Updated results of the phase III COLUMBUS trial further solidify BRAF/MEK combinations as standard of care for BRAF-mutated advanced melanoma
Updated results of the phase III COLUMBUS trial confirm that a combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib (COMBO450) is associated with a significantly longer progression-free and overall survival than BRAF inhibition with vemurafenib alone in patients with BRAFV600-mutant locally advanced unresectable or metastatic melanoma. The median overall and progression-free survival among patients treated with COMBO450 was twice as long as what was seen with vemurafenib.
Background
Based on improved overall survival (OS) and manageable tolerability relative to BRAF inhibitor monotherapy, the combined use of a BRAF and a MEK inhibitor has become standard of care for patient with BRAFV600-mutated locally advanced or metastatic melanoma. Encorafenib is a highly selective ATP-competitive BRAF inhibitor that was developed with an aim to improve the efficacy and tolerability over other approved BRAF inhibitors. In preclinical studies encorafenib demonstrated an increased potency against BRAFV600 mutations with an extended duration of target inhibition and a shorter serum half-life, which might result in delayed resistance development and improved tolerability. Binimetinib on the other hand is a potent, selective allosteric, ATP-uncompetitive MEK1/2 inhibitor. This agent also has a shorter half-life than other MEK1/2 inhibitors, which in turn might facilitate a faster resolution of toxicity upon dose interruption. The phase III COLUMBUS study compared a combination of encorafenib (450 mg once daily) with binimetinib (45 mg twice daily; COMBO450) with either encorafenib (300 mg once daily, ENCO300) or vemurafenib monotherapy (960 mg twice daily, VEM) in patients with BRAFV600–mutant melanoma. In previous reports of this study the COMBO450 combination was shown to be associated with a doubling in both the median PFS (14.9 vs 7.3 months) and median OS (33.6 vs 16.9 months) compared to VEM monotherapy. During ASCO 2019, results of COLUMBUS with an additional 12 months of follow-up were presented.
Study design
COLUMBUS was a two-part, multicenter, randomized, open-label, phase III study including patients from 162 hospitals in 28 countries. Enrollment occurred between December 2013, and November 2015. In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAFV600‒mutant melanoma who were previously untreated or who progressed after first-line immunotherapy were randomized (1:1:1) to COMBO450 (n=192) VEM (n=191) or ENCO300 (n=194).
The median age of patients in the study was 56 years, and approximately 70% had an ECOG performance status of 0. In about a quarter of patients, the lactate dehydrogenase (LDH) level was higher than the upper limit of normal (ULN). More than 80% of patients in the study were staged IVM1b or 1c at study entry and 45% had 3 or more involved organs. Overall, tumor and patient characteristics were similar across the 3 treatment groups. At the time of the analysis, 81%, 89%, and 93% had discontinued therapy in the COMBO450, ENCO300 and VEM arm, respectively. Discontinuations due to adverse events occurred in 10% of patients in the COMBO450 group, in 12% of ENCO300 treated patients, and in 14% of patients receiving VEM.
Efficacy and safety update
Across arms, the median follow-up for OS was 48.8 months, with a median OS of 33.6 months for COMBO450, 23.5 months with ENCO300, and 16.9 months for VEM. Compared to VEM, COMBO450 decreased the risk of death by 39% (HR 0.61 [95% CI 0.48-0.79]). In a landmark analysis, COMBO450 was shown to be associated with a higher OS rate at years 1 (76% vs 63%), 2 (58% vs 43%), 3 (47% vs 31%), and 4 (39% vs 25%). The OS benefit of COMBO450 over VEM was seen irrespective of sex, age, the type of BRAF mutation, the ECOG performance status, the tumor stage, LDH level and the number of involved organs.
Also with respect to PFS, COMBO450 proved to be superior to ENCO300 and VEM with PFS medians of 14.9, 9.6, and 7.3 months, respectively. Compared to VEM, this translates into a statistically significant 49% reduction in the risk of disease progression or death with COMBO450. In the landmark analysis, the PFS rate was higher with COMBO450 than with VEM at years 1 (56% vs 32%), 2 (37% vs 20%), 3 (29% vs 14%), and 4 (25% vs 12%). A confirmed overall response (ORR) by blinded independent central review was observed in 64% of patients for COMBO450, 52% for ENCO300, and 41% for VEM. The median duration of response by central review was 18.6 months for COMBO450 as compared to 15.5 and 12.3 months for ENCO300 and VEM, respectively.
The median exposure to study treatment was 51 weeks for COMBO450, which is substantially longer than the 31 and 26 weeks with ENCO300 and VEM, respectively. Nevertheless, the rate of grade 3/4 adverse events was comparable in the 3 arms (68%, 68%, 66% with COMBO450, ENCO300, and VEM, respectively). Importantly, the incidence of adverse events (all grades) associated with BRAF/MEK inhibitors did not increase substantially with the 12-months of additional follow up. Overall, the safety results were consistent with the known tolerability profile of COMBO450 without any new safety concerns in this update.
Conclusions
Updated results of COLUMBUS confirm the significantly better OS and PFS with COMBO450 compared to VEM in patients with BRAF-mutant advanced melanoma. Landmark analyses show improved OS and PFS rates for COMBO450 versus VEM at year 1, 2, 3, and 4. As such, these results for COMBO450 represent new benchmarks for the treatment of BRAFV600-mutated melanoma and further solidify the role of combined BRAF/MEK inhibition as standard of care in this setting.
Reference
Liszkay G, Gogas H, Mandalà M, et al. Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600–mutant melanoma. Presented at ASCO 2019, Abstract 9512.
