辅助帕博利珠单抗联合Belzutifan的DFS获益在计划治疗期后是否持续？III期肾细胞癌试验重建个体数据分析

Abstract

Background and Objective: Adding belzutifan to adjuvant pembrolizumab improved disease-free survival (DFS) in LITESPARK-022, but its durability beyond the 1-year treatment is unknown. Methods: Following a registered plan, we reconstructed individual patient data from published Kaplan-Meier curves of ten phase 3 adjuvant renal cell carcinoma trials. Within each trial, we estimated restricted mean survival time differences (ΔRMST), hazard ratios (HRs) before and after planned treatment ended, and DFS differences. Key Findings and Limitations: In LITESPARK-022 (central review), the 24-month ΔRMST was 1.34 months (95% confidence interval 0.73–1.95), and the belzutifan arm remained ahead after month 12 (ΔRMST increment 0.74 months/yr, 0.32–1.19). The HR was 0.55 (0.43–0.71) before month 12 and 1.16 (0.87–1.54) afterwards (post/pre ratio 2.10); investigator assessment showed similar attenuation. Similar ratios occurred in KEYNOTE-564 at its first interim analysis (2.02), whose benefit persisted, and in SORCE and PROTECT (2.09, 2.59), whose benefit faded. From months 12 to 30 (post hoc), the DFS difference changed by −3.7 percentage points (−8.1 to 0.8) with central review and 0.6 (−4.0 to 5.0) with investigator assessment. Data were reconstructed, and follow-up was short. Conclusions and Clinical Implications: Relative hazard reductions with belzutifan were greater before month 12; durability of the absolute DFS advantage is uncertain and assessment-dependent, so single-HR projections should be avoided.

Competing Interest Statement

The authors have declared no competing interest.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The only data source was published aggregate data: Kaplan-Meier curves of disease-free (and overall) survival with numbers at risk, and reported summary statistics, from peer-reviewed publications (articles and their supplementary appendices) of phase 3 adjuvant renal cell carcinoma trials, which were openly available before the study began. Individual patient data were reconstructed from these published curves; no individual-level, identifiable, or access-restricted data were used. Full citations of every source publication are given in the manuscript reference list and Supplementary Material.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The statistical analysis plan was registered on the Open Science Framework on 12 October 2026 (https://osf.io/fk8hz; under embargo until publication) and is provided as a supplementary file. The reconstructed individual patient data and analysis code are available from the corresponding author on request and will be deposited on the Open Science Framework at publication.

Funder Information Declared

National Science and Technology Council, https://ror.org/02kv4zf79, 111-2218-E-037-001, 112-2218-E-037-001, 113-2218-E-037-001, 112-2314-B-037-127, 113-2314-B-037-016, 114-2314-B-037-033, 115-2314-B-037-036-MY2, 115-2314-B-037-037-MY3, 115-2622-B-037-001

Kaohsiung Medical University, https://ror.org/03gk81f96, KMUH112-2R59, KMUH113-3R52, KMUH114-4M54, KMUH114-4R59