IDO Inhibitors Emerging as New Players on Checkpoint Blockade Scene

OncLive Staff
Published: Tuesday, Aug 15, 2017
Epacadostat also has shown efficacy in combination with both PD-1 inhibitors in other tumor types. Updated results of the ongoing phase I/II ECHO-202/KEYNOTE-037 trial demonstrate that the combination of epacadostat and pembrolizumab resulted in ORRs of 34% (13 of 38 patients) in metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN), 35% (14 of 40 patients) in advanced urothelial cell carcinoma, and 33% (10 of 30 patients) in advanced renal cell carcinoma.3

For safety data, a pooled analysis of 294 patients treated with the combination during the trial found that treatment-related adverse events (TRAEs) occurred in 67% of participants, including grade ≥3 AEs in 18%. The most common TRAEs included fatigue (29%), rash (17%), nausea (11%) and pruritus (10%). Four percent of study participants discontinued treatment due to TRAEs.3

For nivolumab, findings from the ECHO-204 study indicate that combining the PD-1 inhibitor with epacadostat resulted in a 23% ORR and a 3% CR rate among 31 patients with SCCHN.2 However, the combination did not prove effective in cohorts of patients with refractory ovarian cancer and colorectal cancer also tested during the study.


Indoximod, a small molecule that acts directly on immune cells to reverse IDO pathway-mediated suppression, has generated evidence of activity, as seen in early-phase clinical study results. The addition of indoximod to pembrolizumab led to an ORR of 52% in patients with advanced melanoma, according to findings from a phase II trial reported at the 2017 American Association for Cancer Research Annual Meeting (AACR).4

The combination was evaluated in the single-arm phase II NLG2103 trial in which indoximod was added to physician’s choice of FDA-approved checkpoint inhibitors for melanoma: ipilimumab (Yervoy), nivolumab, or pembrolizumab. Accrued patients had unresectable stage III/IV melanoma, had not received systemic treatment for at least 28 days, and had an ECOG performance status of 2 or lower.

As of March 2017, 102 patients had enrolled, with 94 receiving pembrolizumab and 8 receiving either nivolumab or ipilimumab. In the pembrolizumab arm, patients received the PD-1 inhibitor intravenously at 2 mg/kg every 3 weeks, along with oral indoximod at 1200 mg twice daily in 21-day cycles. At the AACR meeting, data were reported for 60 evaluable patients who received pembrolizumab plus indoximod.

Across the entire cohort, 31 (52%) patients had a response, including 6 CRs (10%) and 25 PRs (42%). The stable disease rate was 22% and the progressive disease rate was 27%. When excluding the 9 patients with ocular melanoma, the ORR, CR rate, and PR rate increased to 59%, 12%, and 47%, respectively.

The most common all-grade adverse events (AEs) included fatigue (60%), headache (33%), nausea (32%), arthralgia (28%), diarrhea (28%), pruritus (26%), rash (23%), and cough (21%). Grade 3 AEs included 1 incident each of fatigue, diarrhea, and rash.

NewLink Genetics, which is developing indoximod, plans to launch a pivotal phase III clinical trial combining the agent with a PD-1 inhibitor in the second half of 2017, according to its website.5

The agent also has demonstrated efficacy in combination with sipuleucel-T (Provenge) in a phase II study of patients with metastatic castration- resistant prostate cancer.6 In the study, 46 patients were randomized to receive twice-daily oral indoximod (n = 22) or placebo (n = 24) for 6 months following treatment with sipuleucel- T. The median radiographic progression-free survival was 10.3 months in the experimental arm compared with 4.1 months for the placebo group (P = .011).

Emerging Inhibitors

Among other IDO inhibitors in development, early study findings for BMS-986205 demonstrate promising signals. BMS-986205, which inhibits IDO1, restored human T-cell proliferation in dendritic cells while lowering levels of the immunosuppressive metabolite kynurenine in preclinical studies.

In a phase I/IIa study, BMS-986205 was escalated from 25 to 200 mg daily across several previously treated advanced malignancies. The median age of patients was 58 years, and approximately 40% were males. The ECOG performance status was 0 or 1, and most patients had stage IV disease (approximately 80%).7

Single-agent oral BMS-986205 was administered once daily for a 2-week lead-in period, followed by nivolumab at 240 mg intravenously every 2 weeks. Expansion cohorts were opened for patients with cervical, SCCHN, and bladder cancer. BMS-986205 showed significant reduction in intratumoral kynurenine in samples from 13 patients.

The drug is being explored in a 3-arm trial in combination nivolumab at 2 doses or with nivolumab plus ipilimumab. The phase I/ II trial seeks to enroll more than 900 patients (NCT02658890).


  1. Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037. Presented at: 2016 European Society for Medical Oncology Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD.
  2. Perez RP, Riese JM, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary phase I/II results of ECHO-204 [ASCO abstract 3003]. J Clin Oncol. 2017;35 (suppl).
  3. Updated data from ECHO-202 trial of Incyte’s epacadostat in combination with Merck’s Keytruda (pembrolizumab) demonstrate clinical activity across multiple tumor types [news release]. Wilmington, DE, and Kenilworth, NJ: Incyte Corporation and Merck; June 5, 2017. Accessed August 8, 2107.
  4. Zakharia Y, McWilliams R, Shaheen M, et al. Interim analysis of the phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma. [AACR abstract CT117]. Cancer Res. 2017;77(13 suppl). doi: 10.1158/1538-7445.AM2017-CT117.
  5. NewLink Genetics. IDO pathway inhibitor clinical development. Accessed August 8, 2017.
  6. Gopalji Jha G, Gupta S, Tagawa ST, et al. A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC) [ASCO abstract 3066]. J Clin Oncol. 2017;35(suppl). record/145096/abstract.
  7. Siu LL, Gelmon K, Chu Q, et al. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial. [AACR abstract CT116]. 2017;77(13 suppl). doi: 10.1158/1538-7445.AM2017-CT116.

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