IDO Inhibitor Increases Pembrolizumab Response in Melanoma

Yousef N. Zakharia, MD

Adding the IDO inhibitor indoximod to pembrolizumab (Keytruda) led to an overall response rate (ORR) of 52% in patients with advanced melanoma, according to findings from a phase II trial reported at the 2017 AACR Annual Meeting.¹

The ORR increased to 59% when excluding patients with ocular melanoma. With these results, lead study author Yousef N. Zakharia, MD, et al, achieved their objective of improving upon the 33.7% ORR with pembrolizumab shown in the pivotal phase III KEYNOTE-006 trial, which compared the PD-1 inhibitor to ipilimumab (Yervoy) in advanced melanoma.²

“These data support phase III development of indoximod plus pembrolizumab for the treatment of advanced melanoma,” said Zakharia, assistant professor in the Department of Internal Medicine at the University of Iowa.

The open-label, nonrandomized, single-arm phase II NLG2103 trial evaluated the addition of indoximod to physician’s choice of FDA-approved checkpoint inhibitors for melanoma: ipilimumab, nivolumab (Opdivo), or pembrolizumab (Keytruda). 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. The primary endpoint of the study was ORR.

Treatment was administered until unacceptable toxicity or disease progression. Imaging was done at week 12 and then every 8 weeks, thereafter. Patients were allowed to cross over to receive another checkpoint inhibitor at progression, while also continuing indoximod.

At the AACR meeting, Zakharia reported data for 60 evaluable patients who received pembrolizumab plus indoximod. The median patient age was 62.3 years (range, 27-88), 67% of patients were male, 87% of patients had stage IV disease, and 73% of patients had an ECOG performance status of 0. Nine patients (15%) had ocular melanoma and about half the patients had received prior therapy.

Across the entire cohort, 31 (52%) patients had a response, including 6 (10%) complete responses (CRs) and 25 (42%) partial responses (PRs). The stable disease (SD) rate was 22% and the progressive disease (PD) 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. Elevated lab values included alanine aminotransferase (2 patients), amylase (1), aspartate aminotransferase (2), alkaline phosphatase (4), creatinine (4), and lipase (2).

Serious AEs potentially related to indoximod included grade 3 arthritis, gastritis, and hearing impairment, as well as grade 2 interstitial nephritis. Three patients discontinued treatment due to serious AEs. Immune-mediated AEs included dermatitis (2 patients), hypothyroidism (2), pneumonitis (2), colitis (1), gastritis (1), and nephritis (1). There were no treatment-related deaths.

Regarding the potential of a triplet regimen with pembrolizumab, ipilimumab, and indoximod, Zakharia said, “What worries me with that combination is the overall toxicity that we are encountering with pembrolizumab/ipilimumab or nivolumab/ipilimumab combinations of PD-1 and CTLA-4 [inhibitors]…I think [a triplet] is an interesting concept, and one would expect that it might increase the efficacy, but it needs to be tested.”

In September 2014 the FDA approved pembrolizumab as a treatment for patients with advanced or unresectable melanoma. The FDA expanded the approval in December 2015 to include the frontline treatment of patients with advanced melanoma, and at the same time, updated the existing label for pembrolizumab to include the treatment of patients with ipilimumab-refractory melanoma.

References

1. 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. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; San Washington, DC. Abstract CT117.
2. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093.

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