IN PATIENTS with unresectable or metastatic melanoma, adding epacadostat to pembrolizumab (Keytruda) did not result in greater clinical benefit over pembrolizumab alone, according to data from the phase III ECHO-301/KEYNOTE-252 study. These results were originally presented at the 2018 ASCO Annual Meeting by Georgina Long, BSc, PhD, MBBS, Co-Medical Director of Melanoma Institute Australia (MIA) and Chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital at The University of Sydney.1 The study was later discussed at the Best of ASCO Chicago by Jeffrey A. Sosman, MD, Professor of Hematology and Oncology at Northwestern University Feinberg School of Medicine in Chicago, along with the year’s other top selected abstracts in melanoma.1,2
Georgina Long, BSc, PhD, MBBS
Jeffrey A. Sosman, MD
Phase II Trial Data
IN A PHASE I/II STUDY, combining epacadostat—a selective oral inhibitor of the IDO1 enzyme—with the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab suggested promising antitumor activity with minimal additive toxicity.
“There was a good rationale to this study,” said Dr. Sosman. “This drug is an IDO1 inhibitor, and there’s good data that high IDO1 is associated with immune dysfunction and even poor prognosis. There’s some data that suggest that IDO1 may be an important resistant mechanism in patients receiving anti–PD-1 therapy in a number of settings. By blocking that, the hope is we can overcome one of the mechanisms of resistance.”
The single-arm phase II study of epacadostat and pembrolizumab demonstrated a 55% response rate in 54 patients. “This was certainly promising,” he noted. “And a lot of people thought it was better than we’ve seen with pembrolizumab [in other studies].” Based on these findings, the investigators conducted a phase III randomized, double-blind study to evaluate the efficacy and safety of epacadostat and pembrolizumab versus pembrolizumab alone in this patient population.
Study Design
PATIENTS HAD histologically confirmed unresectable stage III or IV melanoma and were treatment-naive for advanced or metastatic disease, except for patients with the BRAF V600 mutation, who could have received prior BRAF/MEK therapy. Patients had an Eastern Cooperative Oncology Group performance status of 0 to 1, with no active central nervous system metastases.
A total of 706 patients were stratified by PD-L1 expression and BRAF-mutation status (BRAF-mutant with prior BRAF-directed therapy, BRAF-mutant without prior BRAF-directed therapy, and BRAF wild-type); 72.5% of tumors were PD-L1– positive, 44.5% were BRAF-mutant, and 12.2% received prior BRAF/MEK therapy.
Patients were randomized 1:1 to receive epacadostat at 100 mg twice daily in combination with pembrolizumab at 200 mg every 3 weeks (n = 354; median age, 64 years) or the same dose of pembrolizumab in combination with placebo (n = 352; median age, 63 years).
At the ASCO 2018 Annual Meeting, the investigators presented the final analysis for progression-free survival and the interim analysis for overall survival, co-primary endpoints of the study.
Survival Results ‘Remarkably’ Negative
AFTER A median follow-up of about 14 months, the drug combination did not result in significantly longer survival compared with placebo. The median progression-free survival was 4.7 months with epacadostat and pembrolizumab vs 4.9 months with pembrolizumab alone (P = .517); the progression-free survival rate at 12 months was 37% in both groups. These findings were consistent across PD-L1 and BRAF subgroups. The overall survival rate at 1 year was 74% in both groups, but overall survival was not expected to reach statistical significance, based on the results of this interim analysis (P = .807).
Objective response rates were 34.2% and 31.5% in the combination and pembrolizumab-alone arms, respectively. “The response rate was disappointing, certainly in line with a number of studies with pembrolizumab alone, if not below,” Dr. Sosman noted. “And the response rate was clearly similar in both arms, not just the overall, but in terms of complete and partial responses.” The duration of response was not yet reached.
“This trial was certainly a disappointment, but in the past, disappointing trials were the only trials we reported in melanoma.… Not everything is going to be an improvement.”— Jeffrey A. Sosman, MD
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Grade 3 or worse treatment-related adverse events also occurred in more patients who received the drug combination: 21.8% vs 17.0% in patients who received pembrolizumab and placebo.
Closing Thoughts
“THIS TRIAL was certainly a disappointment, but in the past, disappointing trials were the only trials we reported in melanoma. We’ve gotten really spoiled,” Dr. Sosman said. “But I think there’s an important lesson: not everything is going to be an improvement. Even though there are a lot of good models, it doesn’t always translate. Pembrolizumab and other PD-1 and PD-L1 inhibitors are very active agents in melanoma. Topping them with a significantly improved regimen is a much higher hurdle to get over than we had in the past.”
“The question is, will other people pursue the approach of inhibiting IDO1?” he asked. “If they do, they’re going to need to do it with a different drug and in a different disease setting, looking at intermediate endpoints or having a better trial design.” ■
DISCLOSURE: Dr. Long has received honoraria from Bristol-Myers Squibb, Incyte, Merck, Novartis, and Roche and has served as a consultant/advisor to Amgen, Array BioPharma, Bristol-Myers Squibb, Incyte, Merck, Novartis, Pierre Fabre, and Roche/ Genentech. Dr. Sosman has served as a consultant/advisor (receiving honoraria) to Genentech, Incyte, and Bristol-Myers Squibb.
REFERENCES
1. Long GV, Dummer R, Hamid O, et al: Epacadostat plus pembrolizumab versus pembrolizumab alone in patients with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study. 2018 ASCO Annual Meeting. Abstract 108. Presented June 3, 2018.
2. Sosman JA. Melanoma/skin cancers. 2018 Best of ASCO Chicago. Presented August 11, 2018.
