Adjuvant Immunotherapy in Advanced Melanoma

Jeffrey Weber, MD, PhD

We recently spoke with Jeffrey Weber, MD, PhD, about the role of immunotherapy in the adjuvant setting for patients with stage III melanoma. Dr. Weber is a medical oncologist who specializes in the treatment of melanoma. He is an immunotherapy researcher at New York University Langone Health Center, and is deputy director of the Laura and Isaac Perlmutter Cancer Center, both in New York City.

-Interviewed by Anna Azvolinsky

Cancer Network: First, can you say what is meant by adjuvant therapy for melanoma and describe current FDA-approved immunotherapies available for patients with surgically resected stage III melanoma?

Dr. Weber: The word adjuvant, interestingly, in the English language has many meanings, but the meaning that we use commonly in the clinic is in the sense of ‘added to.’ So, an adjuvant therapy is something that is added to surgery-given after the surgery to decrease the risk that the tumor will return or relapse. In the United States, there are various different adjuvant therapies. For example, for colon cancer we commonly use chemotherapy as adjuvant therapy, and for breast cancer it’s chemotherapy or hormonal therapy. For melanoma, there are actually at least three different approved therapies, all of which are immunologic in nature. The original adjuvant therapy approved by the FDA for melanoma back in the 1990s was high dose alpha-interferon. I should actually say that there are four approved therapies, because a pegylated version of interferon was approved in the last 5 years, again for stage III melanoma at high risk for recurrence. When I say high risk, I usually mean a 50% risk at 5 years or longer of the tumor returning.

Over the last couple of years there have been two new approvals. Back in 2015, the CTLA-4 [cytotoxic T-lymphocyte–associated antigen 4] blocking antibody ipilimumab was approved by the FDA as an adjuvant therapy, and that was given at a pretty high dose of 10 mg/kg. It turned out to be a fairly toxic regimen, although it was the first drug that was shown in a randomized trial, compared to placebo, to actually benefit patients with resected or surgically removed stage III melanoma who clearly had prolonged time to return of the tumor. That is, prolonged relapse-free survival. The patients who received ipilimumab [in clinical trials] also had an increased overall survival.

The most recent approval came at the end of December 2017, when the PD-1 [programmed death 1] blocking antibody nivolumab was approved by the FDA for resected stage III and stage IV melanoma removed and at high risk for recurrence. And again, that is an immunologic drug, and it was approved on the basis of prolonged relapse-free survival-that is, prolonged time to return of the tumor compared with ipilimumab, which as I mentioned was the standard since 2015. So we’ve gone from interferon, to pegylated interferon, to ipilimumab, and now to nivolumab. Hopefully, there will be another regimen approved which is a targeted therapy, only for melanoma patients who have a BRAF mutation. These are the BRAF-targeted oral drugs, dabrafenib and trametinib. That combination in the adjuvant setting still awaits an approval by the FDA.

Cancer Network: You mentioned ipilimumab and nivolumab, checkpoint inhibitor antibodies that are already approved for adjuvant treatment of melanoma. Are there other single-agent checkpoint inhibitor antibodies under investigation in the adjuvant setting, and are there data available from those trials?

Dr. Weber: Yes, a couple of studies have been conducted. The results of one of them just matured, and a press release came out [in early January]. That study was predominantly done in Europe by the EORTC, which is the European Organisation for Research and Treatment of Cancer. The trial, Keynote 054, included over 900 patients with stage III resected melanoma who got either the anti–PD-1 antibody, the other approved anti–PD-1 antibody for metastatic melanoma, or placebo. There was clearly a benefit for those patients who were treated with pembrolizumab, in terms of relapse-free survival compared to placebo. The hazard ratio (that is, the reduction in the risk of relapse) was 0.57, suggesting that by taking this antibody, pembrolizumab, you reduce the risk of recurrence by 43%, compared to getting no therapy. That was a positive study, and we expect to see those results presented at the AACR [American Association for Cancer Research] meeting in April, as well as publication in a scientific journal.

There is another study that is less mature and just finished recently; that was a US intergroup study called SWOG 1604 or S1404, where patients were randomized to get pembrolizumab in the experimental arm and a choice of interferon or ipilimumab in the control arm. The vast majority of patients got ipilimumab in the control arm and only the very rare patient got the alpha-interferon. This study is somewhat similar to the already published study of nivolumab versus ipilimumab, but this time it’s pembrolizumab versus ipilimumab, and we’ll probably know the results sometime in the next year. 

Cancer Network: Beyond monotherapy there are now also combinations being studied in the adjuvant setting. There was a relatively small study described for stage III patients of nivolumab combined with another checkpoint inhibitor, ipilimumab. Could you tell us about those results, and also if there is a larger follow-on trial that is testing that combination?

Dr. Weber: Yes, back when I was at the Moffitt Cancer Center in Tampa, I initiated a pilot trial that was initially 20 patients, who got the combination of ipilimumab and nivolumab. They had stage IIIC and stage IV resected melanoma, which we think of as the bad actors at the highest risk of relapse. And of those 20 patients, more than half couldn’t finish the 12-week induction regimen because we used the high dose of ipilimumab at 3 mg/kg, whereas nivolumab was given at 1 mg/kg. So we did what a lot of practitioners do in current practice, and that is we flip the doses. We gave ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg, and that regimen was much better tolerated.

When I came to NYU 2 years ago, we added another 16 patients for a total of 56, where we not only flipped the doses of ipilimumab and nivolumab, making the combination much better tolerated, but we started giving the nivolumab every 4 weeks according to pharmacokinetic data that had just recently come out. Of those 56 patients with an average follow-up of over 2.5 years, only 1 patient has died and I believe 11 of the 56 have ever relapsed. That is a pretty darn good record, and the best record I’ve had in a pilot adjuvant trial. And again, these were all bad-actor patients with stage IIIC and IV resected melanoma.

So those pilot trial results will eventually get published, but that provoked the large trial of low-dose ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg, and eventually we gave six doses of the nivolumab and used nivolumab as maintenance therapy every 4 weeks at a 480-mg fixed dose. This is a 1-year regimen that is relatively easy to tolerate because you are only getting the nivolumab once every 4 weeks and that was compared to the by-now FDA-approved standard of nivolumab alone. So that head-to-head trial, called Checkmate 915, will end up accruing about 2,000 patients. Of course, in that trial we’ll look at the toxicity of the flip dose of ipilimumab-nivolumab (where the ipilimumab is given every 6 weeks throughout the year, which has produced less toxicity than the higher dose of ipilimumab plus nivolumab). Nivolumab will be given every 3 weeks in the study during the induction-dose phase, and every 4 weeks during the maintenance phase. Hopefully in a few years we’ll have the answer as to whether there is a difference in relapse-free survival between the arms.

Cancer Network: Are there other immunotherapy trials that you and your colleagues are looking forward to reading that will address important clinical questions of adjuvant immunotherapy for melanoma?

Dr. Weber: There will be a trial, we hear, in stage II melanoma-and I assume that will be in stage IIB and IIC disease (which are the highest risk ones)-of pembrolizumab versus placebo. There also may be some upcoming trials with nivolumab in stage II disease but we haven’t heard about that yet. I think these will be useful trials because a good number of patients will relapse-and if you can choose the worst-acting patients (the ones most likely to relapse), those are the perfect patients to go on an adjuvant trial because the magnitude of the benefit is going to depend on the likelihood of relapse.

If you treat 1,000 patients and 500 are never destined to relapse, that means you’ve just treated half of your patients for no benefit. And let’s say the hazard ratio is 0.66; that means you have a one-third reduction in the risk of relapse. But if the risk of relapse is only 1 in 2 and you’ve only benefited one-third of the patients, that means you’ve actually benefited just one-third of one half, which is one-sixth. So that means you need to treat 6 patients to benefit 1 patient. I would rather be in a position where I treat 2 patients to benefit 1 patient, which makes it a much more palatable and economically feasible regimen. So, we look forward to the trials and the results of adjuvant therapy in stage II melanoma. Some of the stage IIC patients have a risk of relapse as high as the stage IIIB patients, so it’s not unreasonable to be testing immunotherapy in that scenario.