Vintafolide—Targeting the Folate Receptor with a Cytotoxic Offers Hope

RESEARCH HIGHLIGHTS Nature Reviews Clinical Oncology 10, 668 (2013); published online 29 October 2013; doi:10.1038/nrclinonc.2013.201

GYNAECOLOGICAL CANCER Vintafolide—targeting the folate receptor with a cytotoxic offers hope PhotoDisc/Getty Images/Steve Cole PhotoDisc/Getty Images/Steve Phase II data from the PRECEDENT trial eight patients (7.5%) abandoned treatment has shown that women with platinum- due to treatment‑related adverse effects. resistant ovarian cancer might gain some One of the benefits of this strategy is benefit with vintafolide, a new drug that as well as being selectively cytotoxic, conjugate comprising desacetylvinblastine an accompanying agent—99mTc- and folic acid. For these patients, who etarfolide—has been developed to assess invariably have poor prognoses, this the extent of folate receptor expression. comes as welcome news. “This companion diagnostic test predicts “Platinum-resistant ovarian cancer if patients are able to respond to this is difficult to treat and, prior to this treatment or not,” explains Naumann. study, about a dozen randomized trials The imaging agent selectively binds the had been conducted in this patient folate receptors and can be visualized with population,” explains lead investigator single-photon emission CT (SPECT). Wendel Naumann. “All of these trials were Indeed, in patients whose lesions all negative, with the exception of the recent expressed the folate receptor, the response AURELIA trial. Similar to AURELIA, our to vintafolide and PLD combination study demonstrated an improvement in therapy was most pronounced: median progression-free survival. Unfortunately, PFS was 5.5 months compared with PRECEDENT was underpowered to show only 1.5 months for those receiving PLD a survival advantage.” alone. “Seeing a PFS with a hazard ratio More than 80% of epithelial ovarian benefit of 0.38 is truly remarkable and cancers express the folate receptor, very encouraging, especially with a drug a vitamin transporter not typically that has limited toxicity,” says Naumann. expressed by healthy cells. Accordingly, Furthermore, in those patients with some its differential expression profile makes degree of folate-receptor expression the folate receptor an attractive target for (10–90%), vintafolide also imparted therapy. Furthermore, patients whose some PFS benefit, whereas those without tumours highly express the folate receptor folate receptor expression did not benefit have poorer prognoses than those whose (HR 0.87 and HR 1.81, respectively). tumours are receptor-negative. Vintafolide Naumann is optimistic about the was designed to bind the receptor future of vintafolide in the clinic: “I think selectively via its folate domain and vintafolide will likely be the first cytotoxic deliver the cytotoxic agent (the vinblastine chemotherapy that will be approved derivative) in a targeted manner straight to in almost 10 years—gemcitabine was tumour cells, sparing healthy cells. the last—and likely to become part of the Patients who had undergone up to standard of care in women with platinum- two previous regimens of chemotherapy resistant ovarian cancer.” Indeed, a were enrolled in the PRECEDENT phase III trial—PROCEED—is currently study, either receiving the standard of enrolling patients in the USA and care of pegylated liposomal doxorubicin Europe (NCT01170650). (PLD) with or without vintafolide. Mina Razzak In the intention to treat population (n = 149), the median progression-free survival (PFS) was 5.0 months for the Original article Naumann, W. J. et al. PRECEDENT: a combination therapy and 2.7 months randomized phase II trial comparing vintafolide (EC145) for PLD alone. Common adverse effects and pegylated liposomal doxorubicin (PLD) in combination of treatment included leukopenia and versus PLD alone in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. doi:10.1200/JCO.2013.49.7685 peripheral sensory neuropathy. In total,