Potential New Approach to Treatment of Melanoma

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Preliminary results suggest that an investigational antibody-drug conjugate called DEDN6526A has activity against melanoma, including cutaneous, mucosal, and ocular melanoma, which is considered difficult to treat. The new drug comes on the heels of trastuzumab emtansine, the first antibody-drug conjugate approved by the FDA for the treatment of breast cancer. The conjugate links an antibody to a toxic chemotherapy that remains inactive until the antibody recognizes a protein on the surface of cancer cells and releases its toxic “payload� into the cancer cells.

This is one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma, explained Jeffrey R. Infante, MD, director, drug development program, Sarah Cannon Research Institute, Nashville, TN. “We are encouraged by the initial responses. DEDN6526A is well tolerated and, more important, benefits a substantial proportion of patients. It is particularly promising to see clinical activity in patients with mucosal, as well as ocular, melanoma, and we hope that patients who enroll in the ongoing expansion phase of the trial gain similar benefit,� Infante told attendees at the 2014 American Association for Cancer Research annual meeting.

Infante presented the results of the dose-escalation phase of the first-in-human phase 1 trial of this new therapy. The antibody recognizes the endothelin B receptor (ETBR), which Infante estimates is elevated in approximately 50% of melanomas; the toxic chemotherapy is monomethyl auristatin E (MMAE). When DEDN6526A is administered to a patient, the antibody attaches to ETBR on the cancer cell surface, and MMAE is released to kill the melanoma cells. Infante said that he and his coinvestigators are still working on a reliable assay to measure ETBR levels to get a more precise handle on how this drug works.

“We need a companion diagnostic to go along with this drug to identify patients who express ETBR. We are working on it,� Infante noted.

The dose-escalation phase included 28 patients with metastatic or unresectable melanoma (17 with cutaneous melanoma, 8 with ocular melanoma, and 3 with mucosal melanoma). Patients were given DEDN6526A every 3 weeks; the maximum tolerated dose was determined as 2.4 mg/kg every 3 weeks, and this is the dose being tested in the expansion phase of the trial.

Adverse events thought to be drug-related included fatigue, chills, alopecia, sensory neuropathy, decreased appetite, headache, nausea, and vomiting. Neutropenia was the most frequent grade 3 adverse event. Infusion- related reactions were also observed, but these were reduced with steroid premedication.

Among 19 patients in the dose-escalation phase who received ?1.8 mg/kg of DEDN6526A, clinical benefit was observed in 12 patients; 2 patients with cutaneous melanoma and 2 with mucosal melanoma had confirmed partial responses. Of the remaining 8 patients, 5 with cutaneous melanoma, 2 with ocular melanoma, and 1 with mucosal melanoma had stable disease for 6 months or longer.

In some cases, disease was stable for a prolonged period. Infante said that 1 patient has been stable and in the study for 2 years.
Infante emphasized that this was an unselected population. It may be that responses will be even better once a companion diagnostic can identify patients with elevated expression of ETBR.

An expansion cohort of an additional 24 patients with melanoma is now being studied.

Thomas J. Lynch, Jr, MD, director, Yale Cancer Center, New Haven, CT, commented on this study. “These are exciting results because there are not that many examples of antibody-drug conjugates that work. The demonstration of clinical response is important. This was not an enriched population, and we still don’t know the biomarker, but if a test is developed to identify responders, then this may turn out to be a new approach to treatment of patients with melanoma,� Lynch stated.

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