Profile of vintafolide (EC145) and its use in the treatment of platinum-resistant ovarian cancer

Mathieu Luyckx, Raffaella Votino, Jean-Luc Squifflet, Jean-François Baurain

Objective:

Our aim was to review the profile of vintafolide (EC145) and its ration for use in platinum-resistant ovarian cancer. First we investigated the folate receptors (FRs), folate’s path-way into cells, and its expression in normal and cancerous cells. After that, we detailed the mechanism of action of vintafolide, and its clinical applications. Finally, we analyzed the results of the different study phases.

Materials and methods:

We conducted a literature search through Pub Med/Medline, Google, ClinicalTrials.gov and websites of pharmaceutical companies. We only selected articles in English. First, we selected All articles investigating folate receptor expression in ovarian cancer, than articles reviewing platinum resistance. We collected papers about vintafolide, while we excluded those talking about synthesis and biochemistry concerns. We read the different Phase I and II studies. Then we added an update on the website of pharmaceuticals companies.

Results:

FR is a bundle-membrane receptor. It is expressed normally in some normal tissues on the apical surface of cells, but highly expressed in ovarian cancer cells (>80%). It collects folate through endocytosis.

Chemotherapy does not modify its expression in ovarian cancer cells. Its expression appears to be mostly associated with a poor prognosis and platinum resistance. Vintafolide is a folate-desacetylvinblastine monohydrazide conjugate. It allows a liberation of the drug into the cytoplasm of cancerous cells via the FR-A (FRA) and endocytosis, with high specificity.

Phase I studies showed a 2.5mg bolus dose to be nontoxic, with moderately adverse events. Phase II clinical trials for the first time demonstrated a statistically significant improvement in disease-free survival in patients with platinum-resistant ovarian cancer.

There was also an improvement in those with a very poor prognosis who had already received three to four lines of systemic chemotherapy. We observed the greater benefits in patients with highly expressed FRA.

Conclusion:

Vintafolide is a promising targeted agent for recurrent platinum-resistant ovarian cancer. First, thanks to its mechanism of action and the characteristics of FRA in ovarian cancer. Second, because of the favorable results observed in the first clinical trials on platinum-resistant ovarian cancer. Phase III clinical trials are currently ongoing and we expect them to confirm these results.