Investigational ADC Shows Signs of Activity in Melanoma

Roxanne Nelson

April 15, 2014

SAN DIEGO — An investigational antibody–drug conjugate (ADC) was found to be safe and tolerable, and importantly, showed signs of activity against different forms of melanoma in patients who had progressed on other therapies.

In a phase 1 trial, DEDN6526A, which is being developed by Genentech (using Seattle Genetics ADC technology), elicited a clinical benefit in 12 of 19 patients who received a dose of at least 1.8 mg/kg.

Of this group, partial response was confirmed in 2 patients with cutaneous melanoma and 2 with mucosal melanoma. In addition, 5 patients with cutaneous melanoma, 2 with ocular melanoma, and 1 with mucosal melanoma achieved stable disease for at least 6 months.

Some patients were able to achieve stable disease for a prolonged period of time, explained lead author Jeffrey R. Infante, MD, director of the drug development program at the Sarah Cannon Research Institute in Nashville, Tennessee. One patient is now approaching 2 years on the study drug.

"The 4 confirmed partial responses were seen in patients with metastatic melanoma, independent of BRAF mutation status," said Dr. Infante during a press briefing here at the American Association for Cancer Research 2014.

He noted that these patients had previously progressed on ipilimumab (Yervoy) and/or chemotherapy.

"If you can stay on the drug for 6 months or get a partial response, that is a meaningful response in an early phase 1 trial," said Dr. Infante.

In this study, 9 of 28 patients (32%) remained on the study drug for more than 6 months.

New Target

DEDN6526A is an ADC that comprises the antimitotic agent monomethyl auristatin E (MMAE) and the humanized immunoglobulin G1 anti-endothelin B receptor (ETBR) monoclonal antibody, and is a novel targeted treatment for melanoma, explained Dr. Infante.

ETBR is a G-protein-coupled receptor that can activate RAF/MEK signaling, and is overexpressed in more than 50% of melanomas. It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread, which could explain its role in the development of melanoma.

In preclinical models, DEDN6526A demonstrated dose-dependent antitumor activity in ETBR-expressing tumor xenografts.

Dr. Infante pointed to the need for a companion diagnostic for ADCs. "It is important to have a tool to help select patients as you move further in development," he said. "In this case, a prototype ETBR immunohistochemistry assay is being developed as a potential companion diagnostic."

Study Details

In this first-in-human phase 1 study, Dr. Infante and colleagues evaluated the safety and pharmacokinetic activity of DEDN6526A in 28 patients with metastatic or unresectable melanoma.

Intravenous DEDN6526A 0.3 to 2.8 mg/kg was administered every 3 weeks to establish the maximum tolerated dose, which was determined to be 2.4 mg/kg. That dose is now being tested in the expansion phase of the trial.

Participants received a median of 2.5 previous therapies and a median of 6 doses of the DEDN6526A.

Clinical benefits were observed starting at a dose of 1.8 mg/kg, and the most common dose-limiting toxic effects were infusion-related reactions. This was mitigated by changing the study protocol to permit patients to receive steroids before their infusion, Dr. Infante explained.

The most common adverse events of any grade that occurred in more than 20% of patients were fatigue (57%), chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), infusion-related reaction (25%), asthenia (21%), peripheral sensory neuropathy (21%), and vomiting (21%).

Treatment-related events of grade 3 or higher that occurred in at least 5% of patients included anemia (11%), neutropenia (11%), leukopenia (7%), and decreased white blood cell count (7%).

For patients who received a clinical benefit, there did not appear to be an association with type of melanoma, BRAF mutation status, or progression on previous immune therapies, Dr. Infante noted.

Evolving Treatments

Treatment has evolved and continues to do so in melanoma, but there is still a tremendous need for targeted chemotherapy in this disease, said study discussant Steven J. O'Day, director of the Los Angeles Skin Cancer Institute at the Beverly Hills Cancer Center in California.

"This is a potential new target for melanoma," said Dr. O'Day, "and a possible predictive companion diagnostic."

He noted that the results are impressive because this was a heavily pretreated population, and many patients had progressed on other therapies. "It was remarkable to me how few grade 3 and 4 toxicities there were," he said. "The benefits were across subtypes and patients were unselected, so it is even more impressive."

The agent's durability and whether the selection of patients can be improved with a predictive diagnostic still have to be determined, noted Dr. O'Day. "We need to consider potential synergy in combination therapy as well."

"The drug should be able to stand on its own, but the field is moving fast with combination therapies, so there may be more opportunities here," he said.

This study was funded by Genentech, a member of the Roche Group. Dr. Infante has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2014: Abstracts CT233. Presented April 7, 2014.

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