Pazopanib is approved by the US Food and Drug Administration for the first-line treatment of metastatic renal cell carcinoma (RCC), but failed to meet its primary endpoint in the PROTECT trial ( Identifier: NCT01235962) as adjuvant therapy for localized disease.1

“The landscape of RCC is seeing a further shift, having transitioned from a cytokine era to oral VEGF-targeted therapies, and now with the expansion of immune checkpoint blockers in various treatment settings,” Aly-Khan A. Lalani, MD, FRCPC, of the Dana-Farber Cancer Institute in Boston, Massachusetts, who was not directly involved with the PROTECT trial, told Cancer Therapy Advisor. He noted, however, that the results of the PROTECT trial likely limit the rationale for pazopanib as an adjuvant therapy in the localized setting.

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Outcomes of the PROTECT Trial

The phase 3 PROTECT trial randomly assigned 1538 patients with non-metastatic, intermediate- to high-grade clear-cell RCC to receive 800 mg of pazopanib or placebo daily for 1 year after undergoing nephrectomy. The starting dose of pazopanib was reduced to 600 mg, however, because of a larger number of toxicity-related discontinuations than expected. This resulted in 2 pazopanib cohorts — intention-to-treat (ITT) populations who received 600 mg or 800 mg. The primary endpoint was amended to disease-free survival (DFS) in the ITT population that received 600 mg. DFS in the 800 mg ITT population was a secondary endpoint.

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The overall population included patients with T1 (<15%), T2 (15%), T3 (82%), and T4 (3%) disease, with most patients (95%) demonstrating no lymph node involvement. The majority of patients (94%) underwent complete nephrectomy, and 95% of patients had clear cell histology.

There was no significant difference in DFS among patients in the 600 mg pazopanib arm compared with placebo (hazard ratio [HR], 0.86; 95% CI, 0.70-1.06; P = .16) during a median follow-up of over 30 months. The lack of benefit remained consistent after an additional 1 year of follow-up (HR, 0.94; 95% CI, 0.77-1.14; P = .51).

“At the higher dose (ITT 800 mg), which comprised only 26% of the study population and was a secondary analysis, the HR of 0.69 (95% CI 0.51-0.94; P = .02) came at the cost of increased toxicity and treatment discontinuation,” Dr Lalani said.

Interestingly, higher trough plasma levels of pazopanib were correlated with longer DFS in this study, as well as in previous studies in the metastatic setting, which provides a rationale for the difference in efficacy between the 600-mg and 800-mg doses.