% (95% CI, 15%-29%) and vemurafenib at 12% (95% CI, 6%-20%).

Blinded independent central review confirmed the overall response rate to be 64% of patients in the combination arm, 52% of patients in the encorafenib arm, and 41% of patients in the vemurafenib arm.

In the poster, the investigators wrote that the subgroup analyses for the comparison arm compared with the vemurafenib arm showed point estimates in favor of the combination.

The updated safety findings demonstrated no new concerns, but in the combination arm, the most common adverse effects were associated with gastrointestinal toxicities. In the combination arm, 44% of patients experienced all-grade nausea compared with 39% of patients in the encorafenib arm and 35% of patients in the vemurafenib arm. More grade 3/4 nausea was experienced by the encorafenib arm (4%) compared with the combination arm (2%) and vemurafenib arm (2%).

Thirty-nine percent of patients in the combination arm experienced all-grade diarrhea, compared with 15% of patients in the encorafenib arm, and 34% in the vemurafenib arm. Grade 3/4 diarrhea was reported in 3% of patients in the combination arm, 2% in the encorafenib arm, and 3% in the vemurafenib arm.

The extended follow-up on the COLUMBUS trial continues to show improved OS and PFS for the combination of encorafenib and binimetinib, and these findings represent new benchmarks for the treatment of BRAF V600—mutated melanoma, the investigators concluded.

References

1. Gogas HJ, Ascierto PA, Flaherty KT, et al. Update on overall survival in COLUMBUS: a randomized phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs Vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant Melanoma. J Clin Oncol. 2020;38:(suppl 15):10012. doi:10.1200/JCO.2020.38.15_suppl.10012
2. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603&#8208;615. doi:10.1016/S1470-2045(18)30142-6
3. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial [published correction appears in Lancet Oncol. 2018;19(10):e509]. Lancet Oncol. 2018;19(10):1315&#8208;1327. doi:10.1016/S1470-2045(18)30497-2

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