PROTECT study: Adjuvant pazopanib has no benefit over placebo in RCC

The identification of an effective adjuvant therapy is an unmet need for locally advanced renal cell carcinoma (RCC), according to the authors of the PROTECT (Pazopanib As Adjuvant Therapy on Localized/Locally Advanced RCC After Nephrectomy) trial, but the study drug did not perform as hoped. The results were recently published in the Journal of Clinical Oncology.

The PROTECT trial was the third report of a double-blind, placebo-controlled, randomized phase 3 trial of adjuvant vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Adjuvant use of similar agents yielded mixed results, although none of the studies showed an overall survival benefit.

Half of patients with initially localized RCC will develop recurrent disease in the 10 years after nephrectomy; that number rises to more than 75% in high-risk patients, at which point the disease is usually not curable. Many clinicians are closely following the use of targeted therapy as an adjuvant strategy for localized RCC, including a series of adjuvant TKI trials.

The ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial failed to demonstrate improvement in disease-free survival (DFS) in RCC patients with intermediate or high risk of relapse. However, S-TRAC (Sunitinib Treatment of Renal Adjuvant Cancer) evaluated the efficacy of adjuvant sunitinib in high-risk RCC after nephrectomy and showed a significant improvement in DFS.

The PROTECT trial evaluated the efficacy and safety of pazopanib compared to placebo in patients with locally advanced RCC at high risk for relapse after nephrectomy. Results showed that pazopanib 600 mg showed no benefit over placebo. Initially, patients started with 800 mg daily, but higher than expected discontinuation rate due to adverse events led to a dose reduction of 600 mg daily.

In an editorial accompanying the study, a group of investigators concluded that there were lessons to learn from the results.

“One of the key learning points from PROTECT is how different patient tolerance of toxicity is among patients with non-metastatic disease versus those with metastatic disease, for whom drug therapy is usually the sole treatment,” remarked the authors.

They went on to suggest that good counseling—especially early in the study—may help to prevent patients from discontinuing the study drug.

In the PROTECT trial, 1,538 patients with resected RCC were assigned to pazopanib or placebo for one year; 403 patients were randomized to 800 mg or placebo, and 1,135 patients were randomized to the lowered dose of 600 mg or placebo daily. After 8 to 12 weeks of treatment, the dose could be maintained or escalated to 800 mg daily. The primary endpoint was DFS assessed by investigator.

The primary objective was to evaluate DFS with pazopanib 600 mg. Secondary objectives were to evaluate overall survival (OS), DFS annually, DFS and OS with initial dose of 800 mg pazopanib compared to placebo, and other health outcomes measures.

The study did not meet the primary DFS endpoint in the intent-to-treat (ITT) group who received 600 mg (ITT_600mg). The primary analysis was not statistically significant. The median duration of follow-up in the group was 30.4 and 30.7 months for pazopanib and placebo, respectively.

The results of the secondary DFS analysis demonstrated a benefit for the ITT_800mg group and for the ITT_ALL; the median duration of follow-up for both treatment arms in the ITT_800mg was 47.9 months. The most common adverse events leading to discontinuation of pazopanib were elevations of ALT and AST. The results of OS and other secondary objectives were inconclusive because data are not mature. Further analysis is planned.

Overall, results from PROTECT demonstrated differences in the outcome between 600- and 800-mg starting dose groups, but the study did not meet its primary DFS endpoint. The primary analysis of DFS with pazopanib 600 mg showed no benefit over placebo in the adjuvant treatment in patients with RCC.

To read more about this study, click here.