Integrating PD-1 Inhibitors into the Treatment of Melanoma

In the past four months, the PD-1 inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab) have been approved for the treatment of advanced melanoma. To gain insight on the integration of these agents and other immunotherapies into clinical practice, OncLive interviewed Jeffery S. Weber, a senior member at Moffitt Cancer Center in Tampa, Fla.

What is the clinical impact of the approval of nivolumab?

This agent gives community oncologists two options for patients who have failed ipilimumab (also known as Yervoy) and yet more temptation to want to use the drug upfront. Nivolumab gives them more options. Obviously, pembrolizumab has been used for two or three months already and doctors, like most people, tend to stay set in their ways and are probably not going to change a lot. The pricing, though, for nivolumab and pembrolizumab may be different for larger groups, so that will probably drive which drug is used. The question also remains if the drugs provide the same benefit, as no head-to-head comparison has been completed yet.

What is next for immunotherapies, as a whole, in melanoma?

Everybody is testing combinations and sequencing now: pembrolizumab, nivolumab, ipilimumab, and T-VEC. This is all a matter of studying the proper combinations. That’s the next step—looking at combinations to try to keep the toxicity down but boost the response rate.

What is the role for chemotherapy in the treatment of melanoma?

Chemotherapy is kind of fading out. For example, in a young patient in good shape, a community oncologist now has three steps immunotherapeutically: ipilimumab, pembrolizumab or nivolumab, and IL-2. If a patient fails all those treatments and is still in good shape, he or she could receive carboplatin and paclitaxel. I’m not sure how many patients would get to that point. Once they’re through three separate regimens, a lot of those patients may not be in a condition to be treated or may not wish to be treated.

What is the role of pembrolizumab and nivolumab in the adjuvant setting or even the neoadjuvant setting?

Our group is the only one that has done an adjuvant study with nivolumab and it was recently published in Clinical Cancer Research. The data looked very nice—very long survival, very long relapse free survival. There will be trials coming up, though, and I suspect they will fill up very quickly because there currently are no large trials in stage 3 and 4 resected melanoma.

Could pembrolizumab and nivolumab make a borderline unresectable lesion into a resectable lesion?

Yes, I think there is a serious promise there. You want a neoadjuvant therapy to have about a 50 percent response rate and nivolumab has about a 40 percent response rate in the frontline. I could see nivolumab in combination with ipilimumab being a potentially promising neoadjuvant regimen and eliciting a 40-plus percent response rate. That would put patients in the range where it could be used clinically and could cause enough tumor regression to try resection. I think there is potential there.

In the absence of a biomarker, what criteria should be used to determine which patients should receive these agents?

Pretty much anybody can tolerate nivolumab and ipilimumab. The combination is more toxic, so that’s a little different.

A common thought is that patients with indolent, low-burden disease, low bulk with normal LDH—whether they are BRAF-mutated or not—should go on immunotherapy to take advantage of the tail on the curve. If they are BRAF-mutated and have high LDH, bulky or aggressive disease, they should go on a combination of a BRAF and MEK inhibitor. To some degree, I think a lot of doctors follow that philosophy. It has never been subjected to a proper randomized trial, but it will.

I think there will be an ECOG trial looking at the BRAF-mutated population and randomizing the sequence of immunotherapy and targeted therapy. That will help to answer the question of who should be treated first with immunotherapy.

I think a lot of docs in the community are still using a BRAF inhibitor plus a MEK inhibitor, even in the indolent, low-burden population because it is so easy to administer the drugs. An oncologist can write a quick prescription and 3 days later, it gets delivered to the patient’s house. Then, an oncologist sees their patient once a month, gets them an EKG, and sends them to the dermatologist. It’s not a lot of work. If they prescribe nivolumab or pembrolizumab, the patient is coming back every 2 or 3 weeks, respectively, to go to the infusion center. Until we see the data from that ECOG trial, we won’t know what the best initial treatment is in the BRAF-mutated population.