Pazopanib 600 mg daily as adjuvant therapy did not prolong disease-free survival for patients with locally advanced renal cell carcinoma (RCC) who had undergone nephrectomy, according to the results of the phase III PROTECT trial (abstract 4507). Pazopanib 800 mg did result in a 31% reduction in risk of recurrence or death, but this was not the study’s primary endpoint.
Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, presented the results of the trial at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6. Based on these results, Motzer said that “pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
According to Motzer, about 30% to 40% of patients with high-risk RCC will relapse after nephrectomy. To better treat these patients, adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy is being investigated to improve disease-free survival. However, results to date have been mixed.
The PROTECT trial included 1,538 patients with pT2, pT3, or greater clear-cell RCC. Patients were randomly assigned to pazopanib or placebo for 1 year. The trial initially gave pazopanib at 800 mg (ITT 800), but after treating 403 patients, the dose was lowered to 600 mg (ITT 600) to improve tolerability, and the primary endpoint was changed to disease-free survival with pazopanib 600 mg. Tumor imaging was performed at baseline; weeks 20, 36, and 52 during the first year; and then every 6 months during years 2 to 5.
Compared with placebo, 600-mg pazopanib failed to significantly improve disease-free survival (hazard ratio [HR], 0.86; 95% CI, 0.70–1.06; P = .16). However, in an analysis of pazopanib 800 mg there was a 31% reduction in disease-free survival (HR, 0.69; 95% CI, 0.51–0.94; P = .02). In addition, in an evaluation of all the patients treated on the study, regardless of dose, pazopanib reduced risk for progression by 20% (HR, 0.80; 95% CI, 0.68–0.95; P = .01).
“The disease-free survival results were conflicting between ITT 600 mg, which was the primary objective, and ITT 800 mg,” Motzer said. “One possibility was a difference in follow-up since the ITT 800 mg cohort was treated in the early part of the study and the ITT 600 mg group was introduced later on.”
According to Motzer, because of the shorter follow-up for the ITT 600 mg group and a trend in favor of pazopanib over placebo, the study was kept blinded to investigators following the primary endpoint analysis. An additional follow-up analysis was performed a year later.
At this point, the HR for disease-free survival still favored pazopanib but there was less of a difference between pazopanib 600 mg and placebo (HR, 0.94; 95% CI, 0.77–1.14). In contrast, the benefit for pazopanib in the ITT 800 mg group was maintained, showing a risk reduction of 34% in favor of pazopanib (HR, 0.66; 95% CI, 0.49–0.90).
Motzer said that the results of the overall survival analysis for the ITT 600 mg group are inconclusive because the data are not yet mature.
Nearly all patients had an adverse event on this study, but grade 3 or 4 adverse events on the pazopanib arm occurred in 60% of patients compared with 21% on placebo. The adverse event profile was similar between the two pazopanib groups.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg 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 profiles,” noted Motzer.