Epacadostat Shows Value in Two SCCHN Trials

For patients with squamous cell carcinoma of the head and neck (SCCHN), as well as several other cancers, second-line treatment with checkpoint inhibitors has yielded a greater overall response rate (ORR) and more durable responses than standard of care. In patients with SCCHN, for example, the PD-1 inhibitor pembrolizumab (Keytruda; Merck) boosts the ORR to 16% from about 13% with cetuximab (Erbitux; Eli Lilly); thus far, duration of response with pembrolizumab ranges from about 2.4 months to 27.7 months, compared with a historical range of 1.2 months to 5.8 months for cetuximab.

Although these data are encouraging, “novel combination treatment strategies are needed to improve efficacy—with limited additive toxicity,” said Omid Hamid, MD, chief of translational research and immunology at The Angeles Clinic and Research Institute in West Los Angeles, CA. One possibility: adding the indoleamine 2,3-dioxygenase (IDO1) inhibitor epacadostat to pembrolizumab. Hamid presented results of the phase I/II ECHO-202/KEYNOTE-037 trial testing that idea at last month's annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL.

Also, results of a related trial—the phase I/II ECHO-204, which combined epacadostat with the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb)—were presented at the ASCO meeting by Karl Lewis, MD, of the Department of Medical Oncology at University of Colorado Anschutz Medical Campus.

Tumors can evade immunosurveillance through multiple mechanisms, Lewis explained, including checkpoint inhibition of T-cell activation and upregulation of IDO1, an IFNγ-induced intracellular enzyme that catalyzes tryptophan degradation in the kynurenine pathway. Depletion of tryptophan and production of kynurenine creates an immunosuppressive tumor microenvironment, so “the thought is that combining epacadostat with a checkpoint inhibitor may improve patient outcomes,” Lewis said.

The pembrolizumab plus epacadostat ECHO-202/KEYNOTE-037 trial included 38 patients with SCCHN; all had previously had radiotherapy, and most had had surgery and received chemotherapy. Fifty-eight percent of the patients had PD-L1–positive tumors, with at least 1% of cells expressing PD-L1, and 18% had PD-L1–negative tumors. PD-L1 status was unknown in 24%. In addition, the disease was tied to human papillomavirus (HPV) in 34% of cases.

Hamid reported that the ORR was 34%, with a disease control rate (DCR) of 61%. Patients who had received no more than two prior therapies had slightly better outcomes, with an ORR of 39% and a DCR of 65%. Notably, PD-L1 expression made virtually no difference in the DCR, and patients with and without HPV-related disease responded to treatment. “The responses are rapid, deep, and durable,” Hamid said, noting that responses thus far have ranged from about 7 weeks to more than 90 weeks, and 10 of 13 responses are ongoing.

Side effects weren't much different than previously reported with pembrolizumab monotherapy, although there was a higher rate of grade 3/4 rash. Overall, adverse events affected 63% of patients, with fatigue and dizziness being the most common. Relatively few immune-related adverse events—hypothyroidism, adrenal insufficiency, and pneumonitis—were reported. With longer follow-up, the picture could change, said discussant Ezra Cohen, MD, associate director of translational science at the University of California, San Diego, Moores Cancer Center, “but at least for now, there isn't a danger signal that this combination cannot be taken forward.”

Results of the phase I/II ECHO-204 trial also support the launch of additional studies. In the SCCHN cohort of this trial, researchers enrolled 31 patients. Ten had PD-L1–positive tumors and eight were PD-L1 negative. PD-L1 status was not known for 13 patients. Ten cases were linked to HPV. The ORR was 23% and the DCR was 61%, Lewis reported, and as with ECHO-202/KEYNOTE-037, responses were seen regardless of PD-L1 positivity and HPV status.

Discussant Gregory Beatty, MD, PhD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, said that epacadostat plus nivolumab might prove effective in other tumor types. Indeed, Lewis noted an ORR of 63% in a cohort of 40 patients with melanoma. However, no efficacy signal was seen in unselected populations of patients with colorectal or ovarian cancers. Data for patients with non–small cell lung cancer (NSCLC), glioblastoma, and lymphoma in ECHO-204 were not yet available, he said.

ECHO-202/KEYNOTE-037 includes multiple cohorts of patients as well, and researchers reported promising results in urothelial carcinoma, renal cell carcinoma, and NSCLC at the ASCO meeting. Phase III trials for these indications and SCCNH are planned. –Suzanne Rose