BRAF/MEK Combinations Continue to Revolutionize Melanoma Landscape

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.

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

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.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.

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

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.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.

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

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. 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.

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

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. 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).

One of the major difficulties in interpreting these [studies] over the next 3 to 5 years is going to be how to compare across trials when we have different control arms. I am not sure that there is an answer to that type of question. We will be left with cross-trial comparisons and all those inherent caveats, but that is going to be one difference when attempting to compare them. Is it better to give a stage III resected patient dabrafenib and trametinib or a single-agent PD-1 drug like nivolumab?

The other big question that remains is whether we should treat all patients in the adjuvant setting or only treat the patients who ultimately have recurrent disease with these agents in the stage IV setting? The majority of these adjuvant trials have not allowed crossover, and, therefore, we do not know if we should give the treatment now or later to only those patients who we really need to treat.

What other key points should community oncologists know regarding the evolving landscape of melanoma?

There are many ongoing questions and I am hopeful we will get more information as we see longer follow-up.The World Congress of Melanoma is always a great meeting because it brings together people from across the entire disease spectrum. Whether it’s from dermatologists making initial diagnoses of melanoma to patients with metastatic disease that is refractory to systemic treatment opportunities.

One thing that we can recognize and be proud of in the field of melanoma is how our treatment advances can be seen advancing many other different types of cancers. That is something we really owe to the whole oncology community. We can contribute to world knowledge for many different patient scenarios from our experiences in melanoma.

Long GV, Hauschild A, Santinami M, et al. Efficacy outcomes in the phase 3 COMBI-AD study of adjuvant dabrafenib (D) plus trametinib (T) vs placebo (PBO) in patients (pts) with stage III BRAF V600E/K—mutant melanoma. Presented at: 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR09-1.