Several angiogenic inhibitors have been approved, and many others are in clinical development for RCC. Two different approaches proven to have clinical activity in blocking the VEGF pathway in RCC are inhibition by small-molecule tyrosine kinase (TK) inhibitors (eg, sunitinib, sorafenib, pazopanib) and binding with an antibody (bevacizumab). Small-molecule TK inhibitors block the intracellular domain of the VEGF receptor, while bevacizumab binds with circulating VEGF and prevents activation of the VEGF receptor.4
In contrast to older immunotherapies, these newer agents demonstrated both significantly superior efficacy and better safety profiles, and thus changed the management landscape of metastatic RCC. Although all phase III pivotal studies showed prolongation in progression-free survival (PFS) and a strong trend toward improved overall survival (OS), only one of these studies increased OS to the level of statistical significance.5
The mTOR pathway, which has a central role in the regulation of cell growth, is dysregulated in multiple cancer types. This pathway stimulates protein synthesis after receiving input from multiple signals including growth factors, hormones, nutrients, and other stimulants. The mTOR pathway is involved in additional critical cellular functions (eg, protein degradation), as well as in angiogenesis, and is most dysregulated in patients with poor prognostic factors such as high nuclear grades.6
Use of mTOR pathway inhibitors represents a relatively novel therapeutic approach in the targeted treatment of malignancies. So far, two mTOR inhibitors, temsirolimus and everolimus, have been approved and widely characterized for treatment of advanced RCC. These agents lead to G1 growth arrest after binding to a protein complex and inhibiting mTOR, and have been shown to be effective in both first-line and second-line advanced RCC.7,8
The first-line trial showed improved overall survival; the second-line trial was halted by the Data & Safety Monitoring Board after 191 progression events were observed, with progression occurring in 65% (90/138) of placebo patients compared with 37% (102/272) of everolimus-treated patients. Patients on placebo crossed over to the active drug after the trial was halted. The significantly improved PFS in the everolimus arm remained consistent throughout trials in all three Memorial Sloan-Kettering Cancer Center risk groups.8
Clearly mTOR inhibitors are proven and highly active agents in advanced RCC and also have proven effects on OS, the hardest endpoint to achieve.
Choice of Therapy
With the availability of 4 VEGF inhibitors and two mTOR inhibitors for advanced RCC, it becomes challenging to choose therapeutic options for a patient. Complicating this choice is the fact that none of these agents has been compared head-to-head in a clinical trial, and a cross-study comparison of efficacy endpoints may lead to erroneous conclusions. The only thing that can be stated definitely about efficacy is that out of four phase III trials of VEGF inhibitors in advanced RCC, one has shown a survival improvement while the other three trials have not shown survival improvements. In contrast, among the two phase III trials of mTOR inhibitors, one has shown survival improvement and one was stopped after an interim analysis showed a high-magnitude difference in PFS.
Side Effects of Targeted Agents
Because the efficacy of these different agents is likely to be similar, the choice of therapy in advanced RCC is more likely to be individualized by physicians on the basis of the patients’ comorbidities and the side effects they can tolerate. There are clearly differences in side effects between the VEGF inhibitors and the mTOR inhibitors, and understanding these differences may help when making personalized decisions. Although all VEGF inhibitors could lead to serious cardiovascular and thromboembolic events, the most serious event related to mTOR inhibitor class is drug-induced pneumonitis. The baseline comorbidities (eg, hypertension, heart disease, or cerebrovascular disease vs preexisting pulmonary dysfunction) are likely the most important factors in choosing between the two classes of agents. Even among VEGF inhibitors, there are some differences between oral VEGF TK inhibitors and bevacizumab. In the following three sections, I discuss the side effects associated with these three broad categories of medications used in advanced RCC: oral small-molecule VEGF TK inhibitors, bevacizumab, and mTOR inhibitors.
Oral VEGF TK Inhibitors
The most extensive data regarding the side effects from oral VEGF TK inhibitors come from patients treated with sunitinib and sorafenib.