Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial

12 major claims checked against the paper's own evidence: all adequately supported.

Recomputed 5 tests: 5 consistent, 0 inconsistent, 5 via agent-written checks.

2 integrity concerns flagged (0 high).

11 copyedit issues flagged (1 major): mostly typo, consistency, punctuation.

Checked 49 references: 42 verified — 5 unresolved, 2 not checked.

3 data/code links checked; 3 live.

Ready after high-priority edits. The manuscript is scientifically sound and well-written overall, but must address: the mislabel in Extended Data Table 3 footnote ('axitinib arm' should be 'sunitinib arm'), the missing effect sizes and confidence intervals for continuous biomarker associations, the unnamed ethics committee, and the absence of public repository deposits for sequencing data. These are all fixable before submission and would be flagged by any competent peer review.

1. 1.
   HIGHother

   Correction: in Extended Data Table 3 footnote, change 'axitinib arm' to 'sunitinib arm' to match the table header.

   This is a factual inconsistency — the table describes sunitinib-arm results, not axitinib — that reviewers and editors will catch and question.
2. 2.
   HIGHreporting

   In the Methods (Inclusion and ethics), name a specific IRB/ethics committee (e.g., 'the trial was approved by Western Institutional Review Board, protocol number XXX') rather than 'appropriate institutional review boards'.

   A generic statement without a named body is considered insufficient by most journals and all three reviewers flagged this as missing.
3. 3.
   HIGHdata code

   Deposit RNA-seq and whole-exome sequencing data in a controlled-access repository (e.g., dbGaP, EGA, GEO) and add accession numbers to the Data availability section.

   These data are the basis for the biomarker analyses; without public deposition, the analyses cannot be independently verified — a core reproducibility requirement.
4. 4.
   HIGHstatistics

   In Table 2 and the main text, report effect sizes (e.g., hazard ratios or odds ratios per 1-SD increase) with 95% confidence intervals for all continuous biomarker associations, not only p-values and direction signs.

   P-values alone do not convey magnitude or precision; effect sizes with CIs are expected for all regression-based associations and are missing from the biomarker results.
5. 5.
   HIGHdata code

   Share custom analysis code (OmicSoft pipeline scripts, R scripts for biomarker models) in a public repository (GitHub, Zenodo) with a persistent DOI, and add the link to the Data availability section.

   No custom code is currently shared, preventing full reproducibility of the biomarker analyses.
6. 6.
   HIGHreporting

   In the Methods or Acknowledgements, explicitly cite the CONSORT 2010 statement (or STROBE for the biomarker component) and state that reporting follows this guideline.

   Although a CONSORT flow diagram is present, the formal guideline citation is missing, which is a standard expectation for clinical trial papers.
7. 7.
   HIGHstatistics

   Add a brief statement in the Methods (Statistical analysis) verifying the proportional hazards assumption for Cox models (e.g., 'The proportional hazards assumption was assessed using Schoenfeld residuals and was satisfied').

   Assumption verification is not currently reported; this is a standard reviewer request for time-to-event analyses.
8. 8.
   HIGHstatistics

   Add an a priori power analysis or sample-size justification for the exploratory biomarker analyses, or explicitly state that the sample size was determined by the parent trial and that the analysis is post hoc/exploratory with no formal power.

   No power analysis is provided; reviewers and readers will want to know whether the study had adequate statistical power for the biomarker comparisons, especially for subgroups.
9. 9.
   HIGHstatistics

   Describe how outliers in biomarker data (e.g., gene expression values, mutation calls) were identified and handled in the Methods (Statistical analysis or Assessments).

   Outlier handling is not mentioned anywhere; this is a standard methodological detail expected for genomic analyses.
10. 10.
    HIGHreporting

    Specify the random sequence generation method (e.g., 'computer-generated random numbers with permuted blocks and a 1:1 allocation ratio, stratified by ...') in the Methods.

    The method of randomization is not described beyond stating 'randomly assigned in a 1:1 ratio', which is insufficient for a trial report.
11. 11.
    MEDIUMreporting

    Provide a brief rationale for the open-label design in the Methods (e.g., 'Given the known toxicity profiles of TKIs and the requirement for dose modifications, blinding was not feasible.')

    The open-label design is stated but not justified; explicit acknowledgment of why blinding was not used strengthens design transparency.
12. 12.
    MEDIUMreporting

    In the Methods (Trial design, participants and treatments), explicitly state the manufacturer/source (company, city, country) for axitinib and sunitinib.

    Investigational drugs are core reagents; their source should be identified for replicability, as is standard for clinical trial reports.
13. 13.
    MEDIUMreporting

    In Table 1 or Methods, include baseline weight (mean ± SD or median with range) of participants to complete the age/weight/health status reporting.

    Weight is a standard demographic variable in clinical trials and its absence is a minor reporting gap.
14. 14.
    MEDIUMreporting

    In the Data availability section, specify the expected timeframe for data access upon request (e.g., 'Data will be shared within 6 months of an approved request').

    The current managed-access statement does not indicate how long data access takes, which would help prospective users.
15. 15.
    LOWcopyedit

    Across the Discussion and Extended Data figures, correct 'pressent' to 'present' and 'PRRM1' to 'PBRM1'; correct 'von Lindau-Hippel' to 'von Hippel-Lindau' in figure legends and table footnotes.

    These are typographical errors that affect readability and accuracy of gene/entity names.
16. 16.
    LOWcopyedit

    In Table 2 footnote, use consistent ASCII plus/minus signs or matched Unicode symbols for '+' and '−' indicators without mixing quote styles.

    Minor punctuation inconsistency that a copyeditor would flag.
17. 17.
    LOWstatistics

    In the Discussion, explicitly acknowledge that the lack of a pre-registered analysis plan for the biomarker component (beyond the parent trial SAP) may affect reproducibility, and consider registering the plan retrospectively.

    Weakens the strength of the exploratory claims; pre-registration would strengthen the biomarker findings.
18. 18.
    LOWdata code

    Verify the 5 references flagged as 'not_found_in_registry' (CheckMate 9ER biomarker analysis, KIM-1 JAVELIN, KEYNOTE-427, TKIs immunomodulatory effects, CheckMate 9ER final follow-up) as they may be mis-cited, preprints, or conference abstracts — correct or add missing identifiers.

    These references could not be located in standard registries; while not retracted, their absence is a potential integrity concern that should be resolved before submission.