ASCO 2017: Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT)

Chicago, IL ( On the heels of two randomized controlled trials (RCTs) recently published assessing adjuvant TKIs in the setting of patients treated with radical nephrectomy for locally advanced renal cell carcinoma (RCC) [1,2], Dr. Motzer and colleagues presented their findings at the 2017 ASCO annual meeting of another phase III RCT assessing adjuvant pazopanib vs placebo in these high risk patients. ASSURE [1] randomized patients 1:1:1 to adjuvant sunitinib vs sorafenib vs placebo, demonstrating no survival benefit for either medication compared to placebo. However, S-TRAC [2] randomized patients to adjuvant sunitinib vs placebo, finding that median duration of disease-free survival (DFS) was significantly longer in the sunitinib group compared to placebo.

Patients enrolled in PROTECT (n=1,538) had either resected pT2 (high grade) or ≥pT3 clear cell RCC after nephrectomy and were randomized to pazopanib vs placebo for 1 year. The starting dose (800 mg) following treatment of 403 patients was lowered to 600 mg to improve tolerability. Subsequently, the primary endpoint was changed to DFS with pazopanib 600 mg (n=1,135), which was performed after 350 DFS events in an intention-to-treat (ITT) analysis. A second DFS analysis was performed after an additional 12 months, and secondary endpoints included (i) DFS with ITT for patients receiving pazopanib 800 mg, (ii) ITT for all patients, and (iii) safety outcomes. Disease characteristics were similar between arms and the results of the primary analysis (DFS ITT for patients receiving pazopanib 600 mg) was not significant (HR 0.86, 95%CI 0.70-1.06). ITT DFS for patients receiving 800 mg (HR 0.69, 95%CI 0.51-0.94) and all patients (HR 0.80, 95%CI 0.68-0.95) was significant, leading to a 31% and 20% risk reduction, respectively. On updated analysis, the 600 mg dose was still insignificant, however the 800 mg dose showed continued risk reduction (HR 0.66, 95%CI 0.49-0.90). There was no difference in OS among any of three analysis groups, however given the prematurity for this endpoint, the final OS analysis will be performed in April 2019. Increased ALT and AST were the most common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT 16% and AST 5%) and 800 mg (ALT 18% and AST 7%) cohort.

In conclusion, this study demonstrated a 31% recurrence reduction for patients treated with 800 mg pazopanib in ITT analysis, but this was a secondary objective of the study. The study did not meet the primary DFS endpoint for 600 mg pazopanib and is not recommended for adjuvant therapy following resection of locally advanced RCC.
Clinical trial: NCT01235962

Presented By: Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Co-Authors: Naomi B. Haas, Frede Donskov, Marine Gross-Goupil, Sergei Varlamov, Evgeny Kopyltsov, Jae-Lyun Lee, Bohuslav Melichar, Brian I. Rini, Toni K. Choueiri, Milada Zemanova, Lori A Wood, Dirk Fahlenkamp, Martin Neil Reaume, Arnulf Stenzl, Weichao Bao, Paola Aimone, Christian Doehn, Paul Russo, Cora N. Sternberg

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, phase 3 trial. Lancet 2016 May 14;387(10032):2008-2016.
2. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016 Dec 8;375(23):2246-2254.