Will PD-1 Agents Edge Out IFN in the Adjuvant Melanoma Setting?

Jeffrey S. Weber, MD, PhD


August 12, 2016

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This is Dr Jeffrey Weber, deputy director of the Perlmutter Cancer Center at the NYU Langone Medical Center. Today we'll be talking briefly about adjuvant immunotherapy trials for patients with resected melanoma.

In the adjuvant melanoma field, high-dose interferon was first approved in 1996. Then in 2011, we had pegylated interferon approved as an adjuvant therapy, both primarily on the basis of relapse-free survival data.

Since that approval of pegylated interferon in 2011, there have been several other mature trials of immunotherapy that have come to the fore. One of them was a biochemotherapy trial[1] published in 2014 in the Journal of Clinical Oncology by Larry Flaherty and colleagues, in which there was clearly a relapse-free survival advantage with three cycles of biochemotherapy as an inpatient compared with high-dose interferon, the approved therapy at that time, but there was no significant survival advantage. Owing to the complexity, the cost, the difficulty, and the toxicity, adjuvant biochemotherapy hasn't received a lot of traction anywhere—certainly not in the United States.

Ipilimumab, the CTLA-4 blocking antibody approved in 2011 for metastatic melanoma, has been tested in a European Organisation for the Research and Treatment of Cancer (EORTC) trial,[2] in which patients were randomly allocated to placebo or ipilimumab at 10 mg/kg (a fairly high dose) given over a total of 3 years—first for 12 weeks of induction therapy every 3 weeks, and then every 12 weeks for the rest of the 3-year period.

In that trial, there was clearly a relapse-free survival advantage that went from 17 to 26 months compared with placebo. The hazard ratio was 0.75, with a very favorable P value in the range of .001, suggesting a clear relapse-free survival advantage—albeit at the cost of a 41% rate of grade III/IV toxicity for the high-dose ipilimumab adjuvant regimen in resected stage 3A, 3B, and 3C melanoma.

Nonetheless, ipilimumab was approved [for adjuvant use] last year by the US Food and Drug Administration (FDA) and has received some traction in the United States among practicing oncologists. The updated survival data from that trial will presumably be presented by the end of this year, possibly at the European Society for Medical Oncology (ESMO) meeting in Copenhagen in October 2016.

Nivolumab has been tested already in a phase 3 randomized trial. In fact, in a pilot trial[3] conducted at my former institution, the Moffitt Cancer Center, patients received either 1 mg/kg, 3 mg/kg, or 10 mg/kg of the PD-1 antibody nivolumab with a peptide vaccine. Only 10 of those 33 patients ever relapsed, with a median follow-up of over 4 years.

With a predominant population of stage 4 resected patients, those were excellent data, provoking a large randomized trial of nivolumab vs ipilimumab—ipilimumab at the standard approved dose of 10 mg/kg and nivolumab at a dose of 3 mg/kg. This is a 1-year regimen, a little different from the original EORTC trial that got ipilimumab its adjuvant approval. This trial was one of the faster-accruing trials, with about 880 patients enrolled in 6 months. It was finished in October of last year. We hope to have mature data in about a year.

Meanwhile, the Eastern Cooperative Oncology Group and the Southwest Oncology Group had an intergroup trial, ECOG 1609, in which patients received either high-dose interferon or were randomly allocated to receive either 3 mg/kg or 10 mg/kg of ipilimumab. That trial finished its accrual well over a year ago, and we will need to wait at least 1-2 more years for that trial to mature to find out whether either dose of ipilimumab is superior to the standard FDA-approved high-dose interferon regimen.

There are two additional ongoing trials. One trial began at the end of 2015, comparing pembrolizumab with interferon or ipilimumab. Both are FDA-approved treatments. The reference arm is pembrolizumab, given for 1 year at a fixed dose of 200 mg every 3 weeks for 1 year. Finally, in stage 3A, 3B, and 3C disease, there is a pembrolizumab vs placebo trial predominantly being done by EORTC, but also partly being done in the United States.

These are very interesting trials, and we look forward to the possibility that the programmed cell death protein 1 (PD-1) antibodies may replace high-dose interferon as the standard regimen and maybe even be superior to ipilimumab as adjuvant therapy for high-risk stage 3 and 4 resected melanoma.

This is Dr Jeffrey Weber. Thank you very much for listening and feel free to comment. Again, thank you very much.


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