COMMENTARY

Epacadostat + Pembro for Melanoma: Beneficial, Well Tolerated

Jeffrey S. Weber, MD, PhD

Disclosures

November 30, 2017

Hello. I am Dr Jeffrey Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Health System in New York City. I am here to describe an abstract[1] that was presented by Dr Omid Hamid at the recent ESMO (European Society for Medical Oncology) meeting in Madrid, Spain. The abstract described a phase 1/2 clinical trial of the combination of pembrolizumab, the PD-1 antibody, and epacadostat, an IDO inhibitor, in patients with advanced melanoma.

IDO is an enzyme that catabolizes the degradation of the essential amino acid tryptophan into its metabolic byproducts, including kynurenine. Because tryptophan is an essential amino acid for T-cell function, it basically acts as an immune stimulant. But it turns out that the metabolic byproducts of this enzyme are probably toxic to the immune system, and thus IDO is a double-edged sword. Many tumor cells and antigen-presenting cells may express IDO, so it acts as yet another immune-suppressive influence. It is not really a checkpoint, but it acts in addition to the checkpoints to suppress T-cell immunity.

One would think that eliminating IDO would be quite favorable, and in animal models, that is indeed the case. Of interest, the IDO inhibitors alone have no real antitumor activity, but this recent study that Dr Hamid presented at ESMO 2017 found quite encouraging activity [against advanced melanoma].

Dr Hamid described a phase 1/2 trial of 63 evaluable participants, of which 54 were treatment-naive patients with metastatic melanoma. The combination of pembrolizumab and epacadostat, an oral drug taken daily, resulted in a 55% response rate in all of the treatment-naive patients, with a disease control rate of 72%. Very impressive. In all, 39 treatment-naive patients received the ultimate dose of 100 mg twice daily, a dose that was subsequently chosen for the phase 3 studies. These patients had an overall response rate of 58%, with a disease control rate of 74% and complete response rate of 8%. The waterfall plot looked quite impressive, with a breakpoint well beyond 50%. As mentioned, the disease control rate was 74%, so that's where the breakpoint was. These were good, sustained responses.

Of all the treatment-naive patients, 30 of the 35 responses were ongoing from 1 to 121 weeks, and of those who finished treatment at 2 years, four of the five patients who were in remission thus far have stayed in remission. Again, very impressive. Of the treatment-naive patients who received the ultimate dose of 100 mg twice daily of epacadostat with pembrolizumab every 3 weeks, 20 of 22 responses are ongoing, suggesting long-term, well-sustained responses. The median progression-free survival (PFS) of the overall population was 12.4 months; for pembrolizumab alone we would expect a PFS of around 7 months. Among the total of 54 treatment-naive patients, median PFS was 22.8 months—again, very impressive.

This was a well-tolerated regimen. Only 6% of patients withdrew because of toxicity. The overall grade 3/4 toxicity rate was about 20%, which is about same—perhaps a bit higher—than would be expected with pembrolizumab alone. The critical rate of select immune-related adverse events had the typical pattern you would expect with pembrolizumab alone, with predominantly liver, skin, endocrine, hepatic, etc, events. There was a 9% rate of grade 3/4 immune-related adverse events and about double that for overall immune-related adverse events, most of which were pretty well tolerated and did not lead to treatment being stopped.

We are looking at a very well-tolerated regimen of the PD-1 antibody pembrolizumab plus epacadostat, with an excellent response rate that parallels what we see with the much more toxic nivolumab-plus-ipilimumab regimen and an equally good PFS out to at least what looks like a year. These impressive data have led to a large, 700-patient randomized phase 3 study of pembrolizumab plus placebo versus pembrolizumab plus epacadostat—the KEYNOTE-252 study. That study is already fully accrued and we hope to receive encouraging data early in 2018.

This is Jeffrey Weber. Please feel free to send your comments and feedback. Thank you very much for your attention.

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