The Future Landscape of RCC Treatment
VEGF has been implicated in carcinogenesis and progression of tumors with clear cell histology. Patients with a germline deletion in the von Hippel-Lindau (VHL) gene frequently develop multiple clear cell RCC tumors at an early age. In addition, a majority of patients with sporadic clear cell RCC demonstrate biallelic loss of the gene. VHL protein is involved in the regulation of VEGF.17 Sunitinib, sorafenib, pazopanib, and bevacizumab (with interferon) all achieve their activity in RCC primarily through inhibition of VEGF, although other pathways are affected as stated previously. Preliminary evidence suggests that progressive RCC tumors retain sensitivity to alternate multikinase VEGFR inhibitors and that continued inhibition of the VEGF/VEGFR pathway remains therapeutically valuable in such patients.18 Currently, it is not known whether any particular aspect of the VEGF pathway is more critical than others in the setting of disease progression after treatment with a multikinase VEGFR inhibitor.
Tivozanib (AV-951) is an oral inhibitor of VEGFR-1, -2, and -3 that is more potent against VEGFR-2 than sunitinib, sorafenib, and pazopanib.19 A Phase 2 trial was reported at ASCO 2011 where 272 patients with RCC and no prior VEGF-targeted therapy were given 16 weeks of open-label tivozanib and thereafter treatment was administered according to response. Those with >25% tumor shrinkage continued the drug, those with >25% increase in tumor size were discontinued and the remainder were randomized to 12 weeks of double-blind tivozanib or placebo. In the overall study population 84% of patients demonstrated progressive disease or tumor change from baseline by week 16. The PFS was 11.7 months for tivozanib. Hypertension occurred in 45% and dysphonia in 22%.20 A Phase 3 trial (TIVO-1) is underway to compare tivozanib to sorafenib in 500 patients who had not been previously treated with either a VEGF or mTOR therapy.21 On January 3, 2012, the manufacturer announced that tivozanib demonstrated statistically significant superiority over sorafenib in this trial for the primary end point of PFS (11.9 months vs. 9.1 months for the entire population and 12.7 months vs. 9.1 months for those with no prior systemic therapy).22 A plan to submit for marketing approval in 2012 was also announced.
Dovitinib (TKI258) is an inhibitor of the fibroblast growth factor receptor (FGFR), the platelet-derived growth factor receptor (PDGFR), as well as VEGFR. Preliminary results of a phase II trial presented at ASCO 2011 enrolled 59 patients previously treated with a VEGFR inhibitor and/or an mTOR inhibitor. The most common adverse events(AEs) (all grades) were nausea (73%), diarrhea (64%), and vomiting (56%). In the 51 evaluable patients, the PR rate was 8%.23 An open-label, phase 3 trial comparing dovitinib to sorafenib in patients who have had 1 prior VEGF-targeted therapy and 1 prior mTOR inhibitor therapy was opened in mid-2011.24 Data collection for the primary end point of PFS is anticipated in mid-2013.
Lenvatinib (E7080) is an orally administered inhibitor of tyrosine kinase enzymes including VEGFR1-3, FGFR1, c-kit, and PDGFR-beta. In the Phase 1 trial, the most common AEs (all grades) were hematuria, fatigue, hypertension, increased transaminases, headache, and proteinuria. The most common grade 3 AEs were hypertension (18.5%), increased AST (11.1%), and thrombocytopenia (11.1%); no grade 4 AEs were observed.25 The agent is currently in Phase 2 trials in a number of malignancies, including advanced RCC that has progressed after 1 prior anti-VEGF therapy.26 Patients (N=180) are randomized to lenvatinib alone or in combination with everolimus. Final data collection for the primary outcome measure is expected in late 2013.