Updated results from the phase III COLUMBUS trial show continued prolonged progression-free and overall survival with the combination of encorafenib and binimetinib compared with BRAF inhibition alone in patients with advanced/metastatic BRAF V600-mutant melanoma.
Helen J. Gogas, MD, PhD
Updated results from the phase III COLUMBUS trial show continued prolonged progression-free and overall survival (OS) with the combination of encorafenib (Braftovi) and binimetinib (Mektovi) compared with BRAF inhibition alone in patients with advanced/metastatic BRAF V600-mutant melanoma.
In an updated analysis of COLUMBUS, which was presented at the 2019 ASCO Annual Meeting, patients randomized to the combination of encorafenib/binimetinib had a median OS of 33.6 months (95% CI, 24.4-39.2) compared with 23.5 months for encorafenib (95% CI, 19.6-33.6) and 16.9 months for vemurafenib (95% CI, 14.0-24.5) at a median follow-up of 48.8 months. Compared with vemurafenib, the combination of encorafenib and binimetinib led to a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.48-0.79), said study co-author Helen J. Gogas, MD, PhD, professor of medical oncology, National and Kapodistrian University of Athens, Greece, in a presentation during the meeting.
Moreover, the updated findings showed that the median progression-free survival (PFS) by blinded central review was 14.9 months (95% CI, 11.0-20.2) with encorafenib/binimetinib, 9.6 months (95% CI, 7.4-14.8) with encorafenib alone, and 7.3 months (95% CI, 5.6-7.9) with single-agent vemurafenib. Median PFS was significantly superior for the combination of encorafenib and binimetinib compared with vemurafenib (HR, 0.51; 95% CI, 0.39-0.67).
The FDA approved the combination of encorafenib and binimetinib for the treatment of patients with metastatic or otherwise unresectable BRAF V600E/K-mutant melanoma in June 2018, marking the third BRAF/MEK inhibitor combination therapy approved for advanced melanoma. The approval was based on earlier findings from the randomized, open-label, three-armed, two-part, phase III COLUMBUS trial.
Encorafenib is a highly selective ATP-competitive BRAF inhibitor with increased potency against BRAF V600 mutations, which had been demonstrated in preclinical models. Binimetinib is a selective allosteric, ATP-uncompetitive MEK 1/2 inhibitor.
In part 1 of the international COLUMBUS study, 577 patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma were randomized 1:1:1 to receive encorafenib 450 mg twice daily in combination with binimetinib 45 mg twice daily (n = 192), encorafenib alone at 300 mg daily (n = 194), or vemurafenib 960 mg twice daily (n = 191).
Additional updated results showed that the overall response rate confirmed by blinded independent central review was 64% in the combination arm, 52% in the encorafenib arm, and 41% in the vemurafenib arm. The rate of complete response was 13%, 7%, and 8%, respectively. Disease control rates were 92%, 84%, and 81% in the encorafenib/binimetinib, encorafenib monotherapy, and vemurafenib arms, respectively. Median duration of response by central review in the 3 arms was 18.6 months, 15.5 months, and 12.3 months, respectively.
A landmark analysis showed higher rates of OS and PFS in the encorafenib/binimetinib arm at 1, 2, 3, and 4 years compared with vemurafenib. Moreover, subgroup analyses showed point estimates in favor of encorafenib/binimetinib for all subgroups examined, including patients with elevated lactate dehydrogenase, patients with V600E and V600K mutations, and in patients with 1 to 4 organs involved at baseline.
Median exposure to study treatment was 51, 31, and 26 weeks for encorafenib/binimetinib, encorafenib, and vemurafenib, respectively. Grade 3/4 adverse events (AEs) were experienced by 68%, 68%, and 66% of patients in the 3 arms, respectively.
“There were no further safety concerns,” said Gogas. “The incidence of AEs with BRAF/MEK inhibitors did not increase much with an additional 12 months of follow-up.”
Treatment discontinuation due to AEs was needed in 16% of the combination arm, 15% of the encorafenib arm, and 17% of the vemurafenib arm, and dose reductions or interruptions were required in 55%, 71%, and 62%, respectively. Treatment is ongoing in 19% of patients assigned to encorafenib plus binimetinib, 10% of those receiving encorafenib, and 5% of patients in the vemurafenib group.
In the modern era of melanoma treatment, long-term survival is fairly common, said discussant Douglas B. Johnson, MD, clinical director, Melanoma, Vanderbilt-Ingram Cancer Center.
“We see with additional follow-up—really no surprise—that the combination of BRAF and MEK inhibitors is still associated with improved OS compared with vemurafenib,” he said. The OS curve plateaus with BRAF/MEK inhibitor combination therapy, “suggesting that we do see durable responses in a subset of these patients,” he said. “That plateau is at about 40%.”
The PFS curve in the combination therapy arm plateaus at about 25%; the discrepancy between the PFS and OS curves may reflect isolated progression treated with radiation or surgery in some patients. However, the main driver may be receipt of subsequent immunotherapy in patients whose disease progresses.
“The big elephant in the room [is]: can we stop targeted therapy on these patients at some point, and if so, who are the patients?” Johnson asked. “Maybe we can use circulating DNA or other metrics to help us but at this point, I think we all feel very uncomfortable with stopping therapy, even in patients with complete responses. It’s also important to note that about 20% of the combination-treated patients, even after a median of 4 years of follow-up, were still actually receiving therapy.”
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 BRAFV600—mutant melanoma. J Clin Oncol. 2019;37(suppl; abstr 9512). meetinglibrary.asco.org/record/173422/poster.