Phase II studies of indoximod with checkpoint inhibitors for advanced melanoma and with chemotherapy for pancreatic cancer may revive interest in IDO pathway inhibition- NewLink Therapeutics.

NewLink Genetics Corporation has announced that data from two Phase II studies of indoximod, used in combination with other agents, were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Results from a single-arm Phase II study of indoximod in combination with checkpoint inhibitors for patients with advanced melanoma were presented by Yousef Zakharia, MD, Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center.

In this study, of 102 total patients enrolled, 101 patients with advanced melanoma were treated with indoximod, an IDO pathway inhibitor, plus standard-of-care checkpoint inhibition as approved for melanoma. 70 patients with cutaneous or mucosal melanoma were treated with pembrolizumab plus indoximod and had an on-treatment imaging, meeting the per-protocol, pre-specified definition of evaluable for efficacy. Of the remaining 32 patients, 15 had uveal melanoma, 4 received ipilimumab, 4 received nivolumab.

Key findings from the 70 evaluable for efficacy patients presented from the study include: ORR for combination therapy of 56%. CR of 19%. Median PFS of 12.4 months. PD-L1 greater than 1% staining of 54% (22/41 patients with archival tissue). ORR by PD-L1 status- PD-L1 (+) patients: ORR of 77%. PD-L1 (-) patients: ORR of 42%. Combination was well tolerated.

Results from the second study which was a Phase II study of indoximod plus chemotherapy for patients with metastatic pancreatic cancer were presented at ASCO by Nathan Bahary, MD, PhD, Associate Professor in the Division of Oncology and Medical Director of the Pancreatic Cancer Program at the University of Pittsburgh Medical Center. Key findings from this study show that the combination was well tolerated with a median Overall Survival (mOS) of 10.9 months and an Overall Response Rate (ORR) of 46.1%. Although the study did not meet the prespecified primary goal of a 30% decrease in the risk of death compared with historical controls, the combination demonstrated potentially promising activity with an immunologic correlation for response to therapy.

Comment: IDO inhibitors were being hailed as the next advance in cancer immunotherapy, but a series of trial setbacks reduced that optimism. A failed phase III trial of Incyte’s candidate epacadostat combined with Merck & Co’s Keytruda (pembrolizumab) and negative data from other studies had the effect of diminishing interest in the class. However NewLink Genetics with new data on its IDO drug indoximod is more bullish following the results of these two studies which may be accounted for by the difference in mechanism of indoximod that differs from direct enzymatic inhibitors— the group that includes epacadostat.