VEGF Inhibitors
VEGF-tyrosine kinase receptor inhibitors (axitinib, pazopanib, sorafenib, sunitinib) block the signaling pathway by binding to the intracytoplasmic region of the receptor. Pazopanib is an angiogenesis inhibitor that acts by VEGF receptor (VEGFR) -1, -2 and -3, and PDGF receptor (PDGFR) α, β and c-kit. In phase III study, pazopanib was compared with placebo, and the progression-free survival (PFS) was longer (9.2 months vs. 4.2 months) and the objective response rate (ORR) was higher (30% vs. 3%) in the pazopanib group (20). In the updated results of survival and safety analysis, the reason why pazopanib treatment did not show a survival advantage was attributed to the permission to pass from placebo group to pazopanib group after disease progression (21).
Sunitinib is a multi-target tyrosine kinase inhibitor acting via VEGFR-1, -2, and -3, PDGF-Rα and β, c-kit, FLT-3, colony stimulating factor receptor (CSF-1R), and neurotrophic factor receptor (RET). In phase III study, sunitinib and IFNα were compared in the first-line treatment. The PFS was longer (11 months vs. 6 months, respectively) and ORR was higher (34% vs. 6%, respectively) with sunitinib treatment. Sunitinib was approved by the FDA for the first-line treatment of mRCC (22).
Both agents showed similar efficacy in phase III COMPARZ study, a non-inferiority study comparing sunitinib with pazopanib (23,24).
Bevacizumab is a monoclonal antibody that binds to circulating VEGF A with high affinity and inhibits signal transduction. In the phase III AVOREN study, the combination of IFNα and bevacizumab was compared with the combination of IFNα and placebo, and PFS in the bevacizumab group was approximately five months longer (10.2 months vs. 5.4 months) (25).
Sorafenib, similar to sunitinib, have inhibitory effects on VEGF, PDGF-R, c-kit and c-MET. In the comparative study, the median PFS was 5.5 months with sorafenib and 2.8 months in the placebo group. Overall survival (OS) was 17.8 months in the sorafenib group and 14.3 months in the placebo group (p=0.0287) (26).
Different current treatment options and their rankings in mRCC treatment are summarized in Table 1 and Table 2.
Table 1
Table 2
In the AXIS study comparing axitinib with sorafenib in the second line treatment of mRCC, higher ORR and longer PFS were shown in the axitinib group (27). Afterwards, the efficacy of axitinib in the first line treatment was investigated. In a study comparing axitinib treatment with sorafenib in the first line treatment, PFS was 10.1 months in the axitinib group and 6.5 months in the sorafenib group (28).
Cabozantinib is a newly developed, powerful VEGF-2 and c-MET dual inhibitor. Recent studies have shown that MET signals are important in sustaining VEGF signals, tumor angiogenesis, proliferation and patient survival (29). These results also indicate that MET signaling may play a role in VEGF inhibitor resistance. In the METEOR study comparing cabozantinib with everolimus in previously treated patients, cabozantinib has been shown to contribute to PFS for approximately four months (7.4 months vs. 3.8 months) (30) and to OS for approximately five months (21.4 months vs. 16.5 months) (31). Dovitinib is a new TKI that targets both VEGF and fibroblast growth factor receptor (FGFR) pathways. Preclinical studies have also shown that this dual-acting TKI has activity against topoisomerase (32). In the phase III study, median PFS with dovitinib and sorafenib treatments were found to be 3.7 and 3.6 months, respectively, and dovitinib did not show an additional contribution to clinical benefit compared to sorafenib treatment. In a phase II study comparing lenvatinib, the combination of lenvatinib and everolimus and everolimus alone, the combination therapy showed PFS and OS advantage against everolimus alone (PFS: 14.6 months vs 5.5 months; OS: 25.5 months vs 15.4 months) (33,34) and was included in the post-first line treatment sequence.