PD-1/IDO Combination Active in Advanced Melanoma

Omid Hamid, MD

A majority of patients with advanced melanoma responded to the combination of pembrolizumab (Keytruda) and the investigational IDO1 inhibitor epacadostat, as reported at the European Society of Medical Oncology congress in Madrid.

In phase I/II results from the ECHO-202/KEYNOTE-037 trial, the combination induced objective responses in 29 of 53 (55%) efficacy-evaluable untreated patients, including seven complete responses. Twenty-two of 38 evaluable patients (58%) responded to the recommended phase II dose of epacadostat (100 mg).

The combination resulted in a median progression-free survival (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.

“Epacadostat and pembrolizumab demonstrated promising antitumor activity in patients with advanced melanoma,” said Omid Hamid, MD, director of the melanoma center at the Angeles Clinic & Research Institute in Los Angeles. “Epacadostat plus pembrolizumab demonstrated a favorable safety profile, consistent with previous reports.

“These results support the ongoing phase III investigation of epacadostat plus pembrolizumab in patients with advanced melanoma.”

The PD-1 inhibitors pembrolizumab and nivolumab (Opdivo) have demonstrated efficacy and good tolerability in advanced melanoma. Previous studies have shown that combination of nivolumab and ipilimumab (Yervoy) led to improved efficacy versus monotherapy but at the expense of increased toxicity. Combination strategies that enhance efficacy and limit toxicity are needed, said Hamid.

Tumors may evade immunosurveillance by a number of mechanisms, including immune checkpoint inhibition of T-cell activation and upregulation of IDO1. Epacadostat specifically inhibits IDO1, Hamid said, and combining it with an immune checkpoint inhibitor might improve outcomes in advanced melanoma and other malignancies.

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).

Hamid said 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 patinets 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 increased (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.