In a phase II trial reported in JAMA Oncology, Mariotti et al found that the addition of the indoleamine 2,3-dioxygenase 1 (IDO1) pathway inhibitor indoximod to a taxane did not improve progression-free survival in first-line treatment of patients with metastatic HER2-negative breast cancer.

As noted by the authors, IDO1 causes tumor immune suppression.

Study Details

The double-blind trial included 164 evaluable patients (modified intent-to-treat population) from sites in the United States and Poland. Patients were randomly assigned between August 2013 and January 2016 to receive either paclitaxel at 80 mg/m² weekly (3 weeks on/1 week off) or docetaxel at 75 mg/m² every 3 weeks plus placebo (n = 79) or oral indoximod at 1,200 mg twice daily (n = 85). Indoximod was given on days 1 to 14 of each 21-day cycle when used with docetaxel and on days 1 to 21 of each 28-day cycle when used with paclitaxel. Patients had to be able to receive taxanes and had to have no previous immunotherapy use and no autoimmune disease. Overall, 74.0% of patients in each group received docetaxel and 26% received paclitaxel. The primary endpoint was progression-free survival.

Progression-Free Survival

The study was prematurely discontinued in June 2017 due to lack of efficacy. Median follow-up was 17.4 months (range = 0.1–39.4 months). Median progression-free survival was 6.8 months (95% confidence interval [CI] = 4.8–8.9 months) in the indoximod group vs 9.5 months (95% CI = 7.8–11.2 months) in the control group (hazard ratio [HR] = 1.2, 95% CI = 0.8–1.8). 

Median progression-free survival in the indoximod group was 8.2 months among patients with hormone receptor­–positive disease and 3.2 months among patients with hormone receptor–negative disease. Overall, median progression-free survival was 8.5 months when indoximod was combined with docetaxel and 3.6 months when combined with paclitaxel. In an analysis among 52 patients with data on IDO1 expression, no differences between groups were observed among 30 with high expression (HR = 0.7, 95% CI = 0.3–1.9) or among 22 with low expression (HR = 2.2, 95% CI = 0.7–7.0).

Objective response was observed in 40% vs 37% of patients (P = .74). Median overall survival was 19.5 months (95% CI = 14.5–24.4 months) vs 20.6 months (95% CI = 18.6–22.5 months; HR = 1.0, 95% CI = 0.6–1.6).

Adverse Events

Grade ≥ 3 adverse events occurred in 60.0% of patients in the indoximod group vs 60.8% of patients in the control group, with the most common in the indoximod group being neutropenia (9.4%), anemia (8.2%), and fatigue (7.1%). Adverse events led to discontinuation of treatment in 12.9% vs 12.7% of patients. Death due to adverse events occurred in four patients (4.7%) vs two patients (2.5%), with no deaths being considered related to treatment.

The investigators concluded, “This randomized clinical trial found that, among patients with [HER2]-negative metastatic breast cancer, addition of indoximod to a taxane did not improve progression-free survival compared with a taxane alone.”

Hatem Soliman, MD, of the Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by NewLink Genetic. For full disclosures of the study authors, visit jamanetwork.com.