IDO Inhibitors Emerging as New Players on Checkpoint Blockade Scene

Adil Daud, MD

As researchers continue to explore immune checkpoints as targets for anticancer therapies, the IDO pathway has emerged as the leading contender to yield the next batch of new drugs in the field. Clinical trial results thus far have been particularly promising for IDO inhibitors combined with antibodies that target the PD-1/ PD-L1 pathway.

The IDO protein, or indoleamine (2,3)-dioxygenase, has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. The enzyme has 2 isoforms, IDO1 and IDO2, that act as the first step in the metabolic pathway that breaks down the essential amino acid tryptophan.

IDO exerts its immunomodulatory effects by shutting down the effector T cells of the immune system. Increased IDO protein levels then drive growth arrest and apoptosis of the effector T cells, a group of immune cells that includes cytotoxic T cells, helper T cells, and natural killer cells that mediate the immune system’s ability to destroy pathogens. By reducing the number of effector T cells, IDO overexpression prevents the immune system from effectively destroying cancer cells.

Researchers have discovered that IDO is expressed on tumor cells and on cells in the surrounding microenvironment, such as dendritic cells in the tumor-draining lymph nodes (Figure). This offers multiple opportunities for targeting the tumorigenic activities of aberrant IDO signaling.

IDO overexpression has been observed in numerous solid tumors, prompting pharmaceutical developers to evaluate pathway inhibitors in a variety of clinical settings. At least 5 IDO inhibitors are in development (Table), mostly in combination with other immunotherapies including therapeutic vaccines and checkpoint blockade agents, or with standard chemotherapies.

Excitement about the potential for the drugs as a class is building. “Everything is starting to come together for these IDO inhibitors,” said Adil Daud, MD, a leading IDO researcher who is a clinical professor at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, in an interview with OncologyLive^®. “For the last few years, there has been a lot of basic science research done showing that IDO is a fundamental mechanism that keeps pregnancy going, is involved in the immune system, and senses the tumor microenvironment.

Epacadostat

“Now, this current generation of inhibitors is in testing, and they seem to be relatively nontoxic when they’re added to PD-1,” he said. “I think that’s something exciting considering all the immune checkpoint combinations that people are talking about. It seems like they can be combined and have a reasonable rate of activity, with the caveat that, currently, we are just talking about phase II trials.” The most advanced agent under study is epacadostat, an orally available inhibitor of IDO1. Findings from early-phase studies into epacadostat have been promising, particularly in melanoma, where the drug is being paired with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) in separate studies.

In phase I study results, 11 of 19 evaluable treatment-naïve patients with melanoma who received the combination achieved an objective response (58%), including 5 patients (26%) with a complete response (CR) and 6 (32%) with a partial response (PR).¹ The disease control rate, which consisted of CRs, PRs, and stable disease, was 74% (14 patients).

The combination has advanced into a pivotal phase III study. The KEYNOTE-252/ECHO-301 trial will randomize 600 patients in a 1:1 ratio to pembrolizumab with either epacadostat or placebo (NCT02752074). The trial is recruiting patients with stage III/IV melanoma who have not received prior or systemic therapy for metastatic or unresectable disease.

Similarly, the pairing of epacadostat and nivolumab has shown positive early results in patients with melanoma. The combination demonstrated an objective response rate (ORR) of 63% and a CR rate of 5% among 74 patients with treatment- naïve melanoma in the multiarm phase I/II ECHO-204 trial, according to findings presented at the 2017 American Society of Clinical Oncology Annual Meeting in June.²

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

Indoximod

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

Emerging Inhibitors

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).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.