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Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond

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Abstract

With immunotherapy enjoying a rapid resurgence based on the achievement of durable remissions in some patients with agents that derepress immune function, commonly referred to as “checkpoint inhibitors,” enormous attention developed around the IDO1 enzyme as a metabolic mediator of immune escape in cancer. In particular, outcomes of multiple phase 1/2 trials encouraged the idea that small molecule inhibitors of IDO1 may improve patient responses to anti-PD1 immune checkpoint therapy. However, recent results from ECHO-301, the first large phase 3 trial to evaluate an IDO1-selective enzyme inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in advanced melanoma, showed no indication that epacadostat provided an increased benefit. Here we discuss several caveats associated with this failed trial. First is the uncertainty as to whether the target was adequately inhibited. In particular, there remains a lack of direct evidence regarding the degree of IDO1 inhibition within the tumor, and previous trial data suggest that sufficient drug exposure may not have been achieved at the dose tested in ECHO-301. Second, while there is a mechanistic rationale for the combination tested, the preclinical data were not particularly compelling. More efficacious combinations have been demonstrated with DNA damaging modalities which may therefore be a more attractive alternative. Third, as a highly selective IDO1 inhibitor, epacadostat was advanced aggressively despite preclinical genetic evidence of tumors bypassing IDO1 blockade. Indeed, a well-grounded literature starting in 2011 points to targeting strategies that account for both IDO and tryptophan 2,3-dioxygenase as more appealing directions to pursue, including dual inhibitors and inhibitors of nodal downstream effector pathways such as aryl hydrocarbon receptor blockade. Overall, the clinical readout from a single trial with significant limitations is by no means a definitive test for the field. While biomarker information yet to be gleaned from ECHO-301 may yet reveal useful information regarding IDO1 pathway drugs, better rationalized compounds and better rationalized trial designs will be important in the future to accurately gauge medical impact.

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Acknowledgements

G.C.P. and A.J.M. acknowledge grant support from the NCI (R01 CA191119) and the W.W. Smith Trust, with additional support from the Lankenau Medical Center Foundation and the Main Line Health System. G.C.P. holds The Havens Chair for Biomedical Research at the Lankenau Institute for Medical Research.

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Authors and Affiliations

  1. Lankenau Institute for Medical Research (LIMR), 100 East Lancaster Avenue, Wynnewood, PA, 19096, USA

    Alexander J. Muller & George C. Prendergast

  2. Kyn Therapeutics, Cambridge, MA, 01238, USA

    Mark G. Manfredi

  3. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA

    Yousef Zakharia

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  1. Alexander J. Muller
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  2. Mark G. Manfredi
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Correspondence to Alexander J. Muller.

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Conflict of interest

G.C.P. and A.J.M. are shareholders and G.C.P. is a former compensated scientific advisor and grant recipient for New Link Genetics Corporation, a biopharmaceutical company that has licensed IDO intellectual property for clinical development from the Lankenau Institute of Medical Research, as described in U.S. Patents Nos. 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454, and 8586636. G.C.P. is a compensated scientific advisor for Kyn Therapeutics Inc. which is developing IDO/TDO/AHR pathway antagonists for cancer treatment. A.J.M. is a grant recipient and compensated scientific advisor for I-O Biotech AG which is developing IDO vaccines for cancer treatment. MM is a shareholder in Kyn Therapeutics. Y.Z. is a recipient of research and conference travel support from NewLink Genetics and an advisory board member for Amgen, Roche Diagnostics, Novartis, Eisai, Castle Bioscience, and Exelixis.

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This article is a contribution to the special issue on Anti-cancer immunotherapy: Breakthroughs and Future strategies - Guest Editor: Mads Hald Andersen

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Muller, A.J., Manfredi, M.G., Zakharia, Y. et al. Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin Immunopathol 41, 41–48 (2019). https://doi.org/10.1007/s00281-018-0702-0

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