Epacadostat Falls Short Again

Aung Naing, MD

Adding the IDO1 inhibitor epacadostat to the PD-L1 inhibitor durvalumab (Imfinzi) failed to induce any clinical responses in patients with pancreatic cancer, according to data from the phase I/II ECHO-203 study presented at the 2018 AACR Annual Meeting.

This is the second setback for epacadostat this month. Previously reported findings from the phase III ECHO-301/KEYNOTE-252 trial showed that adding the IDO inhibitor to the PD-1 inhibitor pembrolizumab (Keytruda) failed to improve progression-free survival in patients with melanoma.

Lead ECHO-203 author Aung Naing, MD, associate professor, Department of Investigational Cancer Therapeutics MD Anderson Cancer Center discussed his study’s findings in a press conference at AACR.

“Epacadostat plus durvalumab was generally well tolerated. In patients with pancreatic cancer, no objective responses were observed. A phase II expansion for pancreatic cancer was not conducted,” said Naing.

He reported data for 34 patients enrolled in the phase I portion of the study with either pancreatic cancer (n = 15), melanoma (n = 1), non—small cell lung cancer (NSCLC; n = 10), or squamous cell carcinoma of the head and neck (SCCHN; n = 8).

The 3 + 3 dose-escalation design for phase I started at a dose of epacadostat at 25 mg twice daily and durvalumab at 3 mg/kg every 2 weeks. The highest 2 dose regimens were epacadostat at either 100 mg or 300 mg twice daily combined with durvalumab at 10 mg/kg every 2 weeks. The combination was intended to be administered for a maximum of 12 months, followed by optional treatment with single-agent epacadostat.

The median age across all patients was 68 (range, 46-84), 62% of patients were male, and all patients had an ECOG performance status of 0 or 1. Thirty-three of 34 patients had received at least 1 prior treatment for advanced or metastatic disease.

Naing only shared efficacy data for the patients with pancreatic cancer. Among those 15 patients, the median age was 66 years (range, 46-72), 60% of patients were male, and 93% (n = 14) had received at least 1 treatment for advanced/metastatic disease. Ten patients had liver metastases and 9 patients had prior surgery.

Nine of the 15 patients with pancreatic cancer received one of the highest two epacadostat doses (100 or 300 mg twice daily) with durvalumab. The median epacadostat exposure was 8 weeks (range, 2-33), which was lower compared with the overall population, potentially due to whipple procedures and/or pancreatectomy, according to Naing.

All 15 patients had discontinued treatment at the data cutoff, due to progression, physician decision, or death.

There were no patient responses in the pancreatic cohort, with 5 patients reaching stable disease, including 1 receiving epacadostat at the 25 mg dose, and 2 each at the 100 mg and 300 mg doses. The median duration of disease control was 22 weeks (95% CI, 13-31).

For the overall 34-patient population, results at the data cutoff of October 29, 2017, showed that 5 patients had completed 12 months of combination therapy and continued to receive single-agent epacadostat. Three of these patients were still receiving treatment at the data cutoff.

Twenty-nine patients were no longer receiving treatment at the cutoff, due to progression, an adverse event (AE), physician decision, or death. The median epacadostat exposure was 12.1 weeks (range, 2-121.9).

The most common all-grade AEs were fatigue (32%), pruritus (15%), diarrhea (12%), nausea (12%), and rash (12%). The 1 dose-limiting toxicity was grade 3 rash requiring systemic steroids at the 300 mg epacadostat dosing schedule.

Grade ≥3 AEs occurred in 7 patients, 3 patients had dose reductions related to AEs, 1 patient had a serious treatment-related AE, and there were no treatment-related AEs leading to death.

“Adverse events of special interest were also observed in 53% of the patients at varying grades. In 6 patients there was diarrhea, 6 patients had pruritus, and 5 patients had skin rash,” said Naing.

The maximum-tolerated dose of epacadostat was not reached and epacadostat at either 100 mg or 300 mg twice daily is being used for the phase II expansion cohorts of the study in patients with NSCLC, SCCHN, urothelial carcinoma, melanoma, gastric or gastroesophageal junction cancer, or triple-negative breast cancer.

Naing A, Powderly JD, Falchook G, et al. Epacadostat plus durvalumab in patients with advanced solid tumors: preliminary results of the ongoing, open label, phase I/II ECHO-203 study. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT177.

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