IN PATIENTS with advanced BRAF V600–mutant melanoma, combining the BRAF inhibitor encorafenib (Braftovi) with the MEK inhibitor binimetinib (Mektovi) improved overall survival compared to vemurafenib (Zelboraf) or encorafenib as monotherapy, with a favorable toxicity profile, according to updated results from the phase III COLUMBUS trial.
Combined BRAF/MEK inhibitor therapy is standard of care in advanced BRAF V600–mutant melanoma, but approved combinations have unique toxicities that may impact the ability to deliver optimal treatment (ie, vemurafenib/cobimetinib [Cotellic] is associated with photosensitivity).
Reinhard Dummer, MD
Jeffrey A. Sosman, MD
These results were originally presented at the 2018 ASCO Annual Meeting by Reinhard Dummer, MD, of University of Zurich Hospital, and colleagues.1 The study was later discussed at Best of ASCO Chicago by Jeffrey A. Sosman, MD, Professor of Hematology and Oncology at Northwestern University Feinberg School of Medicine in Chicago,2 along with the year’s other top selected abstracts in melanoma.
Part 1 of the COLUMBUS trial evaluated encorafenib at 450 mg once daily in combination with binimetinib at 45 mg twice daily (COMBO450), compared to vemurafenib at 960 mg twice daily or encorafenib at 300 mg once a day in patients with advanced BRAF V600–mutant melanoma. Treatment with the drug combination demonstrated a statistically significant improvement in progression-free survival: median progression-free survival was 14.9 months with COMBO450 compared to 7.3 months with vemurafenib monotherapy. At the 2018 ASCO Annual Meeting, the investigators presented a planned analysis of overall survival, a secondary endpoint of the study.
“The best-in-class median progression-free survival of 14.9 months and median overall survival of 33.6 months suggest that COMBO450 is a promising new regimen for the treatment of BRAF-mutant melanoma,” the investigators reported.
“I think the COLUMBUS trial was one of the most important or practice-changing presentations in melanoma [given at ASCO 2018],” said Dr. Sosman.
Improved Survival With COMBO450
THOUGH THE COLUMBUS trial had three arms, the primary comparison was between COMBO450 and vemurafenib. The study included patients with advanced or metastatic BRAF V600–mutant melanoma who were untreated or had shown disease progression on or after first-line immunotherapy. In the adjuvant setting, about a quarter of patients received prior immunotherapy, and in the metastatic setting, less than 10% received any type of immunotherapy. “These numbers were small in terms of affecting outcome,” Dr. Sosman noted.
“The best-in-class median progression-free survival of 14.9 months and median overall survival of 33.6 months suggest that COMBO450 is a promising new regimen for the treatment of BRAF-mutant melanoma.”— Jeffrey A. Sosman, MD
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Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, and prior first-line immunotherapy and were then randomly assigned to COMBO450 (n = 192), encorafenib alone (n = 194), or vemurafenib alone (n = 191). An analysis of overall survival was planned after 232 events in the COMBO450 and vemurafenib arms combined. As of data cutoff, 105, 106, and 127 events contributed to the overall survival analysis in the COMBO450, encorafenib, and vemurafenib arms, respectively.
After a median follow-up of 21.5 months, median overall survival was 33.6 months in patients who received COMBO450, compared with 23.5 months and 16.9 months for patients treated with vemurafenib or encorafenib, respectively. There was also a statistically significant 40% reduced risk of death with COMBO450 vs vemurafenib.
“The median overall survival [with COMBO 450] is 33 months, whereas we know that median overall survival with the other two regimens is more in the neighborhood of 24 months,” said Dr. Sosman. “Now, that could be affected by many things, but at least at this time point, we see that it isn’t affected to any great degree based on the use of subsequent immune approaches, since well under 10% received them. But with time, I think that will be more and more a problem, because anyone in this group will almost certainly get immunotherapy as the standard [before BRAF/MEK inhibitor therapy].”
Updated median progression-free survival was 14.9 months with COMBO450, compared to 9.6 months with encorafenib and 7.3 months with vemurafenib. These data remain consistent with results from COLUMBUS part 1, previously reported in The Lancet Oncology.3
Improved Safety Profile
COMBO450 demonstrated a favorable tolerability profile, with no new safety concerns. Compared to the drug combination, patients who received vemurafenib alone experienced more adverse events, such as elevated photosensitivity, rash, pyrexia, and skin papilloma.
“The COMBO 450 regimen was actually quite impressive….In this group, the benefit was across the board.”— Jeffrey A. Sosman, MD
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“The COMBO 450 regimen was actually quite impressive,” said Dr. Sosman. “Outside of the ‘MEK effect’ [ie, transient retinopathy], most adverse events were decreased compared to the single agent.”
Additionally, he noted that COMBO450 contained 450 mg of encorafenib, compared to a 300-mg dose given to patients who received the single agent. “So, actually, the MEK inhibitor binimetinib decreased the toxicity of the BRAF inhibitor,” he said. “In this group, the benefit was across the board.” ■
DISCLOSURE: Dr. Sosman is a consultant/advisor (receiving honoraria) with Genentech, Incyte, and Bristol-Myers Squibb.
1. Dummer R, Ascierto PA, Gogas H, et al: Overall survival in COLUMBUS: A phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in BRAF-mutant melanoma. 2018 ASCO Annual Meeting. Abstract 9504. Presented June 4, 2018.
2. Sosman JA: Melanoma/skin cancers. 2018 Best of ASCO Chicago. Presented August 11, 2018.
3. 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 19:P603-P615, 2018.