Over the past decade, the field of metastatic renal cell carcinoma therapy has witnessed the development of multiple drugs targeting the vascular endothelial growth factor (VEGF) pathway, based on the underlying biology of renal cell carcinoma that leads to reliance on angiogenic signaling. The initial investigation of these agents compared them to either placebo or interferon, an old standard of care. More recently, comparisons of active VEGF-targeted agents have taken place, providing insight into the relative risks and benefits of each agent. In general, VEGF-targeted agents are able to more effectively control disease for longer periods of time than historic therapy, but since they are noncurative, they involve ongoing therapy with ongoing toxicity.
In this light, recent data from the COMPARZ trial provide a comparison of the benefit and tolerability of sunitinib (Sutent) and pazopanib (Votrient). The results provide reassurance to practitioners that both agents are effective in the initial treatment of metastatic renal cell carcinoma. Progression-free survival was similar and in line with previous studies, with overall survival reaching nearly 2.5 years, likely reflecting the multitude of active agents that renal cell carcinoma patients now receive in sequence.
Noteworthy was the different toxicity profile of the two agents, with more fatigue, mucositis, and hand-foot syndrome seen with sunitinib, and more liver function abnormalities, weight loss and alopecia with pazopanib. Several quality-of-life indicators favored pazopanib, reflecting these toxicity profile differences.
Also notably, the incidence of drug interruption/dose reduction was similar, but more patients treated with pazopanib discontinued because of toxicity. This latter point highlights the difficulty in assessing the comparative safety and tolerability of two agents. That is, examination of toxicity incidence, quality-of-life scores, or the need to modify/discontinue a drug due to toxicity may lead to different interpretations, and no single measure accurately captures comparative safety/tolerability.
In the end, it is most important to develop expertise in optimally administering a given drug that best balances the benefit/risk profile for an individual patient, accounting for comorbidities and how specific toxicities will affect the individual. Further, developing a comfort level about when to modify dose or schedule and when to change to another therapy is critical for maximizing clinical outcome and tolerability.
The benefit of VEGF-targeted therapy with a single agent or sequence of agents has likely been maximized in metastatic renal cell carcinoma, with additional refinements being focused on increasing tolerability through schedule adjustments, drug holidays, and improvements in supportive care. Biomarkers to guide drug selection remain elusive but are still highly sought after. Clinical trials remain a priority to test novel agents and build upon the advances achieved with VEGF-targeted therapy. ■
Dr. Rini is Associate Professor of Medicine at Lerner College of Medicine and Cleveland Clinic Taussig Cancer Institute.
Disclosure: Dr. Rini has received research funding and is a consultant for GlaxoSmithKline and Pfizer.
Pazopanib (Votrient) and sunitinib (Sutent) have been shown to provide progression-free survival benefit compared with placebo or interferon in phase III trials in metastatic renal cell carcinoma. In a noninferiority trial reported in The New England Journal of Medicine by Robert J. Motzer, MD, of...