Kate Johnson

April 05, 2017

WASHINGTON, DC — "Exciting" was the word used by several independent experts after hearing interim phase 2 results on the addition of the investigational IDO (indoleamine-2,3-dioxygenase) pathway inhibitor indoximod to standard pembrolizumab in patients with advanced melanoma.

Results of the NLG2103 study, presented here at the American Association for Cancer Research (AACR) Annual Meeting 2017were "exceptionally high," said Laura Q.M. Chow, MD, the discussant for the study from the University of Washington, Seattle.

"To my knowledge, this is the largest publicly available data on melanoma patients treated with IDO and checkpoint inhibitors," said study investigator Yousef N. Zakharia, MD, from the University of Iowa, Iowa City.

The "robust data" support phase 3 development of the indoximod/ pembrolizumab combination for the treatment of advanced melanoma, he said.

Among 60 evaluable patients treated with the combo therapy, the overall response rate (ORR) was 52% and disease control rate (DCR) was 73%, Dr  Zakharia reported.

While cautioning against head-to-head comparisons, he pointed out that the phase 3 KEYNOTE-006 clinical trial that led to US Food and Drug Administration approval of single-agent pembrolizumab in this setting had an ORR of 33%.

Additionally, trials of other checkpoint inhibitors have shown much higher toxicity.

"Remarkably, the treatment was generally well tolerated. This in contrast to many other combinations of immunotherapeutic agents that often have serious side effects," agreed Anna Vilgelm, MD, PhD, from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, who was not involved in the trial.

This multicenter, open-label, single-arm study included 102 patients with unresectable, metastatic melanoma.

Patients were treated with their physicians' choice of one of three checkpoint inhibitors — pembrolizumab, ipilimumab, or nivolumab — in combination with indoximod, 1200 mg twice daily, until toxicity or progression.

"The majority of patients had stage IV disease, and half had stage 1c,  meaning distant metastases outside the lung and lymph nodes, and all were treatment naive for checkpoint inhibitors," said Dr Zakharia.

Most patients (n = 94) were treated with the pembrolizumab/indoximod combination and were included in this analysis.

Importantly, patients with ocular melanoma (n = 9) were not excluded.

"As we all know, ocular melanoma is an aggressive disease and does not respond to the current available systemic treatments," he noted. Excluding those patients from the final results improved the ORR to 59% and DCR to 80%.

"This is an impressive improvement compared to response rates previously seen in clinical trials where IDO inhibitors and pembrolizumab were used individually," Dr Vilgelm told Medscape Medical News.

"If these response rates and safety profiles remain consistent in a larger cohort, this would suggest that pembrolizumab and indoximod combination can improve outcome for patients with melanoma without further reducing their life quality.  While larger studies of efficacy and safety of therapies that combine IDO inhibitors and anti-PD-1 [programmed cell death-1] agents are needed, these early results are very exciting."

"This is very exciting," agreed Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who moderated the press conference.

"Here's an example of actually taking drugs that are designed to work together based on an extensive body of literature that has been painstakingly accumulated over several decades…which suggests that this is a strategy for enhancing the likelihood of benefit in this disease, and that would be a really important milestone," he told reporters.

However, while calling it a "very surprising and interesting result," meeting discussant Dr Chow cautioned that "to actually really know we need a randomized clinical trial."

"Is this just a spurious finding? Perhaps not, I think there's actually some synergy," she said.

But "there is a very competitive landscape for melanoma," she pointed out. "There are more than 20 PD-1 agents in development, more than 140 melanoma combination trials with immune checkpoint inhibitors, more than 803 immune checkpoint inhibitor combination trials, and over 167,000 patients on immunotherapy trials."

"We will probably spend the rest of our lifetime looking for 'drug X,' and this is a major challenge for the field," she said. "Although we have seen amazing results today and this will be an important drug X perhaps for the future, it's difficult to know where this will fit in the current landscape to improve our cure rates and responses for our patients."

The study was funded by NewLink Genetics. Dr Zakharia has received scientific conference travel support from NewLink Genetics. Dr Chow disclosed she is a consultant or serves on the advisory board for Amgen, Bristol-Myers Squibb, AstraZeneca, Genentech, Pfizer, and Novartis and receives grant/research support from Incyte, Bristol-Myers Squibb, Astra Zeneca, Genentech, Pfizer, and Novartis. Dr Weiner disclosed relationships with AbbVie, Celldex Pharmaceuticals, Cytomx, Genentech, Jounce Pharmaceuticals, Merck, Merrimack Pharmaceuticals, Novartis, Targeted Diagnostics, and Therapeutics, Inc.  Dr Vilgelm has disclosed no relevant financial relationship.

American Association for Cancer Research (AACR) Annual Meeting 2017. Abstract CT117. Presented April 4, 2017.

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