William H. Sharfman, MD
IN JULY 2018, the U.S. Food and Drug Administration (FDA) approved the combination of the oral BRAF inhibitor encorafenib (Braftovi) and the oral MEK inhibitor binimetinib (Mektovi) for BRAF V600E– or V600K– positive metastatic melanoma. The FDA approval was based on the results of the COLUMBUS trial, which were presented at the 2018 ASCO Annual Meeting, published in The Lancet Oncology,1 and reviewed in this issue of The ASCO Post. This was a large phase III trial comparing encorafenib/binimetinib with vemurafenib (Zelboraf) or encorafenib. The authors concluded that the combination was “a new benchmark against which new BRAF-MEK inhibitor therapies for BRAF-mutant melanoma can be measured.” They suggested it might be more efficacious and less toxic than previously approved combinations.
This presents the practicing oncologist with a somewhat unique dilemma. There are already two BRAF and MEK inhibitor combinations approved by the FDA for the treatment of metastatic melanoma: dabrafenib (Tafinlar)/trametinib (Mekinist)2 and vemurafenib/cobimetinib (Cotellic).3 (Dabrafenib/trametinib is also approved as adjuvant therapy for patients with stage III disease, whereas vemurafenib/cobimetinib and encorafenib/binimetinib are not.4)
Should we be switching to this new encorafenib/binimetinib combination for newly diagnosed patients with BRAF V600E– or V600K–mutant metastatic melanoma without a direct comparison to the previously established standard combinations of dabrafenib/trametinib and vemurafenib/cobimetinib? Most of us have accepted that these latter two combinations have similar efficacy (although they have never been compared head to head) with different side-effect profiles, which we have become accustomed to managing based on many years of clinical experience.
Closer Look at COLUMBUS Trial
THE COLUMBUS trial was a two-part trial. In part one, patients with BRAF V600E– or V600K–mutant metastatic melanoma were randomly assigned 1:1:1 to receive single-agent vemurafenib vs single-agent encorafenib vs the combination of encorafenib/binimetinib. Part two randomly assigned patients between encorafenib/binimetinib versus encorafenib, with results to be reported at a later date.
In part one of the COLUMBUS trial, compared with vemurafenib, encorafenib was associated with a better overall response rate (52% vs 41%), median progression-free survival (9.6 vs 7.3 months), and median overall survival (23.5 vs 16.9 months). In regard to toxicity, the overall rate of adverse events, the rate of grade 3 and 4 adverse events, and the rate of adverse events leading to treatment discontinuation were similar with single-agent encorafenib vs vemurafenib. With encorafenib, there were fewer of the most troubling side effects of photosensitivity and pyrexia. There appeared to be more gastrointestinal toxicity with encorafenib, although most cases were not high grade.
“If encorafenib is a superior BRAF inhibitor, can we conclude that, in combination with a MEK inhibitor, it should be superior to the older combinations? That is logical but not necessarily correct.”— William H. Sharfman, MD
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Difficulty in Establishing Superiority
SO, IN this head-to-head comparison, encorafenib was a superior BRAF inhibitor than vemurafenib. This result would fit with the preclinical pharmacology data, which demonstrated that encorafenib has an on-target dissociation half-life of more than 30 hours, much longer than that of the other two BRAF inhibitors.5 Thus, if one was going to use single-agent BRAF inhibition in BRAF V600E– or V600K–mutant metastatic melanoma, such as in a patient with left-ventricular dysfunction, it appears that encorafenib would be the drug of choice.
Trying to determine whether encorafenib/binimetinib is superior to dabrafenib/trametinib or vemurafenib/cobimetinib, or even significantly less toxic, is much more problematic, with no direct comparisons between any of the three combinations. As expected, the combination of encorafenib/binimetinib was superior to single-agent therapy in the COLUMBUS trial, in terms of overall response rate, median progression-free survival, and median overall survival. As noted in prior BRAF and MEK inhibitor combination studies, the combination therapy did not increase the toxicity rate over single-agent BRAF inhibition. In fact, in the COLUMBUS trial, fewer patients required dose reductions or interruptions with the combination therapy than with single-agent therapy.
If encorafenib is a superior BRAF inhibitor, can we conclude that, in combination with a MEK inhibitor, it should be superior to the older combinations? That is logical but not necessarily correct. There are plenty of examples of oncology trials where what appeared logical did not hold up in a phase III head-to-head comparison.
Indirect Comparisons With Previous Trials
BEING FULLY aware of all the pitfalls of cross-trial comparisons, we are left with trying to indirectly compare data from previous trials of BRAF and MEK inhibitor combination therapies with the COLUMBUS trial data. Three large phase III trials comparing combination BRAF and MEK inhibition with single-agent BRAF inhibition in melanoma have been previously published: COMBI-v (dabrafenib/trametinib vs vemurafenib),2 COMBI-d (dabrafenib/trametinib vs dabrafenib),6 and coBRIM (vemurafenib/cobimetinib vs vemurafenib).3 In all these trials, the single-agent BRAF inhibitor activity was similar in terms of overall response rate, median progression-free survival, and median overall survival and similar to the activity of vemurafenib in the COLUMBUS trial.
As expected, the combination therapy was superior to single-agent therapy in in COMBI-v, COMBI-d, and coBRIM. The overall response rate of combination therapy ranged from 64% to 70%, the median progression-free survival ranged from 11 to 12.3 months, and the 1-year survival spanned from 72% to 74.5%. The median overall survival rates for the BRAF and MEK inhibitor combinations were 25.6 months in COMBI-v, 25.1 months in COMBI-d, and 22.3 months in coBRIM.
In the COLUMBUS trial, the objective response rate with encorafenib/ binimetinib was 64%, the median progression-free survival was 14.9 months, and the 1-year survival was 75.5%. The median overall survival was 33.6 months. Again, with the caveat that we are making a cross-trial comparison, the median progression-free and overall survival rates look better for this combination. Are we sure the patient populations in all these studies are similar?
At first glance, it appears they are, and this is supported by the fact that the activity of single-agent vemurafenib was similar in all the trials. However, the authors of the COLUMBUS trial themselves raise the issue that a smaller percentage of patients in their study had an elevated lactate dehydrogenase (LDH) level (29%), with the other studies ranging from 33% to 46%. Could that partly explain the better results in the COLUMBUS trial? It is difficult to know. However, in the long-term follow-up of patients on dabrafenib/trametinib, it has been shown that those with a normal LDH level and fewer than three organ sites of disease do extremely well, with a 5-year overall survival of 51%.7 It would be of interest to know the outcomes in the COLUMBUS trial for those patients with a normal LDH level and fewer than three organs involved.
The incidence of the some of the more troubling side effects of combination therapy appears lower for the encorafenib/binimetinib combination. Pyrexia of any grade was 20% with encorafenib, 52% with dabrafenib/trametinib, and 29% with vemurafenib/cobimetinib. Photosensitivity of any grade was 4%, 4.3%, and 34%, respectively. The incidence of left-ventricular dysfunction was low and appeared to be similar in all the trials. Increased creatine phosphokinase is less common with the dabrafenib/trametinib combination. There were no new adverse events with the encorafenib/binimetinib combination. The incidence of nausea seemed high with the combination but generally did not appear to interfere with treatment.
Making Treatment Decisions Based on Current Data
IN SUMMARY, this phase III COLUMBUS trial demonstrates that encorafenib is a superior BRAF inhibitor than vemurafenib in terms of efficacy and tolerability. Within the limitations of a cross-trial comparison, encorafenib/binimetinib appears to have the better toxicity profile, with much less pyrexia than dabrafenib/trametinib and less photosensitivity than vemurafenib/cobimetinib. In addition, in terms of patient convenience, encorafenib/binimetinib, like vemurafenib/ cobimetinib, does not need to be taken on an empty stomach or require refrigeration.
“I would agree with the COLUMBUS investigators that the encorafenib/binimetinib combination provides a ‘new benchmark’ in BRAF/MEK inhibitor therapy, most certainly in terms of tolerability and most likely in terms of efficacy.”— William H. Sharfman, MD
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Again, within the limitations of a cross-trial comparison, median progression-free survival and overall survival appear to be better with encorafenib/binimetinib. There remains a question as to whether the lower percentage of patients with an elevated LDH level in the COLUMBUS trial contributed to better outcomes. Unfortunately, we are never going to have the benefit of a direct comparison of the three available BRAF/MEK inhibitor combinations to clarify the issues. Possibly, longer-term follow-up of the COLUMBUS trial will provide additional information. Furthermore, we do not have data on the important issue of how often encorafenib works on central nervous system metastasis.
In the meantime, we need to try to make the best treatment decisions for our patients. Based on what we know, I would agree with the COLUMBUS investigators that the encorafenib/binimetinib combination provides a “new benchmark” in BRAF/MEK inhibitor therapy, most certainly in terms of tolerability and most likely in terms of efficacy. ■
Dr. Sharfman is Medical Director, Medical Oncology, Johns Hopkins at Green Spring Station, and Director of Cutaneous Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.
DISCLOSURE: Dr. Sharfman has received honoraria from Bristol-Myers Squibb; is a consultant/advisor with Merck, Bristol-Myers Squibb, Novartis, and Regeneron; and has received research funding from Merck, Novartis; and (institution) research funding from Bristol-Myers Squibb.
1. Dummer R, Ascierto PA, Gogas HJ, et al: Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19:1315-1327, 2018.
2. Robert C, Karaszewska B, Schachter J, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39, 2015.
3. Ascierto PA, McArthur GA, Dréno B, et al: Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248-1260, 2016.
4. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377:1813-1823, 2017.
5. Stuart DD, Li N, Poon DJ, et al: Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. 2012 AACR Annual Meeting. Abstract 3790.
6. Long GV, Stroyakovskiy D, Gogas H, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444-451, 2015.
7. Long GV, Eroglu Z, Infante J, et al: Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. J Clin Oncol 36:667-673, 2018.
Reinhard Dummer, MD
AS REPORTED in The Lancet Oncology by Reinhard Dummer, MD, of the University Hospital Zurich Skin Cancer Center, and colleagues, the phase III COLUMBUS trial has shown a significant improvement in overall survival with the combination of the BRAF inhibitor encorafenib...!-->!-->