Treatment with pazopanib 600 mg had no benefit over placebo for patients who had undergone nephrectomy for localized or locally advanced renal cell carcinoma (RCC), according to results of the phase III PROTECT trial published in the Journal of Clinical Oncology.
However, patients in the intent-to-treat (ITT) 800-mg pazopanib group had a decrease in relative risk for recurrence or death, but this group represented only about one-third of the study population.
“The difference in treatment effect between the two groups might be explained by the better performance of the placebo arm in the ITT600mg group compared with that in the ITT800mg group, although this observation is not based on a randomized comparison,” wrote Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, and colleagues.
Antiangiogenics like pazopanib are a standard part of treatment for patient with advanced RCC. This trial was designed to test pazopanib in patients with locally advanced disease at high risk for relapse after nephrectomy. The study included 1,538 patients with resected disease who were randomly assigned to pazopanib or placebo. The starting dose for pazopanib was 800 mg and 403 patients received this dose. However, to address toxicity attrition the starting dose was decreased to 600 mg and the primary endpoint was adjusted to disease-free survival for pazopanib 600 mg.
The trial failed to meet its primary endpoint. There was no improvement in disease-free survival for patients assigned pazopanib 600 mg compared with placebo. Looking at the smaller group of patients assigned to 800-mg pazopanib, there was a significant improvement in disease-free survival (HR, 0.69; 95% CI, 0.51–0.94) compared with placebo. With 1 year of additional follow-up, patients assigned to 800 mg had a 33.7% decreased relative risk for recurrence or death. The median disease-free survival was 54 months for placebo and not yet reached for pazopanib 800 mg.
“Although the intent of modifying the protocol dose of pazopanib from 800 to 600 mg was to reduce the rate of discontinuation and improve the safety profile, the proportions of patients in both cohorts had similar discontinuation rates and safety,” the researchers wrote. “The rate of pazopanib discontinuation because of adverse events in PROTECT (35% to 39%) was higher compared with that observed in two large phase III studies in advanced or metastatic RCC (14% and 24%, respectively).”
Patients in both the 600 mg and 800 mg groups had a similar duration of exposure, with about one-half of patients completing 12 months of treatment in both groups. Increased ALT and AST were common adverse events that led to treatment discontinuation in the pazopanib 600 mg and 800 mg groups.