Abstract
Adding the investigational IDO-pathway inhibitor indoximod to checkpoint inhibitor therapy resulted in a 52% overall response rate in patients with advanced melanoma enrolled in a phase II trial. The combination strategy has potential as an alternative for patients whose tumors do not respond to standard therapy.
Adding the investigational IDO-pathway inhibitor indoximod (NewLink Genetics) to checkpoint inhibitor therapy led to partial or complete responses in more than half of patients with advanced melanoma enrolled in a phase II trial. The combination has potential to become an effective treatment strategy for patients whose tumors do not respond to PD-1 inhibitor therapy alone, according to preliminary data presented during the American Association for Cancer Research Annual Meeting 2017 in Washington, DC.
In the ongoing single-arm trial, 94 patients with inoperable advanced melanoma received indoximod plus the PD-1 inhibitor pembrolizumab (Keytruda; Merck). After a median follow-up of 10.5 months, investigators reported an overall response rate (ORR) of 52% among 60 evaluable patients, including six complete and 25 partial responses. The combination was well tolerated, with fatigue, headache, and nausea the most frequent side effects, and no grade 4 or 5 events reported.
“Indoximod is an effective inhibitor of the IDO pathway, a key immuno-oncology target,” said the study's lead investigator Yousef Zakharia, MD, assistant professor of internal medicine at the University of Iowa in Iowa City, who presented the findings on April 4. “These robust data reinforce the need for development of a phase III trial of anti–PD-1 therapy with indoximod for advanced melanoma.”
At the AACR Annual Meeting 2017, Yousef Zakharia called for a phase III trial of anti–PD-1 therapy with the IDO pathway inhibitor indoximod for advanced melanoma.
The IDO pathway is involved in suppressing immune responses when appropriate—such as to prevent fetal rejection—by degrading tryptophan and increasing the supply of the metabolite kynurenine, which triggers immunosuppression, Zakharia explained. Tumors can hijack this pathway to evade immune control.
Instead of inhibiting IDO itself, however, indoximod is a tryptophan mimetic that directly influences antigen-presenting cells, such as dendritic cells and macrophages, relieving their immunosuppressive features triggered by IDO-induced low tryptophan levels.
Preliminary data from the trial suggest that blocking both the IDO and PD-1 pathways may be more effective than PD-1 inhibition alone, Zakharia added. For example, in the phase III KEYNOTE-006 trial, which tested pembrolizumab alone in patients with advanced melanoma, the ORR was 33%, much lower than the 52% ORR seen with the indoximod combination. However, the two regimens have not been compared head to head.
Notably, the study included nine patients with ocular melanoma, which has been shown to be less responsive to standard treatment and often results in these patients being excluded from trials, Zakharia said. The ORR with the indoximod–pembrolizumab combination rises to 59% if only patients with cutaneous and nonocular melanomas are included in the analysis.
“If verified, these data suggest that [combining IDO and PD-1 inhibitors] may be a strategy for enhancing the likelihood of benefit in this disease,” said Louis Weiner, MD, director of Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. “It has the potential to be a very important milestone in the development of combinatorial strategies, akin to the combination of multiple checkpoint inhibitors.” –Janet Colwell
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