Summary
A medRxiv preprint analysing reconstructed data from ten phase 3 kidney-cancer trials finds that the added disease-free-survival benefit of belzutifan may weaken after 12 months. Estimates of the later benefit differ by assessment method.
A medRxiv preprint analysing reconstructed data from ten phase 3 trials of adjuvant treatment for renal cell carcinoma found that the disease-free-survival (DFS) advantage associated with adding belzutifan to pembrolizumab in LITESPARK-022 became less pronounced after the planned 12-month treatment period. The estimated longer-term advantage also varied according to how DFS was assessed.
Adjuvant treatment is given after a primary treatment, such as surgery, with the aim of reducing the risk of cancer returning. The analysis focuses on whether an early difference in DFS between treatment groups persists after the treatment period ends.
What the reconstructed analysis found
The researchers reconstructed individual patient data from published Kaplan–Meier survival curves for ten phase 3 adjuvant renal cell carcinoma trials. A Kaplan–Meier curve tracks the proportion of participants who remain free of an event over time. The researchers used the reconstructed data to estimate treatment effects before and after the planned treatment period.
In LITESPARK-022, the estimated 24-month difference in restricted mean DFS time was 1.34 months in favour of the belzutifan arm, based on central review (95% confidence interval: 0.73–1.95). Restricted mean survival time summarises the average time without a DFS event over a specified period. The analysis also estimated that the advantage continued to accumulate after month 12, at 0.74 months per year (95% CI: 0.32–1.19).
The relative hazard estimates changed across the same time point. Before month 12, the hazard ratio was 0.55 (95% CI: 0.43–0.71); after month 12, it was 1.16 (95% CI: 0.87–1.54). The later estimate’s confidence interval spans 1, the value corresponding to no difference in relative hazard. The ratio of the post-treatment to pre-treatment hazard ratios was 2.10.
A post hoc analysis of the absolute DFS difference from months 12 to 30 gave different results depending on assessment method. The difference changed by −3.7 percentage points with central review (95% CI: −8.1 to 0.8) and by 0.6 percentage points with investigator assessment (95% CI: −4.0 to 5.0). Both confidence intervals include zero.
Why the estimates give a mixed picture
A hazard ratio describes the relative rate of events over a period; an absolute percentage-point difference compares the proportions remaining disease-free. These measures answer different questions, and the findings show why a single hazard ratio may not capture how a treatment advantage develops over time.
The authors also compared changes in hazard ratios across other trials. Similar post-to-pre ratios appeared in KEYNOTE-564 at its first interim analysis, where the benefit persisted, and in SORCE and PROTECT, where the benefit faded. In this analysis, the ratio alone therefore did not distinguish between those different patterns.
The researchers conclude that the durability of the absolute DFS advantage in LITESPARK-022 remains uncertain and depends on the assessment method. They advise against using a single hazard ratio to project the longer-term benefit. The analysis is based on reconstructed data from published curves, and the authors identify short follow-up as a limitation. It is a preprint, rather than a peer-reviewed publication.