AACR: Antibody-Drug Conjugate Shows Promise in Platinum-Resistant Ovarian Cancer

Ovarian cancer as seen on CT; source: James Heilman, MD, Wikimedia Commons

Washington, DC-A novel therapy has shown activity in treatment of difficult-to-treat, advanced, platinum-resistant ovarian cancer. The drug, DMUC5754A (Genentech), is part of a new class of drugs called antibody-drug conjugates. The phase I trial results were presented at the American Association for Cancer Research (AACR) Annual Meeting, held April 6–10 in Washington, DC by Joyce F. Liu, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

“Overall the drug was well tolerated, with a toxicity profile that is comparable to other therapeutics currently used in clinical practice,” Liu told Cancer Network. “We think the results are very encouraging in a patient population where response to other therapies is limited.”

DMUC5754A consists of a monoclonal antibody against the protein MUC16, found on ovarian cancer cells at high levels, and a toxin linked by a cleavable linker. Approximately 80% of ovarian cancer patients have tumors that have high expression of MUC16 (also known as CA-125), according to Liu. The toxin is the microtubule-disrupting agent monomethyl auristatin E (MMAE). The antibody directs the toxin specifically to ovarian cancer cells to kill them. Because the antibody delivers the toxin specifically to the ovarian tumor, an especially potent toxin can be used, one that would be too toxic as a general cytotoxic agent that would also affect healthy tissue.

The results from the phase I trial also showed that those patients who had the highest expression of MUC16, the target of the antibody portion of the drug, derived the most benefit from the treatment. This is likely to facilitate the selection of only those patients who are most likely to benefit from treatment in future trials.

Platinum-resistant, advanced ovarian cancer has an unmet need and is difficult to treat. Patients currently have few treatment options. Platinum-based chemotherapy remains the standard way to treat ovarian cancer, and platinum resistance is a major treatment challenge.

The phase I trial evaluated various doses of DMUC5754A in advanced ovarian and pancreatic cancer patients. DMUC5754A was administered at doses ranging from 0.3 mg/kg to 3.2 mg/kg every 3 weeks. Forty-four patients with advanced, recurrent, platinum-resistant ovarian cancer enrolled; of those, one complete response and four partial responses were reported. All patients who responded were treated with a 2.4 mg/kg dose of the drug and had high MUC16 expression in their tumor cells. Six additional patients had minor responses.

Fatigue was the most common adverse event at all dose levels, occurring in more than half of all patients. Other common adverse events were vomiting, decreased appetite, nausea, diarrhea, and peripheral neuropathy. Peripheral neuropathy was manageable and reversible in most patients through dose delay and dose reductions, according to the researchers.

Grade 3 adverse events included fatigue and neutropenia, both occurring in 9% of patients. Neutropenia and uric acid release were the only dose-limiting toxicities during the study. Both occurred at the maximum 3.2 mg/kg dose. Other serious drug-related adverse events were small intestine obstruction in two patients, hypocalcemia in a single patient, and neutropenia in a single patient.

“Neuropathy, which was an anticipated potential toxicity of the drug, did occur, but was manageable and typically reversible with dose reductions or delays,” said Liu.

The role of MUC16 in cancer development and progression is not yet clear. The protein is a large transmembrane protein that is found in abundance on ovarian cancer cells but not healthy tissue. Researchers speculate that the protein may help ovarian tumor cells bind to mesothelial cells that line the peritoneal cavity.

The encouraging activity and safety profile of the antibody-drug conjugate warrants further trials in ovarian cancer patients, according to the study researchers. “I think the major remaining question is how this therapy compares against the standard treatments that we use in platinum-resistant ovarian cancer,” said Liu.

Discussions for further development of DMUC5754A, including a phase II ovarian cancer trial, are ongoing.