Pazopanib demonstrated a statistically significant and clinically meaningful improvement in PFS vs. placebo in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma.
However, the drug exhibited no effect on OS.
The development of novel therapies that target tumor angiogenesis and mTOR pathways has significantly improved clinical outcomes in patients with advanced renal cell carcinoma (RCC), according to researchers.
Cora N. Sternberg
“Since 2005, six targeted agents — sunitinib (Sutent, CPPI CV), sorafenib (Nexavar, Bayer HealthCare), pazopanib (Votrient, GlaxoSmithKline), temsirolimus (Torisel, Wyeth Pharmaceuticals), everolimus (Afinitor, Zortress; Novartis) and bevacizumab (Avastin, Genentech) with interferon alfa-2a — have received regulatory approval in the United States, Europe and other countries worldwide,” Cora N. Sternberg, MD, chief of the department of medical oncology at the San Camillo and Forlanini Hospitals in Rome, and colleagues wrote. “These agents have been included in US and European treatment guidelines as front-line and/or second-line therapies for advanced RCC.”
Sternberg and colleagues conducted the investigation to determine the effectiveness of pazopanib in patients with advanced/metastatic RCC. They enrolled 435 patients with treatment-naive or cytokine-pretreated RCC and randomly assigned them to pazopanib 800 mg daily or a placebo.
Patients were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients were allowed to receive pazopanib.
Overall, patients assigned to pazopanib experienced significantly longer median PFS (9.2 months vs. 4.2 months; HR=0.46). Researchers also observed that trend among treatment-naive patients (11.1 months vs. 2.8 months; HR=0.40) and cytokine-pretreated patients (7.4 months vs. 4.2 months; HR=0.54).
Sternberg and colleagues used a stratified log-rank test to analyze final OS in the intent-to-treat population. Rank-preserving structural failure time and inverse probability of censoring weighted analyses were performed post hoc to adjust for possible crossover.
The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 months vs. 20.5 months; HR=0.91; 95% CI, 0.71-1.16).
However, in inverse probability of censoring weighted analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762). Similar results also were reported in rank-preserving structural failure time analyses (HR=0.43; 95% CI, 0.215-1.388).
“This lack of correlation between OS and PFS is likely due to the extensive crossover of placebo-treated patients to pazopanib via the parallel open-label extension, as well as other subsequent anticancer treatments that patients from both arms received after progression,” Sternberg and colleagues wrote. “Similar confounding issues on final OS analysis were also reported for other phase 3 advanced RCC trials with anti-VEGFR and mTOR inhibitors.”
Disclosure: The researchers report honoraria from, stock ownership in and consulting/adviser relationships with Aveo, Bayer, GlaxoSmithKline, Novartis and Pfizer.