Encorafenib/Binimetinib Delivers Prolonged Survival in BRAF V600–Mutant Melanoma

Reinhard Dummer, MD

The combination of encorafenib (Braftovi) and binimetinib (Mektovi) led to sustained improvements in progression-free survival (PFS) and overall survival (OS), without new safety signals in patients with BRAF V600–mutant melanoma, according to 5-year follow-up data from the phase 3 COLUMBUS trial (NCT01909453).

Specifically, the regimen outperformed both single-agent vemurafenib (Zelboraf) and single-agent encorafenib in inducing long-term OS and PFS benefit. The PFS rates with the combination therapy was 23% in the all-randomized population (n = 192) and 31% in a cohort of patients with normal lactate dehydrogenase (LDH) levels (n = 137). The OS rates in these populations were 35% and 45%, respectively.

At a follow-up of 40.8 months, the median PFS in patients receiving encorafenib plus binimetinib was 14.9 months (95% CI, 11.0-20.2) vs 7.3 months with vemurafenib (95% CI, 5.6-7.9). The HR was 0.51 (95% CI, 0.40-0.67). The HR was 0.79 (95% CI, 0.611.02) vs single-agent encorafenib which had a median PFS of 9.6 months (95% CI, 7.4-14.8). The HR for encorafenib vs vemurafenib was 0.68 (95% CI, 0.52-0.88).

Moreover, at a median follow-up of 70.4 months, the median OS was 33.6 months (95% CI, 24.4-39.2) with the MEK/BRAF inhibition therapy, 16.9 months with vemurafenib (95% CI, 14.0-24.5), and 23.5 months with single-agent encorafenib (95% CI, 19.6-33.6). In comparing the median OS between encorafenib plus binimetinib vs single-agent encorafenib, the HR was 0.93 (95 CI, 0.72-1.19), and in comparing encorafenib plus binimetinib against vemurafenib, the HR was 0.64 (95% CI, 0.50-0.81).

“This 5-year update of COLUMBUS demonstrates the long-term benefits of encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600–mutant melanoma,” wrote Reinhard Dummer, MD, a professor of dermatology with the University of Hospital Zürich, and coinvestigators.

The COLUMBUS study enrolled patients with locally advanced unresectable or metastatic BRAF V600–mutant melanoma who were previously untreated or whose disease had progressed following frontline immunotherapy. These patients were randomly assigned 1:1:1 to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily.

Overall, the 5-year PFS rates were highest with encorafenib plus binimetinib (23%) followed by single-agent encorafenib (19%) and vemurafenib (10%). A subset of patients with normal LDH, the 5-year PFS rates with MEK/BRAK inhibitor combination was 31%, and among those with low tumor burden (normal LDH levels and less than 3 organs affected by tumors; n = 55) the 5-year PFS rate was 39%.

The OS rates were highest in the combination regimen arm (35%) and the encorafenib arm (35%) vs 21% in the vemurafenib arm. For patients with normal LDH, encorafenib plus binimetinib elicited a 45% OS rate at 5 years; for those with low tumor burden, the OS rate was 48%.

Investigators found encorafenib plus binimetinib was superior to vemurafenib in prolonging OS; however, the same did not extend to single-agent encorafenib. In combination with binimetinib and as a single agent, encorafenib performed similarly in terms of OS extension. The exception was for patients with 3 organs affected at baseline: these patients experienced grater OS benefit with the combined regimen.

“The 5-year OS rate was 35% for both the encorafenib plus binimetinib and encorafenib monotherapy arms; however, combination treatment demonstrated significantly longer PFS (median > 5 months) and numerically longer OS (median > 10 months),” study authors wrote. “Compared with encorafenib monotherapy, the encorafenib plus binimetinib arm had numerically greater ORR [overall response rate], disease control rate, and duration of response.”

A central review indicated that 92% of patients treated in the experimental cohort achieved disease control. Moreover, the median duration of response among survivors was 18.6 months (95% CI, 12.7-27.6). Fourteen percent of patients in the combination arm achieved a complete response. In comparison, 8% of patients in the vemurafenib arm and encorafenib arm achieved completer responses.

In addition, a lower percentage of patients receiving encorafenib plus binimetinib received subsequent therapy. Ultimately, 50% of these patients went on to receive further systemic treatments compared with 69% of the vemurafenib arm, and 62% of the encorafenib arm.

The 5-year safety data were also consistent with previous reports. In the combination arm, grade 3/4 adverse events (AEs) occurred in 70% of patients, and AEs led to dose adjustments in 56% of patients. The most common AEs included gastrointestinal disorders (17%), eye disorders (12%), pyrexia (6%), decreased ejection fraction (5%), and increased gamma-glutamyl transferase (5%).

The AEs leading to treatment discontinuation of the investigational regimen in multiple patients included alanine aminotransferase (n = 5; four were grade 3/4), aspartate aminotransferase (n = 4; two were grade 3/4), blood creatinine level increase (n = 2; one was grade 3/4); headache (n = 4; two were grade 3/4); rash (n = 2; both were grade 3/4). Further, 3 patients discontinued because of central nervous system metastases. Throughout the study, 25 patients (13%) died; study authors stated that most deaths were the result of underlying disease.

The median time for patients to experience AEs of interest was within 6 months of treatment initiation. However, AEs such as nausea, diarrhea, visual impairment, and increased transaminases were more likely to occur in the first month of treatment.

Ocular toxicities occurred in the combination arm because of MEK inhibition but were described to be mild or moderate. Ultimately, 16% of patients experienced blurred vision, and 7% of patients experienced retinal detachment, subretinal fluid, and macular edema. One patient discontinued treatment because of reduced visual acuity and retinal disorder.

Left ventricular dysfunction, also represented an AE of interest in this study; 7% of patients experienced this AE. The median time to onset was approximately 3.5 months (range, 0-21).

Reference

Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-Year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. J Clin Oncol. Published online July 21, 2022. doi:10.1200/JCO.21.02659