Women with Highest Expression of Target Protein Benefited Most of Experimental Drug Active in Platinum-resistant Ovarian Cancers

The antibody-drug conjugate DMUC5754A, a novel trial drug of a relatively new class of agents developed by Genentech, a member of the Roche Group, showed strong activity in women with ovarian cancer, even those with hard-to-treat, platinum-resistant disease, in a phase I trial presented at the Annual Meeting of American Association for Cancer Research (AACR), held April 6–10, 2013 in Washington, DC. by Joyce F. Liu, MD, MPH, an instructor in medicine at the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

The researchers noted that women with the highest expression of the drug’s target, MUC16, also known as CA-125 and found in high levels on ovarian cancer cels, gained the most benefit from treatment, which may help researchers predict which patients will benefit from treatment.

MUC16/CA-125 is a membrane associated mucin that possesses a single transmembrane domain. A unique property of MUC16 is its large size. Another unique feature is that MUC16 is found in ovarian cancer cells, but not in healthy tissue.

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MUC16/CA-125 is the most frequently used biomarker for ovarian cancer detection. In addition to diagnosis, monitoring CA-125 blood serum levels is therefor used to determining how ovarian cancer is responding to standard treatment and for predicting prognosis after treatment

Confirming activity
“If the activity of this drug is confirmed in additional trials, this will represent a novel type of therapy for ovarian cancer, with effectiveness in platinum-resistant ovarian cancer, which is the hardest type of ovarian cancer to treat,” explained Liu. “This would represent a real step forward in finding new, effective treatments for advanced ovarian cancer.”

According to Liu, ovarian cancer is the leading cause of death from gynecologic cancers in the United States. It affects more than 22,000 women per year and results in about 16,000 deaths per year. One of the biggest challenges in treating ovarian cancer is the development of platinum resistance, where the cancer cells stop responding to platinum chemotherapy, one of the most effective drugs in treating this cancer. Standard chemotherapies have limited effect against these platinum-resistant ovarian cancers, and women whose cancers have become platinum-resistant inevitably have disease progression.

A new class of drugs
“The drug we tested in this clinical trial, DMUC5754A, is from a new class of drugs called antibody-drug conjugates,” Liu said. “This drug consists of an (monoclonal) antibody and a potent toxin joined by a cleavable linker. The antibody identifies a protein, MUC16, and targets the toxin to kill the cancer cells.” In this case, the toxin used is the microtubule-disrupting agent monomethyl auristatin E (MMAE).

Selectivity
Unlike other cancer treatments, the antibody-drug conjugate releases the toxin with relative selectivity to the MUC16-positive cancer cells. This allows delivery of drugs that would otherwise be too toxic for treatment, according to Liu.

Safety and PK/PD
Liu and her colleagues evaluated the safety, pharmacokinetics and pharmacodynamic activity of DMUC5754A in 44 patients with advanced, recurrent, platinum-resistant ovarian cancer. Researchers reported one complete response and four partial responses. All five of these confirmed responses occurred at the 2.4-mg/kg dose and in patients with high expression levels of MUC16 in their cancer cells.

During the study, two dose-limiting toxicities occurred: one grade 4 neutropenia and one grade 4 uric acid increase, which occurred at the maximum administered dose of 3.2 mg/kg. Grade 3 adverse events included fatigue in 9% of patients and neutropenia in 9% of patients. Fatigue was the most common adverse event at all dose levels and occurred in 57% of patients. Other commonly reported adverse events were nausea, vomiting, decreased appetite, diarrhea and peripheral neuropathy.

The researchers next plan to evaluate this drug in comparison with standard chemotherapy. If confirmed, DMUC5754A may represent new treatment option in ovarian cancer.

Antibody-drug Conjugate
Other drugs in the same class including ado-trastuzumab emtansine/trastuzumab-DM1 (Kadcyla®; Genentech/Roche; T-DM1) for the treatment of women with treatment-resistant HER‐positive breast cancer and Brentuximab Vedotin (SGN-35/Adcetris®; SeattleGenetics/Millennium: The Takeda Oncology Company) for the treatment of relapsed/refractory Hodgkin’s lymphoma. These two drugs have recently entered the commercial phase.

This article was published first online in Onco’Zine, The International Cancer Network.