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Profile of vintafolide (EC145) and its use in the treatment of platinum-resistant ovarian cancer 2019-03-02T17:23:23+00:00

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 rationale 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, before detailing the mechanism of action of vintafolide, its clinical applications, and the results of different study phases.

Materials and methods:

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

Results:

FR is a bundle-membrane receptor that 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, and its expression appears to be mostly associated with a poor prognosis and platinum resistance. Vintafolide is a folate-desacetylvinblastine monohydrazide conjugate, allowing 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 improve-ment in disease-free survival in patients with platinum-resistant ovarian cancer, and in those with a very poor prognosis who had already received three to four lines of systemic chemotherapy. The greater benefits were observed 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, and, 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 are expected to confirm these results.