A Risk-Adapted Framework for Adjuvant Pembrolizumab Plus Belzutifan in Resected Clear Cell Renal Cell Carcinoma

The active-control design of LITESPARK-022 demonstrated improved disease-free survival (DFS) with adjuvant pembrolizumab plus belzutifan compared with pembrolizumab alone but did not directly address the post-nephrectomy comparison of combination therapy versus surveillance. Our objective was to estimate the potential absolute benefit of pembrolizumab and pembrolizumab plus belzutifan against surveillance across baseline recurrence-risk scenarios and to clarify when treatment intensification may be clinically meaningful. Given similar trial designs, we used pembrolizumab as the common anchor between KEYNOTE-564 and LITESPARK-022 and performed an anchored indirect comparison under proportional-hazards and cross-trial transportability assumptions. The estimated DFS hazard ratio for pembrolizumab plus belzutifan versus surveillance was 0.52 (indirect 95% confidence interval, 0.39-0.68). We then translated the relative treatment effects into estimated 24-month DFS probabilities across a range of baseline surveillance risks. Absolute benefit increased substantially as baseline recurrence risk increased. Within LITESPARK-022, combination therapy more than doubled grade ≥ 3 treatment-related adverse events (42.2% vs. 17.9%), an excess incurred independently of baseline risk. These additional events were predominantly anemia and hypoxia, whereas immune-mediated events were not increased. These findings provide a risk-adapted, 2-step framework that first considers whether recurrence risk is sufficiently high to justify adjuvant systemic therapy and then whether the additional efficacy of adding belzutifan justifies additional toxicity. For lower-risk patients, surveillance may remain reasonable and the incremental benefit of adding belzutifan to pembrolizumab may be modest, whereas patients at higher recurrence risk may derive a meaningfully greater absolute DFS benefit from combination therapy.