Dovitinib, an inhibitor of the VEGF and FGF signaling pathways, seems to have only minimal activity in patients with malignant pleural mesothelioma (MPM) who received prior chemotherapy treatment, according to the results of a Phase 2 trial.
The findings appeared in the medical journal Lung Cancer, in a report, “A phase II trial of dovitinib in previously treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group,.
While MPM patients usually receive platinum-folate-based chemotherapy as standard first-line treatment, studies have suggested that adding the VEGF inhibitor Avastin (bevacizumab) can improve their outcomes.
VEGF is involved in the growth of new blood vessels and tumor cell proliferation, and in MPM patients, microvessel density seems to be associated with a negative prognosis.
While this suggests that adding VEGF inhibitors may help MPM patients, other VEGF inhibitors like sunitinib and sorafenib have shown only minor activity in these patients.
Dorafenib is a multitargeted oral inhibitor that inhibits not only the VEGF receptors, but also the receptors for other pro-tumoral and pro-angiogenic growth factors, including PlGF and FGF. Therefore, researchers hypothesized that dovitinib could work in patients with advanced MPM, whose disease progressed after treatment with platinum-antifolate chemotherapy.
The Phase 2 DOVE-M study (NCT01769547) enrolled 12 adult patients with MPM who received 500 mg of oral dovitinib every day for five days. This was followed by two drug-free days, and this cycle was repeated in 28-day cycles. The response to treatment was assessed every two cycles.
Among the participants, only one achieved an unconfirmed partial response. While the cancer did not progress further in half of the patients within three months, all patients eventually progressed or died. Researchers terminated the study due to minimal activity with early progression and poor tolerability by patients.
According to the first authors, the doses used in this trial may not have inhibited FGFR and VEGFR enough. In fact, researchers recorded a low amplification of FGFR1 in only one of 12 tumor samples. “[S]tudies using more potent FGFR inhibitors could be considered,” they wrote, urging more studies to further characterize the FGFR pathway’s role in MPM.