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Several novel and exciting agents are currently in development to treat patients with renal cell carcinoma (RCC), explains moderator Daniel J. George, MD. One such agent, dovitinib, is currently in a phase III trial for patients with RCC following progression on VEGF- and mTOR-targeted therapies.
At this point, the mechanism behind resistance to VEGF receptor inhibition is unknown, states Eric Jonasch, MD. One theory suggests the FGF receptor plays a role in resistance. As such, dovitinib, which targets the FGF and VEGF receptors, could overcome this resistance. In early phase trials, this approach seemed successful for patients refractory to antiangiogenic agents, suggests Jonasch. As a result, a phase III trial comparing dovitinib to sorafenib was undertaken.
In the trial, 564 patients were enrolled and randomized to sorafenib or dovitinib following treatment with a VEGF- and mTOR-targeted agent. Brian I. Rini, MD, questions the reasoning behind including a prior mTOR inhibitor in the inclusion criteria. Testing the agent in this setting seems to represent discordance between seeking FDA approval and fulfilling a clinical need, states Robert A. Figlin, MD. Once the agent is approved, it will likely be investigated in a more applicable setting, Figlin believes.
The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib represents another novel agent under investigation to treat patients with RCC, notes George. Similarly to dovitinib, this treatment hopes to overcome resistance by blocking multiple pathways, suggests Thomas E. Hutson, DO, PharmD. Following promising phase I results, the VEGFR and c-MET inhibitor cabozantinib is being compared to everolimus for patients with RCC that has progressed on a VEGF TKI. In addition to this second-line study, George notes, a phase II first-line study is comparing cabozantinib to sunitinib in RCC.
It's important to note, suggests Figlin, that although these novel agents target FGF and c-MET they also block VEGF, which is an established approach in RCC. Along these lines, the second-line trial comparing cabozantinib to everolimus is similar to those investigating continued VEGF inhibition, believes Hutson. As a result of this, it may be difficult to ascertain whether the benefit comes from VEGF or the other pathways being blocked. However, the first-line trial comparing cabozantinib to sunitinib may help answer some of these questions, believes George.