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

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).

References

  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. www.incyte.com/ir/events-and-presentations.aspx.
  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). meetinglibrary.asco.org/record/153930/abstract.
  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. incyte.com/ir/press-releases.aspx. 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. newlinkgenetics.com/pipeline/. 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). meetinglibrary.asco.org/ 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.



View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
Publication Bottom Border
Border Publication
x