Epacadostat, nivolumab combination shows promise in certain advanced solid tumors

CHICAGO — Epacadostat in combination with nivolumab appeared safe and effective in patients with advanced melanoma and head and neck cancer, according to preliminary data from the ECHO-204 trial presented at the ASCO Annual Meeting.

“Tumors can evade immunosurveillance through a number of mechanisms including immune checkpoint inhibition of T-cell activation, as well as upregulation of the IDO1 enzyme,” Karl D. Lewis, MD, associate professor in the division of medical oncology at University of Colorado Anschutz Medical Campus, said during his presentation. “IDO1 is an interferon gamma-induced intracellular enzyme that catalyzes the first- and rate-limiting step of tryptophan degradation in the kynurenine pathway. In cancer, depletion of tryptophan production of kynurenine and other metabolites in the tumor microenvironment shifts the local immune microenvironment to an immunosuppressive state.”

Lewis and colleagues, including Raymond P. Perez, MD, director University of Kansas Clinical Research Center, conducted the ongoing, open-label, phase 1/2 ECHO-204 trial to evaluate epacadostat (Incyte) — a potent and selective oral inhibitor of IDO1 — in combination with nivolumab (Opdivo, Bristol-Myers Squibb), a PD-1 inhibitor, in patients with advanced solid tumors.

Lewis presented the primary safety, efficacy and tolerability of the combination in patients with advanced solid tumors. The study included patients with non–small cell lung cancer, melanoma, ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, B-cell non-Hodgkin lymphoma and glioblastoma, but some of these data are not yet mature.

Researchers enrolled 241 patients, including 26 patients in the phase 1 and 205 patients in the phase 2 portions of the study.

In the phase 1 dose escalation portion of the study, patients received 25 mg, 50 mg, 100 mg or 300 mg epacadostat twice daily plus 3 mg/kg nivolumab every 2 weeks. In the phase 2 portion, patients received 100 mg or 300 mg epacadostat twice daily plus 240 mg nivolumab every 2 weeks.

The most common treatment-related adverse events in patients treated with 100 mg and 300 mg epacadostat in the phase 1 cohort included rash (21% and 39%), fatigue (14% and 15%) and pruritus (7% and 23%). In the phase 2 cohort, the most common adverse events included nausea (100 mg, 25%; 33 mg, 17%), fatigue (23% and 25%) and nausea (19% and 20%).

The most common treatment-related adverse events in patients treated with 100 mg and 300 mg epacadostat included rash (33% and 22%), fatigue (26% and 31%) and nausea (24% and 19%).

Treatment-related adverse events led to discontinuation in 6% of those who received 100 mg epacadostat and 12% with 300 mg epacadostat. No treatment-related deaths occurred.

Of 40 treatment-naive patients with melanoma, six received 100 mg and 34 received 300 mg.

Researchers reported an ORR in this group of 63% — two patients had a complete response and 23 had a partial response. Ten patients achieved stable disease for a disease control rate of 88%.

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Four patients had progressive disease as their best response.

Responses occurred in both 100-mg and 300-mg dose cohorts, as well as regardless of PD-L1 expression.

The study included an additional 10 patients with melanoma who had received prior treatment. Twenty percent of these patients responded to treatment.

“The majority of patients had a decrease in their tumor burden from baseline; four patients had complete disappearance of all their target lesions, although two of those patients still had nontarget lesions and were considered partial responders,” Lewis said. “The responses tended to occur early and then flatten out; although follow-up is short, we are hopeful from other immunotherapy trials that these will be durable responses.”

Of the 31 patients in the head and neck cancer cohort, seven received 100 mg and 24 received 300 mg. Researchers reported an ORR of 23%, which included one complete response and six patients with partial response. Twelve patients had stable disease for a disease control rate of 61%. Eight patients had progressive disease.

Responses occurred at both doses, regardless of PD-L1 status, and in both HPV–associated and –nonassociated tumors.

Although there were not as many responders in the head and neck cohort as in the melanoma cohort, there is still indication these the responses observed will be durable, Lewis said.

All 26 patients with colorectal cancer received 100 mg epacadostat. Patients demonstrated an ORR of 4% and disease control rate of 24%. Researchers reported ORRs of 25% for patients with microsatellite instability and 0% for patients with microsatellite stable tumors.

Of 29 patients with ovarian cancer, 18 patients received 100 mg and 11 patients received 300 mg.

Researchers reported an ORR of 14% — which included one complete and three partial responses — and disease control rate of 31% in this cohort.

Patients treated with 100 mg showed an ORR of 11% and disease control rate of 28%, and patients who received 300 mg showed an ORR of 18% and disease control rate of 36%.

“Epacadostat plus nivolumab unfortunately did not demonstrate a clear efficacy signal in unselected populations of refractory ovarian cancer and colorectal cancer, although these patients continue to be monitored for any signs of activity,” Lewis said. “These preliminary safety and efficacy results support further investigation of the combination in treatment-naive melanoma and head and neck cancer.” – by Kristie L. Kahl and Alexandra Todak

Reference:

Perez RP, et al. Abstract 3003. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Lewis reports consultant/advisory roles with Roche and Sun Pharma and research funding from Amgen, Incyte and Roche. Perez reports a consultant role with Pharmaceutical Research Associates, and research funding from Agensys, Altor BioScience, Bristol-Myers Squibb, Dompé Farmaceutici, Eli Lilly, Genentech/Roche, Immunogen, Incyte, MedImmune, Millennium, Novartis, Onyx, Regeneron and TetraLogic Pharmaceuticals. Please see the abstract for a list of all other researchers’ relevant financial disclosures.