T-DM1 was the first antibody-drug conjugate to gain US Food and Drug Administration approval for HER2 (human epidermal growth factor 2)-positive metastatic breast cancer. A preliminary study suggests that a second antibody-drug conjugate is active in platinum-resistant ovarian cancer, and if the encouraging early results are confirmed by clinical trials, this would fulfill an unmet need for a difficult-to-treat cancer with limited treatment options.
The antibody-drug conjugate DMUC5754A includes a monoclonal antibody that recognizes the MUC16 protein expressed by ovarian cancer cells, which is linked to a potent antimitotic toxin called MMAE (monomethyl auristatin E). The antibody targets MUC16 and the toxin is released selectively into tumor cells that express MUC16, limiting the effects of the toxin on healthy tissues and organs.
MMAE is so potent that it could not be delivered directly to patients, explained lead author Joyce Liu, MD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
The phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of DMUC5754A in 44 women with advanced, recurrent, platinum-resistant ovarian cancer. Among these heavily pretreated patients, 1 complete response and 4 partial responses were reported. All 5 of the responses were observed in patients with high expression of MUC16 in their tumor cells.
The maximum tolerated dose was identified as 2.4 mg/kg, and the antibody-drug conjugate was given every 3 weeks. Dose-limiting toxicities included one grade 4 neutropenia and one grade 4 uric acid increase, occurring at a higher dose level. Grade 3 adverse events included fatigue in 9% of patients and neutropenia in 9%. Fatigue was the most common adverse event at all dose levels, occurring in 57% of patients. Nausea, vomiting, decreased appetite, diarrhea, and peripheral neuropathy were also reported.
“If the activity of this drug is confirmed in additional trials, this will represent a real step forward in finding new, effective treatments for advanced ovarian cancer,” Liu said.
Reference Liu J, Moore K, Birrer M, et al. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: a phase I study of safety and pharmacokinetics. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-290.
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