Clinical Trials Are Critical in High-Risk Melanoma

The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy to reduce their chances of recurrence. However, health care professionals have not yet perfected the science of which agents to provide certain patient populations.

During an interview with CURE, Anna C. Pavlick, DO, associate professor of hematology and medical oncology and medical director of the Clinical Trials Office at the Perlmutter Cancer Center at NYU Langone Medical Center, discussed adjuvant therapy for patients with high-risk melanoma.

“I reviewed the historical data looking at interferon as the only adjuvant we had for many years, and now we have the checkpoint inhibitor ipilimumab (Yervoy) that has been approved to be given in the adjuvant setting for stage 3 patients,” Pavlick said in an interview during the meeting.

You lectured on the utility of interferon in the adjuvant setting for melanoma treatment. How often is this therapy used toay?

Pavlick emphasized the importance of clinical trials, adding that increased participation in clinical trials will bring effective change in what treating physicians can offer patients, as well as coming to a better understanding on what are the best options to treat high-risk melanoma.There are very isolated groups throughout the United States that believe that data. If looking at the East coast and West coast regions of the country, we are “non-interferon believers.” However, the middle of the country is still using interferon. If you talk to an oncologist on the East coast, we would say that we don’t really use it. I would never say “never;” however, I haven’t administered it to patients in the past three to five years. I would rather put patients on a clinical trial and look for something much more promising with less toxicity — with the hope that it will impact their survival — when I know that interferon with its toxicity is not going to impact their survival.

What trends are we seeing in ongoing clinical trials, and what types of patients would be best for each type of trial?

Depending upon a patient’s stage of disease, the earlier-stage high-risk patients — like those with 2b, 2c and 3a disease — are those who may be interested in a vaccine trial. We look at different peptides that may be able to immunize patients to decrease their risk of recurrence. We don’t know if a certain peptide is going to benefit the patients. However, most vaccines have very minimal toxicities, they’re tolerable, and patients can come in and receive the vaccine and then go to work afterward since they are not sick. We are hoping that we are able to find one that may be able to help them.

For patients that have high-risk disease — such as 3b, 4c and resected stage 4 disease — we are looking at the usefulness of using checkpoint inhibitors in an earlier setting rather than waiting for patients to develop metastatic disease. There are plenty of clinical trials that are looking at single-agent PD-1 inhibitors, comparing interferon or Yervoy with a PD-1 inhibitor, or there are combination trials looking at what we call “flip doses.”

What determines how long you administer adjuvant therapy to your patients?

Were there any recent adjuvant data in melanoma presented at the 2017 ASCO Annual Meeting?

The way we give combination immunotherapy is usually 3 mg/kg of Yervoy with 1 mg/kg of Opdivo (nivolumab) during a patient’s induction. What we have done is flipped the doses, so we are giving 1 mg/kg of Yervoy and 3 mg/kg of Opdivo. The toxic drug in that combination is the Yervoy, but we also think it’s really important to stimulate those T cells to generate a better immune response. We want the patients to get Yervoy se doses, we will be able to get the same great responses with the standard doses but with a lot less toxicity.If the patients are going to participate in a research study, the length of treatment is dictated in the protocol. If you’re participating in a vaccine study, some vaccine studies run six months, and some run a year. Most adjuvant studies don’t run more than one year, even with the inhibitors it’s the same thing. The trial studying Yervoy and interferon versus pembrolizumab has treatment over one year. Then, you watch.What was presented at ASCO that we all found intriguing was a study comparing 3 mg/kg to 10 mg/kg of Yervoy, because the 10 mg/kg dose is what is approved for the adjuvant setting, but the 3 mg/kg dose is what is approved for patients with metastatic disease. We know that 10 mg/kg gives a lot of toxicity — more than the 3 mg/kg — and so we put those two doses in a head-to-head comparison.

We saw that the rate of relapse-free survival for the two doses is actually the same, but this is a very early look at the data. We don’t have a comparison for survival we can use as evidence that if we give a patient the 3 mg/kg dose, their survival is going to be as good as the 10 mg/kg dose. We can tell patients the toxicity is a little bit better, but what really matters most is survival, so if we can provide the same survival benefit at a lower dose, and with less toxicity, that’s certainly what we want to do.