Jenny J. Kim, MD
Assistant Professor, Oncology
The Sidney Kimmel Comprehensive
Johns Hopkins Medicine
Brian I. Rini, MD
Associate Professor, Medicine
Cleveland Clinic Lerner College of Medicine
Department of Solid Tumor Oncology
Taussig Cancer Institute
Case Western Reserve University
With seven targeted therapies approved for metastatic renal cell carcinoma (RCC), researchers and drug developers are now focusing on understanding the best way to sequence these therapies and on identifying predictive biomarkers of response.
Which Targeted First-Line Agent?
Five of these agents are oral and fall into two categories: multityrosine kinase inhibitors against vascular endothelial growth factor (VEGF) or inhibitors of the mammalian target of rapamycin (mTOR). Based on recent large phase III randomized clinical trials, two VEGF inhibitors are now the standard of care for first-line RCC.
Sunitinib was among the first VEGF inhibitors approved for RCC and is still widely used as a result of strong clinical data showing greater progression-free survival (PFS) and overall survival (OS) in treatment-naïve patients compared with interferon alfa (IFN-α).1
The second widely used oral VEGF inhibitor is pazopanib; studies have demonstrated that pazopanib improved PFS in treatment- naïve metastatic RCC compared with placebo.2
The recent phase II RECORD-3 trial3
, comparing first-line everolimus, an mTOR inhibitor, followed by sunitinib to the reverse sequence, showed that treatment with sunitinib first produced longer PFS for patients.
The COMPARZ trial,4
reported at the 2012 annual European Society for Medical Oncology (ESMO) Congress in Vienna, Austria, directly compared the efficacy of pazopanib to sunitinib in patients with metastatic, treatment-naïve RCC. While both drugs demonstrated similar efficacy (31% overall response rate in the pazopanib arm vs 25% in the sunitinib arm; 28.4 months OS in pazopanib arm vs 29.3 months in sunitinib arm), patients perceived pazopanib to have a better side-effect profile compared with sunitinib. Patients on pazopanib had less hematological toxicity, hand-foot syndrome, rash, fatigue, and peripheral edema.
From the experience at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Jenny J. Kim, MD, assistant professor of Oncology, said that both sunitinib and pazopanib are being used in the frontline setting for these patients, although these agents have slightly different side-effect profiles. Kim and her colleagues have noticed that in their experience, patients tend to have more hand-foot syndrome and stomatitis with sunitinib and more liver toxicity with pazopanib. With the approval of pazopanib in 2009, it has been well incorporated along with sunitinib into the gastro-urology practice at Johns Hopkins in the treatment of metastatic RCC.
“There is a trend toward favoring pazopanib recently,” said Kim. “This is most likely due to a lack of hand-foot syndrome, which seems to affect patients’ day-to-day quality of life.” This observation in clinical practice is consistent with what was seen in the COMPARZ trial.
It is important to mention, Kim noted, that discontinuation rates were similar for both sunitinib and pazopanib in the study, although patient subjective toxicity experience was better with pazopanib.
One potential explanation may be that there were higher liver toxicities with pazopanib compared with sunitinib, which led to discontinuation of pazopanib in the trial.
Another small, 168-patient study, the PISCES trial,5
reinforced the COMPARZ trial data, showing that 70% of patients on the trial preferred pazopanib while 22% preferred sunitinib. “While these trials are not perfect, they will likely have an impact on the oncologic community as more ‘tangible’ data comparing the two agents,” said Kim.