Based on trial results from the randomized Phase II PRECEDENT trial for vintafolide (MK-8109/EC145; Merck and Endocyte), an investigational folate small molecule drug conjugate or SMDC, published in the Journal of Clinical Oncology (JCO), the official journal of the American Society of Clinical Oncology, a regulatory application is currently under review with the European Medicines Agency for the treatment of folate-receptor positive platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin (PLD). Enrollment is ongoing in the pivotal Phase III PROCEED clinical trial with vintafolide, along with investigational companion imaging agent etarfolatide (EC20), in platinum-resistant ovarian cancer.

As reported in the online edition of the October 14, 2013 edition of JCO online, results from the Phase II PRECEDENT trial showed that administration of vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in women with platinum-resistant ovarian cancer resulted in a median progression-free survival (PFS) of 5.0 months compared to 2.7 months for those treated with PLD alone (HR=0.63; 95% CI 0.41–0.96; p=0.031) in the intent-to-treat (ITT) population. Those patients shown to have folate receptor-positive tumors, as defined by all selected target lesions being folate receptor-positive (FR%100) using the investigational folate receptor-targeted companion diagnostic imaging agent etarfolatide, demonstrated greater benefit, as measured by PFS, from treatment with vintafolide plus PLD versus PLD alone. Median PFS benefit in these patients was 5.5 months compared to 1.5 months for PLD alone (HR=0.38; 95% CI 0.17–0.85; p=0.013).

Folate Receptor-Positive Platinum-Resistant Ovarian Cancer
In 2013, it is estimated that there will be 22,240 new cases of ovarian cancer in the United States and over 40,000 new cases in the European Union. Ovarian cancer is one of the most lethal cancers of the female reproductive system. Overall, approximately 80 percent of patients relapse after first-line platinum-based chemotherapy. Platinum-resistant ovarian cancer is a challenging disease with a high unmet need. This type of cancer recurs within six months of completion with a platinum-containing regimen, the standard of care for ovarian cancer. Based on the Phase II PRECEDENT trial data, an estimated 80 percent of platinum-resistant ovarian cancer patients have been found to have folate receptor-positive disease as assessed by etarfolatide scanning, and approximately 40 percent express the receptor, as detected by etarfolatide, in all of their target tumor lesions.

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A promising strategy
Etarfolatide is being developed by Endocyte as a non-invasive method to identify tumors that express the folate receptor. “The combination of vintafolide plus PLD demonstrated significant improvement in progression-free survival over standard treatment in women with folate receptor-positive platinum-resistant ovarian cancer,” said R. Wendel Naumann, M.D., Associate Director, Gynecologic Oncology, Carolinas HealthCare System’s Levine Cancer Institute, Charlotte, N.C., and corresponding author of the publication. “Targeting the folate receptor, which is expressed on the majority of epithelial ovarian cancers, is a potentially promising strategy, especially when combined with a companion diagnostic that is designed to identify patients who are most likely to respond to the treatment, a hallmark of personalized medicine.”

The Phase II PRECEDENT trial was an international, multi-center, randomized study of 149 women with platinum-resistant ovarian cancer. Patients were randomized to receive vintafolide plus PLD or PLD alone at a standard dose, until disease progression or death. The primary endpoint of the study was PFS. Secondary endpoints included response rate and overall survival (OS). In the ITT population, no difference was observed in overall survival (HR=1.010; 95% CI 0.679–1.503; p=0.957). Endocyte first presented results from the Phase II PRECEDENT trial at the 2011 American Society of Clinical Oncology Annual Meeting.

Well Tolerated
Vintafolide is an investigational proprietary, injectable, folate SMDC consisting of folate (vitamin B9) linked to a potent vinca alkaloid chemotherapy agent, desacetylvinblastine hydrazide (DAVLBH). Vintafolide is designed to target the chemotherapy agent to rapidly growing cancer cells that actively take up folate via the folate receptor. The folate receptor is expressed in a wide variety of cancers including ovarian cancer.

The combination of vintafolide and PLD was generally well tolerated, and no drug-related mortality or statistically significant difference in the incidence of drug-related serious treatment-emergent adverse events (TEAEs) was observed:

  • In the vintafolide and PLD arm vs. PLD arm, anemia, neutropenia and thrombocytopenia were reported in 16.6% vs. 10.4%, 19.1% vs. 10.4%, and 2.7% vs. 3.0% of all cycles, respectively.
  • Stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome) occurred in 16.6% vs. 22.8%, and 19.1% vs.15.8% of cycles, respectively.
  • The frequency of fatigue was similar between arms, 15.8% of vintafolide and PLD arm cycles, and 14.9% of PLD arm cycles.

Companion diagnostics
Etarfolatide (EC20) is an investigational folate receptor-targeted companion diagnostic imaging agent that is being developed as a non-invasive method to identify tumors that express the folate receptor. These tumors are the molecular target of Endocyte’s folate receptor-targeted therapeutic compounds such as vintafolide. Folic acid is used with etarfolatide for the enhancement of image quality. Etarfolatide is under review with the EMA and has been granted orphan drug status by the European Commission.

Ongoing Clinical trials
Vintafolide in combination with PLD is currently under review with European Medicines Agency (EMA) for the treatment of adult patients with folate receptor-positive platinum-resistant ovarian cancer. Vintafolide has also been granted orphan drug status by the European Commission. Vintafolide, along with investigational companion imaging agent etarfolatide, is currently being evaluated in a Phase III PROCEED clinical trial for platinum-resistant ovarian cancer and a Phase IIb TARGET trial for non-small cell lung cancer (NSCLC). A Phase II randomized trial of vintafolide in folate receptor-positive triple negative breast cancer is expected to be initiated in the near future.