Blocking IDO1 Helps Shrink Bladder, Cervical Tumors

The race to bring the first inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) to market heated up this month as researchers presented new data on the antitumor and immunomodulatory activity of BMS-986205 (Bristol-Myers Squibb) in combination with the company's PD-1–targeting agent nivolumab (Opdivo).

Reporting at the Society for Immunotherapy of Cancer's 2017 annual meeting in National Harbor, MD, Jason Luke, MD, of the University of Chicago Medicine in Illinois, showed that this combination was reasonably safe among the first 289 patients enrolled in the phase I/IIa CA017-003 trial. Serious adverse events occurred in 11% of participants, although generally not at the 100-mg dose selected for further evaluation.

The efficacy data also look promising for the two tumor types disclosed. Among 25 patients with bladder cancer, the objective response rate (ORR) was 32% and the durable response rate (DRR), which includes cases of stable disease, was 44%. For the 22 patients with cervical cancer, the ORR was 14% and the DRR was 64%. These results “compare favorably against anti–PD-1/PD-L1 inhibitors alone in these diseases,” says trial investigator Lillian Siu, MD, of Princess Margaret Cancer Centre in Toronto, Canada. In previous trials of nivolumab monotherapy, ORRs ranged from about 17% to 20% for previously treated bladder and cervical cancer.

Luke expects IDO1 inhibition combined with PD-1/PD-L1 blockade to soon become the “new backbone” for immunotherapy. “The two targets nearly always go together,” he says, “and since it's not toxic to combine them, we should do so.”

IDO1 inhibitors work by blocking the breakdown of a crucial amino acid, tryptophan, in the tumor microenvironment. This helps tip the immune balance from regulatory T cells toward cytotoxic ones. Luke confirmed BMS-986205's activity in the study, showing that at most doses tested, serum levels of the tryptophan metabolite kynurenine dropped by half, on average. The number of cytotoxic T cells also increased for the majority of patients, across a range of tumor types.

Michael Platten, MD, of Heidelberg University in Germany, describes these biological indicators of activity as “intriguing,” but says “there is no striking finding in this phase I/IIa study without a proper comparator and in a mixed patient population that would allow differentiation to other programs.” Yousef Zakharia, MD, of the University of Iowa in Iowa City, who has been involved in trials of the rival IDO1 inhibitor indoximod (NewLink Genetics), agrees. “I don't think we can differentiate between the three agents,” he says. “The data across the board look promising that this is an important pathway to target.”

The most obvious difference between BMS-986205, indoximod, and the other leading IDO1 inhibitor in clinical development, epacadostat (Incyte), is in the former's pharmacokinetics and pharmacodynamics. BMS-986205 can be taken once a day, whereas the other two require twice-daily dosing. What's more, says Luke, “this is the most potent IDO1 inhibitor out there”—although whether that stronger inhibition translates into a clinical difference remains to be seen.

Top-line results from a phase III study of epacadostat plus pembrolizumab (Keytruda; Merck) in patients with advanced melanoma are expected next year. Data from comparable pivotal melanoma trials of BMS-986205 or indoximod, in conjunction with PD-1 inhibitors, won't be known until 2020, at the earliest. “First to market will have a big advantage,” says Luke, who also had a hand in testing epacadostat for lung cancer, “but given that the future is clearly in combinations, they will all have a role,” he says of these agents. –Elie Dolgin