Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma

Abstract

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.

Kidney Cancer Research Network of Canada (KCRNC) consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials

“…The S-TRAC trial showed DFS benefit, without OS benefit [2]. The PROTECT trial failed to show DFS benefit, except for pazopanib 800mg subgroup, where accrual was interrupted due to adverse effects [3]. In all three reports, data have not reached adequate maturity for final…”

“…The search yielded seven prospective randomized trials of adjuvant targeted agents after nephrectomy for patients with high-risk nmRCC: ASSURE [1], S-TRAC [2], PROTECT [3], SORCE [6], EVEREST [7], ATLAS [8] and ARISER [9] (Table 1). The ARISER trial examined a carbonic anhydrase IX inhibitor (girentuximab).…”

“…Secondly, it is important to note the effect of central vs. investigator review on reported DFS in all patients, as well in higher-risk sub-group in the S-TRAC study. Fifth, it is of note that a third prospective randomized controlled trial of a VEGFR inhibitor, the PROTECT trial that relied on pazopanib, also failed to demonstrate an OS benefit [1][2][3]. However, its results regarding DFS are equivocal.…”

“…In this report, we review the current evidence regarding adjuvant targeted agent therapy after nephrectomy for nmRCC and provide a meta-analysis of the three published vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs)-based adjuvant trials [1][2][3], as discussed at the 2017 Canadian Kidney Cancer Forum (CKCF) [5] and endorsed by the Kidney Cancer Research Network of Canada (KCRNC)…”

33rd Annual Congress of the European Association of Urology in 2018: Review of oncological topics

“…Что касается обсуждаемого вопроса целесообраз-ности адъювантного лечения у больных раком почки высокого риска прогрессирования, перенесших нефр-эктомию, то несмотря на одобрение сунитиниба в ка-честве адъюванта Европейским агентством лекарст-венных средств, такое показание не вошло в рекомендации ЕAU в 2018 г. для сунитиниба, а также пазопаниба и сорафениба из-за спорного характера результатов в доступных исследованиях по адъювант-ной терапии [7][8][9].…”