1. Samson, Kurt

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Additional data from a phase I study has shown the combination of the immunotherapy drugs epacadostat and pembrolizumab improved progression-free survival in a small number of treatment-naive patients with advanced melanoma.

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Epacadostat is a potent selective IDO1 enzyme inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1), an enzyme overexpressed in many cancers. It induces immune tolerance by suppressing T-cell response.


An earlier dose-escalation study found the combination to be generally well-tolerated and led to favorable responses in about one-third of patients.


Preliminary data from a phase I/II trial, published last November, showed an ORR of 53 percent, and disease control rate of 75 percent, in 19 patients evaluated for efficacy. The trial involved a total of 60 patients who received epacadostat doses ranging from 50 to 300 mg twice daily together with a dose of pembrolizumab 200 mg every 3 weeks (J Immunother Cancer 2015;3(Suppl 2)O7).


Updated data from the ECHO-202 trial was presented in early October at the European Society for Medical Oncology Annual Congress 2016, in Copenhagen, Denmark (Ann Oncol 2016;27:379-400). A number of trials against other cancers are also underway.


In the new review, which involved 19 patients treated with the combination, progression-free survival (PFS) was 74 percent at 6 months and 57 percent at 1 year.


While median PFS has yet to be reached, the updated data showed complete response rates increased to 26 percent. The objective response rate and disease control rate were similar to previously published data, at 58 percent and 74 percent. The new data also includes additional safety data.


In the initial phase I group of 62 patients, the combination was well tolerated, with the most common treatment-related adverse events being fatigue, rash, pruritus, arthralgia, diarrhea, and nausea. Adverse events of grade 3 or higher occurred in 19 percent of patients, including rash in 8 percent and increased lipase in 5 percent, and 5 patients discontinued treatment due to AEs.


ECHO-202 is evaluating the safety and efficacy of the combination. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from the trial.


The ECHO clinical trial program is investigating the efficacy and safety of epacadostat as a main component of combination therapy against different cancer types. Ongoing phase I and phase II studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors plan to enroll more than 900 patients across a wide of solid tumor types as well as hematological malignancies.


Key Melanoma Findings

Early data from the trial showed that in 19 patients with advanced melanoma, the combination of pembrolizumab (two doses studied-2 mg/kg or 200 mg every 3 weeks) with epacadostat (four doses studied-25, 50, 100 or 300 mg twice daily) demonstrated an overall response rate (ORR) of 53 percent (n=10/19), including three complete responses (CRs) and seven partial responses (PRs).


The disease control rate (DCR) was 74 percent (n=14/19). Treatment-related adverse events were consistent with previously reported safety data for pembrolizumab as a single agent. Fifteen percent (n=9/60) of patients assessed for safety across tumor types experienced grade 3 investigator-assessed, treatment-related adverse events, including rash (8%), arthralgia (2%), AST increased (2%), mucosal inflammation (2%) and nervous system disorder (2%). Three patients discontinued treatment-one for grade 3 arthralgia, one for grade 3 AST increased, and one for grade 2 nervous system disorder. No grade 4 treatment-related adverse events or deaths were observed.


The disease control rate was 74 percent. In treatment-naive patients, the ORR was 56 percent and the disease control rate was 75 percent.


The most common adverse events were rash, arthralgia, and increased aspartate aminotransferase levels, all of which were manageable. There were no grade 3 or 4 treatment-related adverse events, and only 5 percent of patients discontinued treatment.


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.


Commenting on the new phase I data, Suzanne L. Topalian, MD, Professor and Director of the melanoma program, Sidney Kimmel Cancer Center at Johns Hopkins School of Medicine in Baltimore, said the new data suggest the two drug work together.


"This study explores an interesting treatment regimen with two drugs that work by different mechanisms and might have additive or synergistic effects against cancer when combined," she said.


Pembrolizumab (anti-PD-1) works by blocking an immune checkpoint expressed on antitumor immune cells to reactivate them, while epacadostat, inhibits a metabolic factor which has immunosuppressive properties.


"The study shows that the treatment combination is generally well-tolerated and has activity in several cancer types," explained Topalian, co-investigator in the phase III trial of the combination in melanoma. "However, randomized trials will be needed to assess whether the treatment combination provides an advantage over single-drug therapy with anti-PD-1."


Kurt Samson is a contributing writer.