Companies Scaling Back IDO1 Inhibitor Trials

At the American Society of Clinical Oncology's (ASCO) Annual Meeting in June 2017, researchers presented promising safety and efficacy data from early-phase trials of Incyte's IDO inhibitor epacadostat. Now, less than a year later, the company is “significantly downsizing” its epacadostat program and halting some trials due to negative results. Two other companies have signaled that they, too, will end IDO inhibitor trials.

Incyte announced in April that a phase III study of epacadostat combined with the PD-1 inhibitor pembrolizumab (Keytruda; Merck) for the treatment of inoperable or metastatic melanoma will be stopped. Patients in this study, dubbed ECHO-301/KEYNOTE-252, who received the combination experienced no improvement in progression-free survival compared with pembrolizumab alone. Data regarding overall survival were not yet available, but are “not expected to reach statistical significance,” the company said.

Further, although the combination of epacadostat and the PD-L1 inhibitor durvalumab (Imfinzi; AstraZeneca) was found to be safe for the treatment of advanced solid tumors, it yielded no responses in 15 patients with pancreatic cancer enrolled in the phase I/II ECHO-203 trial, according to data presented last month at the American Association for Cancer Research (AACR) Annual Meeting 2018.

Tumors evade immunosurveillance through multiple mechanisms—for example, checkpoint inhibition of T-cell activation and upregulation of IDO1, an IFNγ-induced intracellular enzyme that catalyzes tryptophan degradation in the kynurenine pathway, explained Aung Naing, MD, of The MD Anderson Cancer Center in Houston, TX, who presented the ECHO-203 findings. Because tryptophan depletion and kynurenine production creates an immunosuppressive tumor microenvironment, researchers had hypothesized that combining epacadostat with a checkpoint inhibitor such as durvalumab might be an effective treatment strategy, he said.

Epacadostat's lack of effectiveness in pancreatic cancer didn't surprise Gregory Beatty, MD, PhD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia. “It was reported almost 20 years ago in many patients with pancreatic cancer that T cells, both systemic and intratumoral, are hypofunctional,” he noted. “While more recent work has correlated increased T-cell infiltrates with improved outcomes for patients with surgically resected pancreatic cancer, these patients are uncommon.”

Given the ECHO-203 results to date, no additional studies of the combination in pancreatic cancer will be conducted. However, Naing said that researchers will expand enrollment for phase II assessments in other solid tumors, including non–small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), melanoma, urothelial carcinoma, gastric cancer, and triple-negative breast cancer.

Other Incyte trials will be modified or end. On May 1, the company announced that two pivotal trials of epacadostat in combination with pembrolizumab for the treatment NSCLC (ECHO-305 and ECHO-306) will be converted into randomized phase II trials. In addition, enrollment will be discontinued for four other phase III trials of that drug combination—in urothelial carcinoma, HNSCC, and renal cell carcinoma—and for two phase III trials of epacadostat plus the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb)—in NSCLC and SCCHN. Further, a phase III trial of epacadostat in combination with durvalumab for the treatment of NSCLC will not be initiated.

Although preliminary phase II data submitted for presentation at next month's ASCO Annual Meeting show a favorable response rate for the IDO inhibitor indoximod plus pembrolizumab versus pembrolizumab alone in advanced melanoma (55.7% vs. 33%, respectively), drugmaker NewLink Genetics announced on May 3 that a phase III study will not be initiated. In addition, the company said that it has “deprioritized” indoximod research in pancreatic cancer; a phase II study to be presented at the ASCO meeting did not meet its primary endpoint: an improvement in median overall survival from a historical 8.5 months for standard care to at least 12.1 months for indoximod.

As well, Bristol-Myers Squibb has terminated two studies of its IDO inhibitor BMS-986205—one in SCCHN and another in NSCLC—noting on ClinicalTrials.gov that “business objectives have changed.”

Halting so many trials of IDO inhibitors in various cancers, based at least in part upon the results of ECHO-301, “doesn't make sense to me,” said Ezra Cohen, MD, of the University of California, San Diego, Moores Cancer Center. “All of a sudden, the enthusiasm is completely gone for all of those other histologies, when those are the ones that might actually deliver [strong results].”

One possible explanation for the negative findings in the ECHO-301 melanoma trial could be selection bias. “PD-1 inhibitors are not effective for all patients, particularly those with liver metastases,” Beatty explained, adding that fewer patients with liver metastases were enrolled in the early, nonrandomized trials, so “high rates of response were seen with combination therapy.”

“Patient selection is a major determinant of outcomes in immunotherapy,” he continued, “but further research is needed to know how to identify the subsets of patients most likely to benefit. I believe that this inadvertent patient selection bias misled the community on the generalized benefit that might be achieved with combination IDO plus PD-1 therapy.”

In melanoma, “you have to look deeper to get an answer as to why the trial was really completely negative,” Cohen said. “I would step back and say, ‘Let's look at these data more closely, let's look at the tumor samples, let's see if there's a patient group that might have benefited, and then maybe go back to melanoma when you have answers to those questions.” For example, he noted that patients weren't tested for IDO expression prior to starting therapy, but having that information could help determine likely responders.

Despite the negative findings from ECHO-301 and the pancreatic cancer cohort of ECHO-203, Suzanne Topalian, MD, of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore, MD, said at the AACR meeting that studies of IDO inhibitors, including epacadostat, should continue. “There are other IDO inhibitor drugs in the clinic aside from epacadostat, and they all have different chemical properties,” she said. “This is certainly not a reason to abandon this entire area of investigation.” –Suzanne Rose