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BRAF/MEK Combinations Continue to Revolutionize Melanoma Landscape

Danielle Bucco
Published: Wednesday, Nov 01, 2017

Dr. Michael A. Postow
Michael A. Postow, MD
The BRAF/MEK inhibitor combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was found to reduce the risk of relapse or death by 53% compared with placebo for patients with BRAF-mutant stage III melanoma, according to findings from the phase III COMBI-AD study.

“We see better efficacy with combinations, particularly with BRAF/MEK inhibitors, over BRAF inhibitors alone,” said Michael A. Postow, MD. “The overall survival was improved in that group of patients [treated with dabrafenib and trametinib].”

After a median follow-up of 2.8 years, the 3-year relapse-free survival rate with the combination versus placebo was 58% versus 39%, respectively.

Early data for the overall survival (OS) benefit showed that 86% of the patients treated with the dabrafenib and trametinib combination were alive at 3 years versus 77% with placebo.

In an interview with OncLive during the 2017 World Congress on Melanoma, Postow, a medical oncologist specializing in melanoma at Memorial Sloan Kettering Cancer Center, discussed the impressive efficacy seen with combining BRAF and MEK inhibitors for patients with melanoma.

OncLive: What are some promising treatments in the pipeline for patients with resected stage III melanoma?

Postow: Most of the treatments that are effective for resected stage III melanoma are drugs that have been shown to already be beneficial for patients with stage IV melanoma or unresectable stage III melanoma. For example, drugs such as PD-1 antibodies or BRAF and MEK inhibitors, either alone or in combination.

Now that we have seen efficacy of those drugs in unresectable stage III and IV patients, we now have evidence that they can help treat earlier stage melanoma, resected stage III melanoma, or what I call the “invisible enemy” for patients who have melanoma that you cannot see on scans but, unfortunately, know is present.

Can you discuss the efficacy of combining BRAF and MEK inhibitors?

We have 2 BRAF and MEK studies that have been presented so far for stage III resected patients. The patient population was different in each of the studies. One was called the BRIM8 study, which tested vemurafenib (Zelboraf) versus placebo. The other is for patients with stage III melanoma called the COMBI-AD study. That tested dabrafenib plus trametinib versus placebo for patients with stage III resected melanoma.

Both studies had interesting biologic effects demonstrating efficacy of both single-agent BRAF inhibition and the combination of BRAF/MEK inhibition with dabrafenib and trametinib for patients with resected stage III melanoma. The recurrence-free survival was improved for the BRAF/MEK inhibitor combination therapy with dabrafenib and trametinib for these patients.

It also looked like the OS was improved in that group of patients. There were some caveats on the way some of the statistics were preformed, but we are seeing a benefit. There are clearly biologic effects of both single-agent BRAF inhibition with vemurafenib, and [combination activity] dabrafenib and trametinib in this population of patients with resected high-risk BRAF-mutant melanoma. 

Do you envision the future treatment landscape to be with combinations or will single agents still play a role?

In this patient population, many have been cured from surgery alone. We are hoping to do the best we can with efficacy and minimal toxicity. These patients do not have obvious disease and they may have been cured from surgery. However, as we have seen in the metastatic landscape, we see better efficacy with combinations, particularly with BRAF/MEK inhibitors over BRAF inhibitors alone. I am hopeful that combinations can also translate to more efficacy in this micrometastatic setting.

It is important to be mindful of toxicity in this group of patients, many of whom are already cured from surgery. However, after seeing the efficacy improvements in stage IV [disease], we will hopefully see the same results in stage III [patients]. We just need to be careful on how we do studies. 

What other challenges would you like to see addressed in the next 5 to 10 years?

One of the biggest challenges in this group of patients is that all of our adjuvant trials have various control arms. Some adjuvant trials are [composed of] observation control arms, whereas some have active control arms, such as the CheckMate-238 study of [adjuvant] nivolumab (Opdivo) versus adjuvant ipilimumab (Yervoy).

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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