Risk-dependent Benefit of Adjuvant Pembrolizumab in High-risk Clear Cell Renal Cell Carcinoma: A Multi-institutional Study.
Abstract
Background
Adjuvant pembrolizumab improves outcomes in high-risk clear cell renal cell carcinoma (ccRCC), but baseline recurrence risk varies substantially.
Objective
To evaluate treatment selection, outcomes, toxicity, and risk-stratified benefit. DESIGN, SETTING, AND
Participants
A retrospective cohort of consecutive patients with KEYNOTE-564-eligible ccRCC treated surgically at five U.S. tertiary centers (2021-2025).
Intervention
Adjuvant pembrolizumab or surveillance, selected through routine care. OUTCOME
Measurements
AND STATISTICAL ANALYSIS Disease-free survival (DFS) was evaluated using a 90-day postoperative landmark, multivariable Cox regression, and inverse probability of treatment weighting (IPTW), stratified by ASSURE risk category. Immune-related adverse events were assessed.
Results
AND
Limitations
Among 739 patients, 288 received pembrolizumab and 451 underwent surveillance; median follow-up was 18.4 months. Treated patients had more adverse pathologic features; 16% experienced grade ≥3 immune-related adverse events. The landmark cohort included 686 patients with median follow-up of 19.8 months, including 212 who initiated pembrolizumab by 90 days. Initiation by 90 days was not significantly associated with DFS in unadjusted (hazard ratio 1.02), multivariable-adjusted (0.91), or IPTW analyses (0.90). At 18 months after the landmark, absolute risk differences favoring pembrolizumab were -9.4%, 3.6%, and 5.7% across low-, intermediate-, and high-risk groups, respectively (interaction p = 0.8). Limitations include nonrandomized treatment allocation and limited follow-up.
Conclusions
Baseline recurrence risk varied markedly among eligible patients. Potential absolute benefit appeared greater with higher baseline risk, although the interaction was nonsignificant. Individualized counseling and improved prognostic and predictive tools remain important. PATIENT SUMMARY After kidney cancer surgery, treatment decisions should consider individual recurrence risk and potential side effects. Serious toxicity affected 16% of recipients.