August 2017 VOL 8, NO 8
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2017 Annual Meeting of the American Association for Cancer Research
Novel Combo Boosts Immune Response in Melanoma
The novel combination of the investigational IDO pathway inhibitor indoximod plus pembrolizumab led to higher response rates in patients with advanced melanoma than what is seen with pembrolizumab alone, according to interim analysis of a phase 2 clinical trial reported at the 2017 Annual Meeting of AACR.
The overall response rate (ORR) to first-line pembrolizumab in advanced melanoma was 33% in the pivotal phase 3 KEYNOTE-006 trial, while the ORR in the phase 2 trial for the combination of indoximod plus pembrolizumab was 52%.
“These results justify moving the combination of indoximod plus pembrolizumab forward to a phase 3 trial,” said lead author Yousef N. Zakharia, MD, University of Iowa, Iowa City.
The IDO pathway is a key player in cancerogenesis, he explained.
“Several IDO inhibitors in development are being studied in multiple solid tumors and hematologic malignancies,” Dr Zakharia said.
The phase 2, open-label, single-arm study enrolled 102 patients with stage III (13%) or IV (87%) advanced unresectable melanoma treated with indoximod plus pembrolizumab until disease progression. At the meeting, data from 60 patients were reported. Of these, 40 had cutaneous melanoma, 9 had ocular melanoma (a type of melanoma that has very poor response to any therapy), and 11 had non-ocular melanoma.
Patients could switch to a second checkpoint inhibitor (mainly ipilimumab) at progression and continue on indoximod.
In 60 patients, ORR was 52% (31 patients); 6 of these were complete responses and 25 were partial responses. ORR was 59% in patients with cutaneous or non-ocular melanoma; 6 were complete responses and 24 were partial responses. The disease control rate (response plus stable disease) was 73% in the overall population and 80% in the group with cutaneous/non-ocular melanoma.
“This is the largest publicly available data set on IDO inhibitors plus checkpoint inhibitors,” Dr Zakharia noted.
In this study, as in other studies of different therapies, ocular melanoma had a poor response to combination therapy.
“We had impressive responses in non-ocular melanoma, with many patients near CR,” he noted. Most responses occurred within the first months of treatment.
The combination was well tolerated. The majority of adverse events were as expected, with few grade 3 events and no grade 4 events. Serious adverse events potentially related to indoximod were reported in 4 patients (grade 3 arthritis, gastritis, hearing impairment, and grade 2 interstitial nephritis), and 3 of these patients discontinued treatment. No treatment-related deaths were reported.
Dr Zakharia and colleagues were not able to identify biomarkers for response in the patients studied to date. “One could arguably say that the combination appears to get a better response with higher PD-L1 expression, but this needs to be interpreted with caution,” he noted.
Press conference moderator Louis Weiner, MD, Director of the Georgetown-Lombardi Cancer Center, Washington, DC, called these results “exciting” and, if validated, “would represent a real advance.”
“It’s too soon to tell, but the approach of priming the immune response with novel strategies looks promising,” he said. “It will be a vigorous competition among ways to manipulate checkpoint inhibitors, but we don’t know who will win.”
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