Update Confirms Benefit of Pembrolizumab Plus Indoximod in Melanoma

Charles J. Link, Jr, MD

Adding the IDO inhibitor indoximod to pembrolizumab (Keytruda) led to an overall response rate (ORR) of 61% in patients with advanced melanoma, according to updated phase II data scheduled to be presented at the Third International Cancer Immunotherapy Conference in Frankfurt/Mainz, Germany.

The updated data include a higher complete response (CR) rate of 20% compared with the 12% CR rate previously reported at the 2017 AACR Annual Meeting.¹ The median progression-free survival (PFS) with the combination was 12.9 months, with a 1-year PFS rate of 56%.

“We are encouraged by the progression-free survival and the improvement in complete responses observed in the trial,” Charles J. Link, Jr, MD, chairman, CEO, and Chief Scientific Officer of NewLink Genetics Corporation, the developer of indoximod, said in a statement. “The updated data further support our decision to initiate a pivotal trial for patients with advanced melanoma.”

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. 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.

The data being reported at the Third International Cancer Immunotherapy Conference are for 51 patients with cutaneous, mucosal, and melanoma of unknown primary origin who received pembrolizumab plus indoximod.

The 61% ORR included 10 CRs (20%) and 21 partial responses (41%). Ten additional patients also reached stable disease, for a disease control rate of 80%. Progressive disease was experienced by 10 patients.

Safety data for pembrolizumab plus indoximod were presented at the AACR meeting and included 9 additional patients with ocular melanoma, for a total of 60 patients.

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.

A pivotal trial is now evaluating indoximod plus pembrolizumab or nivolumab versus single-agent pembrolizumab or nivolumab in patients with stage III unresectable and metastatic stage IV melanoma. The enrollment goal is 600 patients and PFS and overall survival are the coprimary endpoints.

“Our team is excited to move forward with this pivotal trial,” Eugene Kennedy, MD, vice president of Clinical and Medical Affairs at NewLink, said in a statement. “We believe that allowing physicians the choice of either pembrolizumab or nivolumab accurately reflects current clinical care and should aid in enrolling the trial by the end of 2018.”

1. Zachariah Y, McWilliams R, Shaheed M, et al. Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indexed in combination with pembrolizumab for patients with advanced melanoma. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; San Washington, DC. Abstract CT117.