Background
Phase III RCT (N=1,943) of resected high-risk non-metastatic RCC (intermediate-high or very-high risk, pT1b grade 3-4 through pT4 or node-positive), any clear-cell or non-clear-cell histology, post-nephrectomy.
Interventions and follow up
Arm A: Sunitinib 50mg/d 4wk on / 2wk off x1yr
Arm B: Sorafenib 400mg BID x1yr
Arm C: Placebo
Note: starting doses reduced after high early AE/discontinuation rates (sunitinib and sorafenib), then re-titrated as tolerated
Primary endpoint: DFS
Median follow-up: 5.8yr
Arm B: Sorafenib 400mg BID x1yr
Arm C: Placebo
Note: starting doses reduced after high early AE/discontinuation rates (sunitinib and sorafenib), then re-titrated as tolerated
Primary endpoint: DFS
Median follow-up: 5.8yr
Results
mDFS (A vs B vs C): 5.8yr vs 6.1yr vs 6.6yr; HR 1.02, 97.5% CI 0.85-1.23, P=.80 (sunitinib vs placebo)
mDFS sorafenib vs placebo: HR 0.97, 97.5% CI 0.80-1.17, P=.72
mOS: no significant difference across arms
mDFS sorafenib vs placebo: HR 0.97, 97.5% CI 0.80-1.17, P=.72
mOS: no significant difference across arms
Adverse events
Grade ≥3 AEs (A vs B vs C): hypertension 17% vs 16% vs 4%; fatigue 17% vs 7% vs 3%
Dermatologic: hand-foot syndrome 15% vs 33% vs 1%; rash more frequent with sorafenib
Tolerability: high rates of dose reduction and discontinuation prompted protocol dose modification
Dermatologic: hand-foot syndrome 15% vs 33% vs 1%; rash more frequent with sorafenib
Tolerability: high rates of dose reduction and discontinuation prompted protocol dose modification
Conclusions
Adjuvant VEGFR TKIs (sunitinib or sorafenib) did not improve DFS or OS versus placebo in resected high-risk RCC.
Key Limitations
Heterogeneous histology (clear-cell and non-clear-cell included); substantial dose reductions and discontinuations may have limited delivered TKI exposure; broad risk eligibility.
Clinical Context
Negative adjuvant TKI trial that, alongside PROTECT, contrasts with the positive S-TRAC sunitinib result; informed ASCO/ESMO caution regarding adjuvant TKI. Adjuvant immunotherapy (pembrolizumab, KEYNOTE-564) has since become the preferred adjuvant option in eligible patients.