As many of us are aware, metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. As evidenced by new data in The Lancet Oncology, physicians may now have access to an important new advancement that can make a real difference for patients (2018;19(10):1315-1327, 2018;19(10):1263-1264). The name of the study, COLUMBUS, is fitting as it breaks new ground in the treatment landscape of metastatic melanoma.
As background, there are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations—a key target in the treatment of metastatic melanoma (Eur J Cancer 2013;49(5):1073-1079). The current National Comprehensive Cancer Network guidance recognizes the importance of BRAF testing for patients with metastatic disease as a means of selecting the most appropriate treatments for patients.
Fortunately, the landscape of treatment options for patients continues to expand. Patients with stage III disease following resection now have access to adjuvant therapy with dabrafenib and trametinib. For those with advanced or metastatic melanoma, important developments include immunotherapies and targeted therapies, as well as combinations that have gained approval in recent years. As a key investigator in numerous oncology clinical trials, including those investigating BRAF/MEK inhibitor combinations, it has been an honor to be on the forefront of this paradigm shift.
Historically, targeted BRAF/MEK inhibitor combinations in BRAF-mutant melanoma were limited to two options—dabrafenib and trametinib, and vemurafenib and cobimetinib.
Now, we have a third and important new treatment option.
In June, the FDA approved encorafenib capsules in combination with binimetinib tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation, as detected by an FDA-approved test. Encorafenib is not indicated for the treatment of patients with wild-type BRAF melanoma. More recently, the European Commission (EC) approved the combination for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test, in September. Neither drug requires refrigeration and they can be taken with or without food.
Both approvals are great news for patients with melanoma and the health care professionals that care for them.
Background on the COLUMBUS Trial
The COLUMBUS trial is noteworthy because it demonstrated the compelling benefits of encorafenib + binimetinib, providing the basis for the FDA and EC approvals of this targeted combination. Plus, updated findings from the trial were recently published in The Lancet Oncology, which further underscore the value that encorafenib + binimetinib can bring to patients with BRAF-mutant melanoma.
The COLUMBUS trial is a two-part, international, randomized, open-label phase III trial evaluating the efficacy and safety of encorafenib in combination with binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation.
In part 1 of the study, patients were randomly assigned (1:1:1) to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily, oral encorafenib 300 mg once daily, or oral vemurafenib 960 mg twice daily. The primary endpoint of the trial was progression-free survival (PFS) as assessed by blinded independent central review.
Results from part 1 demonstrated that encorafenib 300 mg alone improved PFS compared to vemurafenib. Earlier this year, data presented at the ASCO Annual Meeting revealed that encorafenib 300 mg once daily extended overall survival to 23.5 months (19.6-33.6) compared to the 16.9 months (14.0-24.5) observed with vemurafenib (960 mg twice daily) [HR: 0.76 (95% CI: 0.58-0.98); nominal 2-sided p=0.033] (J Clin Oncol 2018; doi:10.1200/JCO.2018.36.15_suppl.9504). This is likely a result of encorafenib's unique pharmacologic profile and on-target dissociation half-life of >30 hours, which can lead to sustained target inhibition (Clin Cancer Res 2017;23(18):5339-5348).
Encorafenib when used as a single agent increases the risk of certain adverse reactions compared to encorafenib in combination with binimetinib. In patients receiving encorafenib 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving encorafenib in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). Additional safety information can be found in the U.S. Prescribing Information for encorafenib.
Part 2 of the COLUMBUS study, for which results will be published separately, aimed to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. The dose of encorafenib in the combination arm was 50 percent higher than the single agent maximum tolerated dose of 300 mg, and this higher dose was possible due to improved tolerability when combined with binimetinib. The combination was generally well-tolerated and reported dose intensity and adverse events were consistent with results of part 1.
In part 2, the median PFS for patients treated with this combination was 14.9 months compared to 9.6 months for patients treated with single agent encorafenib, with HR of 0.75 (95% CI: 0.56-1.00, p=0.051). In addition to the combination's improvement over vemurafenib, single-agent encorafenib also achieved a higher OS and PFS than what has been observed in other BRAF inhibitor monotherapy trials.
Although the COLUMBUS trial was not designed to compare encorafenib and binimetinib with established BRAF/MEK inhibitor combinations—and this should not serve as a head-to-head comparison—the consistency and similarity in vemurafenib results across multiple endpoints is an important validation of the results. Median PFS for vemurafenib was 7.3 months (95% CI: 5.6-8.2) in COLUMBUS and COMBI-v, and 7.2 months (5.6-7.5) in the coBRIM trial. Median overall survival in the vemurafenib groups in these studies was also similar: 16.9 months (95% CI: 14.0-24.5) in COLUMBUS, 18.0 months (15.6-20.7) in COMBI-v, and 17.4 months (15.0-19.8) in coBRIM (Lancet Oncol 2018;19(10):1315-1327).
While other approved BRAF/MEK inhibitor combinations have unique toxicities that may impact their ability to deliver optimal treatment, binimetinib's shorter half-life results in a potentially easier dose modification. The incidence of pyrexia (15%) and photosensitivity (4%) all grades was therefore much lower than what has been observed with other BRAF/MEK inhibitor combinations.
All secondary efficacy analyses, including the prospectively planned analysis of overall survival (OS), are descriptive in nature. Over 200 sites across North America, Europe, South America, Asia, and Australia participated in the trial.
Overall Survival & Other Findings
The COLUMBUS trial confirmed previous research which demonstrated the benefit of adding binimetinib to encorafenib.
The combination of encorafenib + binimetinib reduced the risk of death compared to treatment with vemurafenib alone [HR: 0.61 (95% CI: 0.47-0.79, p <0.0001)] in the planned, descriptive analysis of OS. Additionally, median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy.
Again, impressive yet not surprising, encorafenib + binimetinib improved PFS, compared with vemurafenib in patients with BRAF V600E or BRAF V600K-mutant melanoma in the COLUMBUS trial. Mature mPFS for encorafenib + binimetinib I was 14.9 months (95% CI 11.0-20.2) compared to vemurafenib with 7.3 months (5.6-7.9), [HR 0.51, (95% CI 0.39-0.67; two-sided p<0.0001)].
For reference, The Lancet Oncology manuscript noted that the performance of vemurafenib, the control arm, was consistent across efficacy endpoints and with its performance in other BRAF/MEK inhibitor combination trials, where it also served as a control. Also, importantly, the use of post-trial immunotherapy in the study was limited and consistent with other published pivotal trials of BRAF/MEK inhibitors in advanced BRAF-mutant melanoma.
With 18 months of additional follow-up relative to the initial publication of the COLUMBUS results, the safety profile of the combination remained generally consistent with the prior report in which encorafenib + binimetinib was generally well-tolerated.
Observed grade 3 or 4 adverse events in more than 5 percent of patients with encorafenib + binimetinib were increased gamma-glutamyltransferase (9%), increased blood creatine phosphokinase (7%), and hypertension (6%). The most common adverse reactions (>25%) in patients receiving the treatment were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. Additional safety information can be found in the manuscript.
Interpretation, Next Steps
The COLUMBUS trial results published in The Lancet Oncology provide important context and new hope around the potential of BRAF/MEK inhibitors in metastatic or unresectable BRAF V600E/K -mutant melanoma.
We now have additional data demonstrating the combination of encorafenib + binimetinib provides clinically meaningful efficacy, as shown by improvements in both PFS and OS and a permanent discontinuation rate of 5 percent of patients receiving the combination treatment.
The COLUMBUS trial is ongoing, but I—like many of my peers—am encouraged by the consistency of results and have already started treating certain patients with this important new treatment option.
I look forward to further exploring this combination therapy in the real-world setting and to evaluating additional treatment regimens for our patients with melanoma—as well as other cancers.