How to optimize the use of adjuvant pembrolizumab in renal cell carcinoma: which patients benefit the most?

Purpose: The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab.

Methods: Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery.

Results: In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21-35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6-69.2) as compared to 76.2% (95% CI 72.2-79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2-40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1-88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence.

Conclusions: Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab.