The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the combination of the BRAF inhibitor encorafenib (Braftovi) and the MEK inhibitor binimetinib (Mektovi) for the treatment of adult patients with
V600–mutant unresectable or metastatic melanoma, according to Array BioPharma, the company developing the regimen.
The CHMP recommendation is based on the phase III COLUMBUS trial, in which at a median follow-up of 36.8 months, combining encorafenib at 450 mg daily and binimetinib at 45 mg twice daily (COMBO450) reduced the risk of death by 39% versus vemurafenib (Zelboraf) monotherapy. The median overall survival (OS) was 33.6 months (95% CI, 24.4-39.2) versus 16.9 months (95% CI, 14.0-24.5), respectively (HR, 0.61; 95% CI 0.47-0.79;
The 2-year OS rates were 58% versus 43% and the 3-year OS rates were 47% versus 32% with COMBO450 versus single-agent vemurafenib, respectively. The OS benefit with the combination was maintained across all subgroups including those defined by sex, age, BRAF status, LDH level, tumor stage, and number of organs involved at baseline.
The European Commission will now review the application for its final decision. If approved, the combination would be available for use in the 28-member EU, along with Norway, Liechtenstein, and Iceland.
“Following the recent US FDA approval of Braftovi plus Mektovi for advanced BRAF
-mutant melanoma, we are pleased to move one step closer to European approval," Ron Squarer, chief executive officer, Array BioPharma, said in a statement. "We are proud that the combination of Braftovi and Mektovi represents a new standard of care for BRAF
-mutant melanoma patients in critical need of additional treatment options.”
The COLUMBUS findings also showed a trend toward an OS benefit with COMBO450 versus single-agent encorafenib at 300 mg daily (ENCO300). The 33.6-month median OS with COMBO450 compared favorably with the 23.5 month (95% CI, 19.6-33.6) median OS with ENCO300. The HR ratio of 0.81 (95% CI, 0.61-1.06) for the comparison was not statistically significant at the time of the data presentation (P
Comparing the 2 BRAF inhibitors as single agents, there was statistically significant OS benefit with ENCO300 versus single-agent vemurafenib. The median OS was 23.5 months versus 16.9 months (95% CI, 14.0-24.5) in the 2 arms, respectively (HR, 0.76; 95% CI, 0.58-0.98; P
The full COLUMBUS trial included 921 patients with BRAF
V600-mutant melanoma, with 577 in part 1 and 344 in part 2. In part 1, patients were randomized in a 1:1:1 ratio to receive COMBO450 (n = 192), ENCO300 (n = 194), or vemurafenib at 960 mg twice daily (n = 191). In part 2, patients were randomized 3:1 to encorafenib at 300 mg daily plus binimetinib at 45 mg twice daily (n = 258) or ENCO300 (n = 86).
The OS data above are from the latest study update for the 577-patient part 1 of the trial that were reported at the 2018 ASCO Annual Meeting. The part 1 ASCO update also showed that at a median follow-up of 32.1 months, the median progression-free survival (PFS) was 14.9 months (95% CI, 11.0-20.2) with COMBO450 versus 7.3 months (95% CI, 5.6-7.9) with single-agent vemurafenib (HR, 0.51; 95% CI, 0.39-0.67; P
<.0001). The 2-year PFS rates were 37% versus 20% and the 3-year PFS rates were 28% versus 13% with COMBO450 versus single-agent vemurafenib, respectively.
The COMBO450 median PFS also compared favorably with the 9.6-month (95% CI, 7.4-14.8) median PFS with ENCO300 (HR, 0.77; 95% CI, 0.59-1.00; P
= .0498). The median PFS with ENCO300 was improved over the median PFS with vemurafenib monotherapy (HR, 0.68; 95% CI, 0.52-0.88; P
The overall response rate (ORR) per central review was 64% (complete response [CR], 11%; partial response [PR], 52%) in the COMBO450 arm, compared with 52% (CR, 7%; PR, 44%) in the ENCO300 arm, and 41% (CR, 8%; PR, 32%) in the vemurafenib arm. The median duration of response was 18.6 months (range, 12.7-24.1), 15.2 months (range, 11.1-27.6), and 12.3 months (range, 6.9-14.5), in the 3 arms, respectively. The disease control rates were 92%, 84%, and 81%, respectively.
Patient characteristics for part 1 of the trial were well balanced across treatment arms. The median age of patients ranged from 54 to 57 years and the majority had an ECOG performance status of 0 (~72%). LDH levels were greater than or equal to the upper limit of normal for about one-third of patients, and about two-thirds of patients had IVM1c tumor stage at study entry. One percent of patients in each arm had prior ipilimumab (Yervoy) in the adjuvant or neoadjuvant setting. In the advanced/metastatic settings 3%, 5%, and 3% of patients had received ipilimumab in the COMBO450, ENCO300, and vemurafenib arms, respectively.
At the time of the data cutoff for the ASCO presentation, 78% of patients in the COMBO450 arm had discontinued treatment, along with 87% of patients in the ENCO300 arm and 91% of patients in the vemurafenib arm. The primary reason for discontinuing treatment was progressive disease at 52%, 52%, and 57%, in the 3 arms, respectively. Adverse events (AEs) were the secondary reason for discontinuation, at 10%, 13%, and 13%, respectively.
Systemic therapies administered following treatment administration included anti–PD-1/PD-L1 (20% in COMBO450 arm, 21% in ENCO300 arm, and 25% in vemurafenib arm); anti–CTLA-4 (17%, 16%, 19%); anti–CTLA-4 plus anti–PD-1/PD-L1 (3%, 2%, 2%); BRAF inhibitor plus MEK inhibitor (5%, 14%, 20%); BRAF inhibitor alone (6%, 8%, 13%), and chemotherapy (7%, 12%, 12%).
The median duration of treatment exposure was 51 weeks with COMBO450, compared with 31 weeks with ENCO300 and 26 weeks with vemurafenib monotherapy. Grade 3/4 AEs occurred in 64%, 67%, and 66% of the 3 arms, respectively. On-study deaths or death within 30 days of stopping study treatment occurred in 12%, 8%, and 11% of the 3 arms, respectively.
Dummer R, Ascierto PA, Gogas H, et al. Overall survival in COLUMBUS: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco in BRAF-mutant melanoma. J Clin Oncol. 2018;36 (suppl; abstr 9504).