Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial

Abstract

Importance: Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial.

Objective: To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane.

Design, setting, and participants: This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020.

Interventions: A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment.

Main outcomes and measures: The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis.

Results: Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms.

Conclusions and relevance: This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone.

Trial registration: ClinicalTrials.gov Identifier: NCT01792050.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Han reported receiving grants from the Department of Defense, personal fees for serving on a speakers bureau from Eli Lilly, and institutional research funding from Arvinas, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Novartis, Pfizer, G1 Therapeutics, Horizon Pharma, Seattle Genetics, and Zymeworks outside the submitted work. Dr Kennedy reported employment and stock ownership from Lumos Pharma during the conduct of the study and employment and stock ownership from NewLink Genetics outside the submitted work. Dr Vahanian reported being a former executive at NewLink Genetics. Dr Link reported receiving personal fees and employment from NewLink Genetics during the conduct of the study and outside the submitted work; in addition, Dr Link had a patent to indoximod licensed. Ms Tennant reported receiving personal fees and employment from NewLink Genetics during the conduct of the study and outside the submitted work. Ms Schuster reported stock ownership from NewLink Genetics (now Lumos Pharma) outside the submitted work. Mr Smith reported employment from NewLink Genetics during the conduct of the study. Dr Soliman reported receiving institutional research funding from NewLink Genetics Inc during the conduct of the study and institutional funding from Amgen and personal fees from Celgene, AstraZeneca, Novartis, Eisai, and Puma Biotechnology outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Consort Diagram

Figure 2.. Outcomes in the Entire Study Population and Within the IDO1-Analyzed Population

A, Progression-free survival in the modified intention-to-treat (mITT) population; B, Overall survival in the mITT population; C, Progression-free survival in the indoleamine 2,3-dioxygenase 1 (IDO1)-low population; D, Progression-free survival in the IDO-high population. HR indicates hazard ratio.