Key Points: Immunotherapy for the Treatment of Melanoma

Despite their recent approval to be a first-line treatment for patients with metatstatic melanoma regardless of BRAF mutation status, Opdivo (nivolumab) and Yervoy (ipilimumab) have not yet become the standard of care, says Tara C. Gangadhar, MD, an assistant professor of Medicine, Perelman School of Medicine at the University of Pennsylvania.

“There is reluctance to go in the direction of dual checkpoint blockade, even though it is approved, because we are all really waiting for the randomized data and survival data,” she says. “Consideration for clinical trials as first-line treatment for patients with advanced melanoma should remain part of our decision-making in our conversation with patients.”

Melanoma has been one of the frontrunners of the immunotherapy movement, but there is still much for oncologists to understand, adds Gangadhar.

What role do you see the combination of Opdivo and Yervoy playing for frontline treatment for metastatic melanoma?

In an interview with CURE, Gangadhar discusses what oncologists need to know about using immunotherapies—including how to choose between monotherapy and combination regimens—the importance of understanding how immunotherapy responses may differ from cytotoxic chemotherapy responses, and when a patient should be taken off treatment.Gangadhar: Opdivo and Yervoy is a frontline option, but I do not think it is the only frontline option. Patients with melanoma are so unique that the treatment plan has to be individualized for each patient. In some patients, we would choose this dual checkpoint blockade option.

In all patients, oncologists should consider whether there is a clinical trial option available in the first-line setting that includes PD-1 blockage in combination with another agent. For patients who are not candidates for a clinical trial, they should also consider single-agent checkpoint blockage. I would consider them all reasonable options.

Oncologists' preference is to use a single agent in the frontline setting in the absence of randomized data showing an improved outcome with the combination of Opdivo and Yervoy and the absence of long-term survival data, considering the increased toxicities. That being said, while the default at my center is single-agent therapy, there may be some patients, in unique situations, who may benefit from dual checkpoint blockade.

How should immunotherapies be used in the frontline setting for melanoma?

Oncologists are very actively participating in clinical trials with novel immunotherapy combinations in the hopes of finding other combinations that are very active, but perhaps come with less toxicities. In comparison to cytotoxic chemotherapy, where a tumor will shrink or grow after a treatment is initiated, there can sometimes be a delay in response with immunotherapy.

At that time, if you assess a patient with cross-sectional imaging, you may see that the tumor looks larger. However, on a subsequent scan you may see that there has been a response. This is called an atypical response. That may be because the immunotherapy is taking a longer time to work. It could also be because there is an immunotherapy-related inflammation happening in the tumor that looks radiographically like a larger tumor when, in fact, a subsequent response assessment would reveal a good tumor shrinkage and response.

Are these atypical responses more common with certain immunotherapies over others?

When should an immunotherapy regimen be stopped?

Oncologists are becoming more familiar with these atypical response patterns. They recognize that it is a possibility but, ultimately, they make their clinical decision to continue therapy based on the patient’s clinical status. In the absence of any obvious clinical decline, palliative needs or decline in performance status, a patient with a small amount of progression can be treated and then reassess with subsequent response assessments.In general, oncologists have developed this concept of an atypical response in the context of CTLA-4 blockade with Yervoy. With that agent, it was not uncommon to see an atypical response; however, it is much less frequent with PD-1 blockade. There are still some patients who still experience an atypical response pattern or mixed response with a PD-1 agent on their initial assessment scans.The question of when to stop immunotherapy is a very interesting one. In our practice, we routinely stop patients on the treatment of PD-1 blockade at the time of a confirmed complete response after approximately six months of treatment. We can follow those patients closely over time, and we don’t see that patients have relapsed.

However, these drugs have only been available for a few years, so the follow-up time that we have is, on average, one to two years since oncologists started and stopped patients. Oncologists do have evidence for the rare patient who does develop resistance after stopping therapy that we can reinitiate treatment PD-1 blockage and they can regain tumor control.

While we have made significant advances in immunotherapy and increasing response in melanoma, there is more progress to be made.