Epacadostat/Pembrolizumab Combo Shows Activity in Advanced Melanoma

A novel combination immunotherapy regimen of epacadostat plus pembrolizumab shows promising clinical activity and is generally well-tolerated by advanced melanoma patients, according to a new study presented at the Society for Melanoma Research 2015 International Congress, held November 18–21 in San Francisco.

Epacadostat is a potent, selective, oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), which is an enzyme overexpressed in many cancers and induces immune tolerance by suppressing T-cell response, said Omid Hamid, MD, of the Angeles Clinic and Research Institute in Los Angeles. IDO1 inhibition demonstrates antitumor activity that is synergistic with programmed death 1 (PD-1) blockade, he said.

In a prior dose-escalation study in patients with metastatic melanoma, the combination of epacadostat with ipilimumab was generally well-tolerated and led to responses in about one-third of immunotherapy-naïve patients.

Hamid reported the preliminary results of a phase I/II study of epacadostat with pembrolizumab in 60 patients with advanced or metastatic cancers. In the dose-expansion phase, patients received epacadostat doses ranging from 50 to 300 mg twice daily, along with a flat dose of pembrolizumab 200 mg every 3 weeks.

Nineteen melanoma patients with a median age of 60 were evaluable for efficacy. Most had good performance status and the majority had not received prior systemic therapies. About one-third had elevated lactate dehydrogenase levels; one-third were positive for BRAF and two-thirds for programmed death ligand 1 (PD-L1).

Dose-limiting toxicities (DLTs) were seen in a few patients in the lower doses and in 6 patients who received the 300-mg twice-daily dose. The maximum tolerated dose was not exceeded at any dose evaluated.

“Treatment-related adverse events were similar to those seen with single-agent pembrolizumab or vemurafenib,” Hamid said. The most common were rash, arthralgia, and increased aspartate aminotransferase levels, which were all manageable. There were no grade 3 or 4 treatment-related adverse events, and only 5% of patients discontinued treatment.

The overall response rate (ORR) was 53% and the disease control rate was 74%. In treatment-naive patients, the ORR was 56% and the disease control rate was 75%.

Nine of the patients have had “rapid, deep, durable responses and continue to respond,” Hamid said. Six of these patients were PD-L1–positive and one was PD-L1–negative, with other biomarker results still pending.

“Efficacy results suggest promising clinical activity with this combination therapy. Few patients experienced DLTs or grade 3 treatment-related adverse events, and there were no grade 4 treatment-related adverse events or deaths. The discontinuation rate for treatment-related adverse events was low,” concluded Hamid.

The recommended dose for the phase II portion of this study is epacadostat 100 mg twice daily based on the overall efficacy and safety profile. All phase I dose groups will continue to be evaluated. So far, 21 melanoma patients have been enrolled in the phase II portion.

A phase III study using pembrolizumab as the control arm is planned in patients with advanced melanoma, with initiation expected in the first half of 2016.

“I have great belief in this combination moving forward,” Hamid said. “It is important to see combination immunotherapies that do not have significant toxicities and discontinuation rates.”