Combination Immunotherapy Being Investigated in Advanced Melanoma

Treatment-resistant melanoma is becoming increasingly common, even with the advent of immune treatments, which have transformed how cancer is treated. It’s now being tested in patients with unresectable or metastatic melanoma, and researchers hope to enhance outcomes by combining two types of immunotherapy to treat the disease. First-in-class IDO1 inhibitor epacadostat and the FDA-approved checkpoint blocker Keytruda (pembrolizumab) are part of the combo therapy for patients.

A medicine like epacadostat, which targets IDO1, can reverse the immune system’s cancer suppression, allowing the body’s natural defenses to kick into high gear. Inhibitors of the body’s checkpoints, such as PD-1 (programmed cell death 1), PD-L1, and CTLA-4, all work similarly.


The phase 3 KEYNOTE-252/ECHO-301 trial, which is enrolling patients at more than 120 locations, will randomize 600 patients, at a ratio of 1-1, to Keytruda either with epacadostat or with placebo (NCT02752074) (NCT02752074).

If you have melanoma that is not treatable by surgery or local treatment, you may be eligible for this trial. The trial excludes patients who have previously received systemic therapy for their condition, particularly immunotherapies targeting the PD-1/PD-L1 pathway, IDO1, or CD137. However, those already treated with an anti-CTLA-4 therapy are authorized to participate.

Researchers expect that by combining Keytruda, an intravenous PD-1 inhibitor, with epacadostat, an oral PD-1 inhibitor, they will improve the 21 to 33% overall response rates that Keytruda monotherapy demonstrated in the clinical trials that led to its FDA clearance in melanoma.

“Combination is the next step for immuno treatment. We’ve got certain combinations showing efficacy but increased toxicity, so we’re looking for something that does better,” said Omid Hamid, M.D., director of melanoma therapeutics and chief of translational research and immune-oncology at The Angeles Clinic and Research Institute in Los Angeles. epacadostat is Hamid’s primary research focus, and he participates as an investigator in the clinical trial.


There was an objective response (58%) in 11 of the 19 eligible treatment-nave patients who received the combination of epacadostat and Keytruda, 5 of whom had a complete response and 6 of whom had partial responses (PR). 74% of individuals with a CR, PR, or stable disease were in disease control (14 patients).

No matter how much of the enzyme PD-L1 was expressed by the target lesions (liver, lung, and lymph nodes), they all responded to Keytruda, regardless of how much or how little was present. Although updated results from the 2016 ESMO meeting indicated median progression-free survival (PFS) after more than 56 weeks of follow-up, the median PFS was not met. 74% at 6 months and 57% at 12 months for the PFS rate.

In addition to the three previously treated patients, one patient had a CR, one had a PR, and one had progressive disease after combining the two treatments. PD-L1 was positive in the tumors of 55% of patients with M1c stage melanoma, which had progressed to the visceral organs.

In a press release, Tara C. Gangadhar, M.D., an assistant professor at the Hospital of the University of Pennsylvania in Philadelphia and a lead investigator of the phase 1 study, said, “The regimen showed excellent efficacy… with no additional toxicity from the combination” and is among the exciting potential options for melanoma patients under study.

As a result, “we detected responses in all dose cohorts and tumor sites and in previously-treated melanoma patients,” said Hamid.

Non–small cell lung cancer, renal cell carcinoma, and endometriosis were among a wider group of participants with advanced solid malignancies in the phase 1 study. Each patient was given either 25mg, 50mg, 100, or 300mg twice-daily doses of epacadostat in that trial section. Epacadostat is being tested at a dose of 100 mg twice daily in the third phase of the experiment. Every 3 weeks, beginning on the first day of the trial’s first week, patients in both study arms receive Keytruda intravenously.

Read more about The Benefits of Health Information Technology in Today’s Society


Compared to Keytruda alone, there were no additional toxicities in the phase 1 study group when using the combination. Among all trial participants, fatigue (39%), rash (39%), itching (23%), joint pain (19%), and diarrhea (19%) were the most common treatment-related adverse events (18%). Epacadostat may cause liver damage, according to Hamid, who found a rise in aspartate aminotransferase levels in patients receiving greater dosages of the drug.

This experiment, if successful, will pave the way for further studies into whether Keytruda and epacadostat combination therapy are as effective as previously thought. According to Hamid, “The next stages are to look at this combination in other solid cancers (such as lung, head and neck, and kidney), establishing that it is tolerated and has efficacy, and then going on to other tumor types.” In addition, as a part of its medication development efforts, Incyte Corporation has begun testing a new compound called KEYNOTE-252/ECHO-301.