Novel Agent May Change Landscape in Treatment of Melanoma Subset

The MEK inhibitor binimetinib is a promising option for patients with NRAS-mutant melanoma who progressed on immunotherapy, according to Reinhard Georg Dummer.

Results of the open-label phase 3 NEMO trial, which were presented during the 2016 American Society of Clinical Oncology Annual Meeting, most recently demonstrated the agent’s potential. In the study, binimetinib was found to reduce the risk of progression or death by 38 percent when compared with dacarbazine in this subgroup of patients.

Additionally, median progression-free survival (PFS) with binimetinib was 2.8 months versus 1.5 months with dacarbazine. The objective response rate with binimetinib was 15 percent, including one complete response, compared with 7 percent for dacarbazine.

In patients previously treated with immunotherapy, the median PFS was higher, at 5.5-months with binimetinib versus 1.6 months with dacarbazine.

“This is especially relevant for patients who are treated with immunotherapy because, nowadays, most patients start with an immunotherapy treatment,” says Dummer, professor, Department of Dermatology, University of Zurich Hospital. “Unfortunately, 50 percent of the patients fail. For those patients, it is important to have other options.”

Can you provide an overview of the NEMO trial?

What are the exciting takeaways from this study?

In an interview with CURE, Dummer shares the encouraging phase 3 findings from the NEMO trial and how it shakes up the treatment paradigm for patients with NRAS-mutated melanoma.NEMO was designed four years ago based on data that the MEK inhibitor binimetinib can increase the response rate in patients with NRAS-mutated melanoma. There are several melanoma subtypes based on driver mutations in an important pathway, which is called the MAPK pathway. Most of them are mutated for BRAF, and there are many medications around for BRAF-mutated patients. However, 20 percent are mutated for NRAS and, here, we don’t have any specific treatments, although there is a huge medical need.This study is a prospective randomized trial in a very special patient population and, also, was in an environment of competitive recruitment with many other studies. Nevertheless, the study managed to recruit patients and randomize them to binimetinib or the standard chemotherapy that is used worldwide, which is dacarbazine.

The randomization in the patient populations worked nicely, so we have two very comparable groups and the results are positive. We have a positive impact on PFS, so this means patients who are on binimetinib have a better outcome and the disease is under control for a longer time. The hazard ratio is 0.62, which is close to a 40 percent improvement overall.

Therefore, we did an analysis of the patients who had prior immunotherapy. In this patient population, the benefit was even greater than in the overall population. The median PFS interval with binimetinib was 5.5 months versus 1.6 months. The difference is even better.

The other question is, “How does binimetinib have an impact on tumor burden?” It does much better; it has a better response rate. Also, the disease-control rate is better in the binimetinib group.

What is the safety profile of this agent?

Together, all these data show that we have now an alternative to chemotherapy. Chemotherapy is of very limited value in patients with NRAS-mutated disease, so in patients who fail immunotherapy, we can offer a new medication—binimetinib—for patients with NRAS-mutated melanoma.We know a lot about MEK inhibitors. Most of the adverse events are mild; to manage them, you need to know them. There are certain organs that are affected the most, and there are muscular toxicities that are reflected by an elevation by the muscle enzyme CPK.

Also, there are some skin toxicities. Patients may get a rash, which can look like very severe acne, so you have to help them as it can interfere with their social life. It is not dangerous, but it’s very unpleasant for patients.

What are the next steps here?

The other problems are gastrointestinal symptoms, such as nausea and diarrhea, but with some additional medications and dose interruption, it can be managed. However, in a number of patients, we had to discontinue treatment due to these adverse events.It’s a very important study because, for the first time, it has looked at a special population in melanoma, defined by the NRAS mutation. It’s a good first step but, certainly, we want to improve the outcome and we want longer PFS. One way to do that is through combination studies. There are already studies on the way, for example, with cyclin-dependent kinase inhibitors. With that, the other question is, “Is this molecule a good partner for combination with immunotherapy? Could this be parallel treatment or could this be sequential treatment?”