Expert Shares Challenges, Considerations When Using Immunotherapies in Melanoma

Michael A. Postow, MD

The field of melanoma recently gained an influx of immunotherapy approvals, and advancement in the field doesn’t seem to be slowing down.

When the FDA expanded the drug’s label in December 2015, pembrolizumab (Keytruda) became the first anti—PD-1 therapy approved for previously untreated patients with advanced melanoma, regardless of BRAF status.

In February 2016, the anti—PD-1 nivolumab (Opdivo) followed suit, receiving an expanded approval for the treatment of patients with melanoma who harbor BRAF V600 mutations.

The approval applies to both nivolumab as a single agent and in combination with ipilimumab (Yervoy). This is a combination that was first approved in patients with BRAF V600 wild-type unresectable or metastatic melanoma in October 2015.

While these approvals have significantly expanded treatment options, they also come with challenges, says Michael Postow, MD, a medical oncologist specializing in melanoma at Memorial Sloan Kettering Cancer Center.

“We are excited now that we have so many great immunotherapy agents in melanoma,” he says. “The question is, ‘are these agents better by themselves or in sequence with one another, or are they better all in different combinations?’”

OncLive: What is on the horizon for the use of immunotherapy combination regimens in melanoma, and what questions remain to be answered?

In an interview with OncLive, Postow discusses the benefits and challenges of combination regimens versus single-agent regimens, the possibility of targeted agents with immunotherapies, and the management of toxicities with immunotherapies. Postow: We have seen really impressive efficacy from both pembrolizumab and nivolumab as single agents. We are now trying to figure out if we should be giving patients these drugs by themselves or in combination—such as the combination of nivolumab and ipilimumab, which is FDA approved.

The combination of nivolumab and ipilimumab has really demonstrated significant promise. Phase I trial data from Dr. Mario Sznol recently showed that the combination has a very high response rate and, now that we have followed patients for several years, we have seen really impressive long-term survival.

Based on the favorable results from the study, we’ve actually been testing that combination against each of the drugs as a single agent. We’ve seen that the combination is impressive in that context, as well.

Do you see potential for immunotherapies in combination with targeted agents in melanoma?

We have the progression-free survival data and the response rate data already. What we are excited for, and what we are waiting for, is the overall survival data. This will tell us if patients who received both drugs had better overall survival than those who just received either nivolumab or ipilimumab as a single agent. We need that information, which we hope will be ready in the next year. We hope that we are going to see some positive results. We have investigated targeted drugs against MEK and BRAF in combination with immunotherapies. Some drugs in the targeted therapy context, like vemurafenib (Zelboraf), could not be combined with ipilimumab. Ipilimumab and vemurafenib, unfortunately, resulted in a high rate of liver inflammation and skin rash. Therefore, it was decided that the combination should not be given outside of clinical studies.

Another issue that arose was when dabrafenib (Tafinlar), trametinib, and ipilimumab were combined in a triplet that resulted in a high rate of gastrointestinal events, mainly colitis and perforation. Based on that, we do not recommend ipilimumab to be combined with trametinib and dabrafenib.

There are some unique considerations with combining targeted therapy drugs with immunotherapy drugs, such as ipilimumab. However, as we move forward and start building combinations of PD-1 agents with targeted drugs, I suspect that will be more tolerable than ipilimumab combinations with targeted therapy drugs. The side effect profile is much more tolerable with PD-1 drugs than ipilimumab and it should be a better partner with targeted agents.

What challenges remain in the side effect management of immunotherapies?

It is something that we need to do very carefully and it is something that I would not recommend doing outside of clinical studies. We need more data on all of these topics. Side effects are a big issue with checkpoint blockade. Unfortunately, not all patients get through the regimen without any side effects. There are established algorithms based on the types of side effects patients are having that will allow them to be treated with different immunosuppressive agents, like steroids or infliximab (Remicade), to help them mitigate their side effects.

The problem with what we know now about side effect management, is that it is really just based upon overall clinical experience. We haven’t done any prospective trials to really decide what the best side effect management practices should be. Should we be giving infliximab earlier to patients with colitis or diarrhea? Should we be giving steroids at different doses than we are currently?

We need more prospective trials to really see what the best management strategy is for these side effects. However, this is a very hard trial to do and that is why we haven’t done it yet. I encourage everyone to continue to report side effects that they may be seeing and try to publish interesting adverse events and the strategies they used to managed them, so we can understand and learn from each other.