RCC is a highly vascular tumor and it represents an excellent target for antiangiogenic treatment due to the dominant role of the vascular endothelial factor (VEGF)/VEGF receptor (VEGFR) pathway in carcinogenesis and tumor expansion. This has led to the approval of these agents for the management of metastatic disease. These include sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib and lenvatinib. Improvement in progression free survival (PFS) and overall survival (OS) was shown in a series of different trials in patients with metastatic RCC (mRCC).
Despite these favorable results, the role of VEGF inhibition in the adjuvant setting after nephrectomy remains unclear. The recently published S-TRAC trial investigated the efficacy and safety of sunitinib in preventing disease relapse in high risk patients with resected RCC.1 Only high-risk clear-cell RCC (T3N0M0 or T4N0M0 or node-positive) patients were randomized in a 1:1 fashion to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The study met its primary endpoint: median duration of disease free survival (DFS) was longer in patients receiving sunitinib (6.8 vs 5.6 years, hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.59 to 0.98; P = 0.03). Toxicity profile of sunitinib was comparable to that reported in trials on metastatic setting. Adverse events Grade 3 or more were reported in 63% of patients receiving sunitinib, but the rate of serious adverse events was similar in both arms. Treatment discontinuation due to toxicity was considerable and occurred in 28% of the patients.
Apart for the S-TRAC, five more trials studied the role of adjuvant systemic therapy in RCC. Only two of them have been reported so far. The ASSURE trial studied the adjuvant use of sorafenib and sunitinib in high-grade T1b or greater, resected, non-metastatic RCC.2 Median disease-free survival (DFS) was 5·8 years for sunitinib (p=0·8038), 6·1 years for sorafenib (p=0·7184), and 6·6 years for placebo. The PROTECT trial investigated the adjuvant use of pazopanib in clear-cell, T2 and Grade 3-4, >T3, N+ disease.3 The results 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 reasons for the discrepancy between the results of S-TRAC, ASSURE and PROTECT are not clear. S-TRAC aimed at a higher-risk population than ASSURE and PROTECT. ASSURE required negative surgical margins, whereas STRAC accepted microscopic (R1) residual disease. Presence of predominant clear cell histology was mandatory in S-TRAC but not in ASSURE. Clear-cell RCCs seem to be more dependent on the VEGF pathway, which may have underpowered the results of ASSURE. Another factor contributing to the discordance between the results of the three trials may be the difference in the treatment dosage and compliance. Only S-TRAC maintained a full starting dose throughout the study. On the contrary, both ASSURE and PROTECT adopted a suboptimal starting dose following initial dropout rates due to toxicity, which were thought to be unacceptable. This may have increased efficacy in the case of S-TRAC, as suggested by previous studies, associating higher exposure to sunitinib with higher response rates. Finally, progression was centrally assessed in S-TRAC but not in ASSURE.
We are still left with the question whether the current practice of follow up after nephrectomy for localized RCC should be changed. Certain points should be taken into consideration:
- Whether DFS is the most appropriate endpoint for adjuvant therapy trials in the current treatment paradigm of RCC remains questionable. Many agents used in metastatic disease prolong survival. In that sense S-TRAC may be viewed as an early vs. late sunitinib study. For this reason, definitive conclusion about the wide application of this strategy, should be drawn after maturation of OS data. The current median follow up of 5.4 years is not adequate, when considering the natural history of RCC.
- Furthermore, no information regarding the use of sunitinib at relapse has been made available yet. Another important question is the way adjuvant sunitinib may influence sensitivity to VEGFR TKIs at relapse. Data from metastatic setting suggest reduction of efficacy of subsequent therapies after sunitinib failure. This was noted in both RECORD-1 and CheckMate-025 trial, where prior progression on sunitinib correlated with poorer outcome of second line treatment.
Speaker: Aristotelis Bamias, MD, is Αssociate Professor at the Medical School, University of Athens, in Greece
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at The 15th Meeting of the EAU Section of Oncological Urology ESOU18 - January 26-28, 2018 - Amsterdam, The Netherlands
1. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. The New England journal of medicine 2016; 375(23): 2246-54.
2. 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, randomised, phase 3 trial. Lancet (London, England) 2016; 387(10032): 2008-16.
3. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). Journal of Clinical Oncology 2017; 35(15_suppl): 4507-.