With clinical news pouring from pharma giants matching up the indoleamine 2,3-dioxygenase 1 (IDO1) blocker mechanism with PD-1 immune checkpoint inhibitors, Newlink Genetics Corp.'s interim results from NLG2103 – a phase II study evaluating its IDO pathway blocker indoximod as a combo candidate in advanced melanoma – seemed to take a back seat.
"In comparison to other clinical trials combining anti-PD-1 with CTLA-4 [therapy], the toxicity was significant at that point, with grade 3-4 toxicity as high as 55 percent," said lead trial NLG2103 investigator Yousef Zakharia, assistant professor of medicine in the division of hematology, oncology and blood and marrow transplantation at the University of Iowa and Holden Comprehensive Cancer Center. "Obviously, we need to interpret these data with caution, since it's not a head-to-head combination," he added.
The outcomes available at this point involve a cohort of 60 evaluable patients, including those with ocular melanoma, who received indoximod plus Keytruda (pembrolizumab, Merck & Co. Inc.) which turned up a 52 percent (31/60) overall response rate (ORR) and a 73 percent (44/60) disease control rate (DCR). Patients with non-ocular melanoma achieved a 59 percent (30/51) ORR and an 80 percent (41/51) DCR. The combo was generally well-tolerated, with low rates of grade 3 or higher adverse events. Data were presented at the American Association for Cancer Research (AACR) annual meeting in Washington. NLG2103 goes on, evaluating the duality of indoximod with standard-of-care checkpoint inhibitors approved for patients with advanced melanoma: Keytruda; Yervoy (ipilimumab), from New York-based Bristol-Myers Squibb Co. (BMS); or Opdivo (nivolumab), also from BMS. Evaluable patients are defined as those having at least one on-treatment imaging study. The primary outcome measure is ORR and secondary outcome measures include DCR, as well as safety and tolerability.
More results from NLG2103 will roll out at future meetings. IDO is fast becoming a "key immuno-oncology target," Zakharia said, as promising preclinical data "indeed seem to be translating into clinical benefit. At the end of the day, the [possibility of treatment with the immune system] does not stop at PD-1 and CTLA-4. There are multiple other targets, pathways. IDO is one of the most exciting."
Other trials are underway that are designed to test indoximod when used with chemotherapy against breast, brain and prostate tumors, as well as acute myeloid leukemia, he told BioWorld Today. There's an experiment in pancreatic cancer, too, testing the drug with gemcitabine and Abraxane (nab-paclitaxel, Celgene Corp.)
Newlink has a second IDO inhibitor, GDC-0919, partnered with Genentech, a unit of Basel, Switzerland-based Roche Holding AG. Jefferies analyst Biren Amin noted in a late-February research report that data on that compound lie ahead. Newlink "remains unable to speak about GDC-0919, as Roche controls the communication around this asset. However, management continues to expect that an update will be provided soon." Newlink "reiterated [as part of its earnings report] that the ongoing phase I trial of GDC-0919 includes multiple solid tumor cohorts, some with atezolizumab [Tecentriq, Roche AG] combo, with a total target enrollment of 305 patients," he said. During the February conference call, analysts made known their thirst for biopsy data related to the melanoma study, but company officials said nothing's available yet.
There are a salt formulation and a prodrug of indoximod coming down the pike. CEO Charles Link said on the earnings conference call that "once we have the novel formulation of the salt in the clinic, that will be used in all of the indoximod studies on a go-forward basis, with the exception of one pediatric trial. The indoximod prodrug, NLG802, is a new chemical entity," and therefore must go through a "standard rigorous phase I development process before it would be available to move into phase II testing," he said.
Also at AACR in melanoma, BMS provided the first overall survival (OS) data with Opdivo in combination with Yervoy in a phase III trial, CHECKMATE -067, which enrolled 945 patients with previously untreated advanced melanoma. Data showed the pairing reduced the risk of death by 45 percent [hazard ratio (HR) 0.55; 95 percent CI: 0.42-0.72; p<0.0001] vs. Yervoy alone. As monotherapy, Opdivo reduced the risk of death by 37 percent (HR 0.63; 95 percent CI: 0.48-0.81; p<0.0001) compared with Yervoy, an anti-CTLA-4 drug, as a monotherapy. Two-year OS rates were 64 percent for the combination regimen, 59 percent for Opdivo alone and 45 percent for Yervoy alone. Safety data were consistent with earlier results.
Other IDO work involves BMS, which is going up against Kenilworth, N.J.-based Merck & Co. Inc. and which recently broadened its pact with Incyte Corp., of Wilmington, Del., the firms moving their program into late-stage trials to test the combination of epacadostat, Incyte's oral selective IDO enzyme inhibitor, with blockbuster Opdivo. Phase III registrational studies will be done in first-line non-small-cell lung cancer across the spectrum of PD-L1 expression, and in first-line head and neck cancer. Preliminary data from the ongoing ECHO-204 study evaluating the safety, tolerability and efficacy of Opdivo in combination with epacadostat in select advanced cancers helped the company pull the phase III trigger. Incyte's deal with BMS comes on the heels of a collaboration nailed down lately with Merck. (See BioWorld Today, May 28, 2014.)
Shares of Ames, Iowa-based Newlink (NASDAQ:NLNK) ended Tuesday at $20.79, down $2.30, or 10 percent.