Combination Immunotherapy Being Investigated in Advanced Melanoma
A study pairs an IDO inhibitor with PD-1 checkpoint blockade.
BY Ariela Katz
PUBLISHED July 10, 2017
While immune therapies have revolutionized the treatment of melanoma and other cancers, many patients develop resistance to treatment over time. Researchers are investigating a novel drug combination that pairs two kinds of immunotherapy to treat patients with unresectable or metastatic melanoma to potentially improve outcomes. The combination includes the first-in-class, experimental IDO1 inhibitor epacadostat and the checkpoint blockade agent Keytruda (pembrolizumab), which is approved by the Food and Drug Administration (FDA) to treat the disease.
When a cancer overexpresses the enzyme IDO1, the immune system is prevented from attacking the disease; targeting IDO1 with a drug like epacadostat can stop that suppression, allowing the immune system to move into high gear. Checkpoint inhibitors do the same thing by blocking the activity of different proteins manufactured by the body: PD-1 (programmed cell death 1), PD-L1 or CTLA-4.
The phase 3 KEYNOTE-252/ECHO-301 trial, which is enrolling patients at more than 120 locations, will randomize 600 patients, in a ratio of one to one, to Keytruda either with epacadostat or with placebo (NCT02752074).
The study is open to adult patients with stage 3 or 4 melanoma that is not amenable to surgery or to local treatment. Patients who have received prior systemic treatment for their disease, particularly immunotherapies directed at the PD-1/ PD-L1 pathway, IDO1 or CD137, are excluded from the trial. However, those previously treated with an anti-CTLA-4 therapy are permitted to participate.
In pairing the intravenous PD-1 inhibitor Keytruda with orally administered epacadostat, investigators are hoping to improve upon the 21 to 33 percent overall response rates that Keytruda monotherapy demonstrated in the clinical trials that led to its FDA approvals in melanoma.
“Combination is the next step for immune therapy. We’ve had some combinations that are showing efficacy but higher 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. Hamid has conducted early-stage research into epacadostat and is serving as an investigator on the trial.
EVIDENCE FOR THE COMBINATION
In a phase 1 study that tested the combination of epacadostat and Keytruda, 11 of 19 evaluable treatment-naïve patients achieved an objective response (58 percent), including five patients (26 percent) with a complete response (CR) and six participants (32 percent) with a partial response (PR). The disease control rate, which included all those who achieved CRs, PRs or stable disease, was 74 percent (14 patients).
Responses were observed in all sites of target lesions, including liver, lung and lymph nodes, and regardless of whether, or how much, of the enzyme PD-L1 they expressed — a characteristic sometimes considered a signal that a cancer is likely to respond to Keytruda. After a median follow-up of more than 56 weeks, the median progression- free survival (PFS) had not been reached at the time updated study results were reported at the 2016 ESMO conference in October. The PFS rate was 74 percent at six months and 57 percent at 12 months.
Among an additional three patients who were previously treated for advanced melanoma, the combination resulted in one patient each with a CR, a PR and progressive disease. Overall, 55 percent of the patients with melanoma in the study had M1c stage disease, which had spread to visceral organs, and 55 percent were PD-L1–positive at baseline.
“The regimen showed excellent efficacy … with no evidence of synergistic or additional toxicity from the combination” and is among the exciting potential options under study for patients with melanoma, said 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.
“We saw responses in all dose cohorts and all tumor sites, and in previously treated patients with melanoma, so it’s a well-tolerated regimen, and it’s a combination that makes sense,” added Hamid.
The patients with melanoma in the phase 1 study were among a larger group of participants with advanced solid malignancies including non–small cell lung cancer, renal cell carcinoma and endometrial adenocarcinoma. In all, 62 patients were enrolled in that portion of the study; they received epacadostat at doses of 25 mg, 50 mg, 100 mg or 300 mg twice daily. In the phase 3 trial, epacadostat is being administered at 100 mg twice daily. Keytruda is administered to those in both arms of the trial intravenously every three weeks, starting at day one on the first week.
Regarding safety, there were no increased toxicities with the combination compared with Keytruda alone across the phase 1 study population. The most common treatment-related side effects of all severities among trial participants were fatigue (29 percent), rash (29 percent), itchiness (23 percent) joint pain (19 percent) and diarrhea (18 percent). Increased aspartate aminotransferase levels, a possible indication of liver damage, were seen especially in patients taking higher doses of epacadostat, according to Hamid.
Should the phase 3 trial prove as successful as the earlier study, it will set the stage for further investigations into the efficacy of the Keytruda and epacadostat combination. “The next steps are that we’re looking at this combination in other solid tumors, including lung, head and neck, and renal, showing that it’s tolerable and that it has benefit, and then moving to other tumor types,” said Hamid. The KEYNOTE-252/ECHO-301 trial is being conducted by Incyte Corporation, which is developing the drug.
Omid Hamid, M.D., can be reached through Twitter @OmidHamidMD or through The Angeles Clinic (theangelesclinic.org).