Epacadostat/Durvalumab Combo Well Tolerated in Solid Tumor Trial

A combination of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor epacadostat with the anti–programmed death ligand 1 (PD-L1) antibody durvalumab was well tolerated in a phase I trial of patients with multiple solid tumor types. The combination is now being studied in multiple phase II expansion cohorts.

IDO1 is an intracellular enzyme that catalyzes the rate-limiting step of tryptophan degradation. Previous research suggests it could be a promising therapeutic target.

“Epacadostat is a potent and highly selective IDO1 inhibitor,” said Aung Naing, MD, of the MD Anderson Cancer Center in Houston, during a press conference on Tuesday. Naing presented results of the ECHO-203 study at the American Association for Cancer Research Annual Meeting (AACR), held April 14–18 in Chicago.

The study included patients 18 years of age and older with melanoma, non–small-cell lung cancer (NSCLC), squamous cell cancer of the head and neck (SCCHN), or pancreatic cancer. All patients had either failed to respond to at least one prior treatment regimen for locally advanced or metastatic disease, or were intolerant to the treatment. The analysis presented at the AACR meeting included 34 patients, five of whom completed 12 months of combination therapy with epacadostat and durvalumab, while the other 29 discontinued due to disease progression, an adverse event, physician decision, or death.

The median age in the trial was 68 years, and 62% of the cohort were male. Fifteen patients (44%) had pancreatic cancer, followed by NSCLC (29%), SCCHN (24%), and melanoma (3%).

The safety profile of the combination therapy was similar to that seen with durvalumab monotherapy, according to Naing. There was one dose-limiting toxicity in the trial, a grade 3 rash at the dosage of epacadostat at 300-mg twice daily plus durvalumab at 10-mg once every 2 weeks.

A total of seven patients (21%) had an adverse event of grade 3 or higher, and treatment-related AEs led to dose interruptions in seven patients (21%). Three patients (9%) needed a dose reduction due to a treatment-related AE, and 1 patient (3%) had a serious treatment-related AE. No treatment-related AEs led to death in the trial.

AEs of special interest, which focused on immune-related AEs, were reported in 53% of the cohort, including diarrhea in 6 patients, pruritus in 6 patients, and rash in 5 patients. The maximum tolerated dose was not reached for epacadostat. Epacadostat dose levels of 100-mg twice daily and 300-mg twice daily are being evaluated in a phase II trial.

An analysis of the pancreatic cancer patients in the trial showed no responses to the combination therapy, with a disease control rate of 33% (five patients with stable disease). The exposure to epacadostat was lower in these patients than in patients with other tumors.

“Epacadostat plus durvalumab was generally well tolerated in patients with advanced cancers,” said Naing. No expansion cohort in pancreatic cancer is being conducted, but phase II expansions are now ongoing in patients with NSCLC, SCCHN, urothelial carcinoma, melanoma, gastric or gastroesophageal junction cancer, and triple-negative breast cancer.

Suzanne L. Topolian, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, moderated the press conference on Tuesday, and she noted that epacadostat is being studied “in literally dozens of clinical trials,” though the ECHO-203 study marks the first data on administration of this agent in combination with an anti–PD-L1 inhibitor.