Roy Baynes, MD, PhD
The combination of the PD-1 inhibitor pembrolizumab (Keytruda) and the IDO1 inhibitor epacadostat failed to improve progression-free survival (PFS) versus single-agent pembrolizumab in patients with unresectable or metastatic melanoma, according to findings from the phase III ECHO-301/KEYNOTE-252 trial.
Merck (MSD), the developer of pembrolizumab, and Incyte, the manufacturer of epacadostat, also reported in a statement that the study is expected to miss the coprimary endpoint of significantly improving overall survival (OS). Based on the recommendation of an external data monitoring panel, the trial has been stopped.
“We look forward to sharing the comprehensive data analysis from ECHO-301/KEYNOTE-252 with the scientific community at an upcoming medical meeting,” Roy Baynes, MD, PhD, senior vice president and head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said in a statement.
The phase III double-blind ECHO-301/KEYNOTE-252 study (NCT02752074) randomized over 700 patients with unresectable or metastatic melanoma in a 1:1 ratio to pembrolizumab in combination with either epacadostat or placebo. Patients were stratified by PD-L1 status and BRAF mutation status.
Beyond the coprimary endpoints of PFS and OS, secondary outcome measures included objective response rate, safety, and tolerability. Merck and Incyte noted in their statement that the safety profile was similar to previously reported outcomes with the combination.
Early-stage data had shown promise for the combination. In phase I/II results from the ECHO-202/KEYNOTE-037 trial presented at the 2017 ESMO congress, the combination induced objective responses in 29 of 53 (55%) efficacy-evaluable untreated patients, including 7 complete responses. Twenty-two of 38 (58%) evaluable patients responded to the recommended phase II dose of epacadostat (100 mg).
The combination resulted in a median PFS of 22.8 months in the previously untreated group, and had yet to be reached in the patients who received the phase II dose of epacadostat.
Investigators designed the phase I/II ECHO-202/KEYNOTE-037 to evaluate the epacadostat-pembrolizumab combination for patients with advanced melanoma. The protocol excluded patients with prior exposure to an IDO inhibitor or PD-1 inhibitor.
The primary outcome was objective response in the per-protocol cohort. Data analysis included 65 patients (63 treated per protocol), including 54 (53 per protocol) who had no prior treatment of any type for advanced disease.
Overall, 35 of 63 (56%) responded to the combination, including nine complete responses. The disease control rate (DCR), defined as response plus stable disease, was 71% (45 of 63). DCR for patients with no prior treatment was 72% (38 of 53) and 74% for untreated patients who received the phase II dose (28 of 38).
Responses occurred across all key patient subgroups, including patients with BRAF-positive or negative tumors (50% response rate vs 56%), normal vs elevated LDH (62% vs 48%), liver metastases (46%) or without (62%), and M1c stage (49%) or not (64%).
Overall, 30 of 35 responding patients had ongoing responses at last follow-up, and duration of response ranged from 1 to 121 weeks.
The median PFS was 12.4 months (90% CI, 6.2-23.8) for all per-protocol patients. PFS at 6, 12, and 18 months was 65%, 52%, and 49%, respectively, for all patients in the per-protocol analysis. Median PFS for treatment-naïve per-protocol patients was 65% at 6 months, 52% at 12 months, and 52% at 18 months. Six-month PFS was 64% for untreated patients who received the 100-mg dose of epacadostat, 55% at 12 months, and 55% at 18 months.
A safety analysis that included all 65 enrolled patients showed that the most common adverse events (all grades) were rash (46%), fatigue (43%), pruritus (29%), arthralgia (17%), diarrhea (15%), nausea (12%), increased AST (12%), increased lipase (11%), ALT increase (11%), and liver enzyme elevation (11-12%). Grade 3/4 adverse events occurred in 20% of patients and consisted of 4 cases of increased lipase, 3 of rash, 2 each of liver enzyme elevation (AST or ALT), and 1 each of fatigue and arthralgia.
Treatment-related adverse events led to dose interruptions in 16 (25%) patients, dose reductions in 7 (11%), and discontinuation in 4 (6%).
Treatment-related serious adverse events consisted of one case each of arthralgia, autoimmune hepatitis, and colitis. As of the data cutoff, all these events had resolved except the patient with arthralgia.
Among adverse events of special interest, hypothyroidism and severe skin reactions occurred in 4 patients each, colitis and uveitis in 2 each, and autoimmune hepatitis in 1 patient. Grade 3/4 adverse events of interest consisted of 3 cases of severe skin reaction, 2 of colitis, and 1 of autoimmune hepatitis.
Hamid O, Gajewski TF, Frankel AE, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma: Phase 1 and 2 efficacy and safety results from ECHO-202/ KEYNOTE-037. n: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1214O.