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.
Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, de Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Wu S, Markensohn J, Zhang Y, Loboda A, Vajdi A, Perini RF, Burgents J, Powles T
- DOI
- 10.1038/s41591-025-03867-5
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/e6e22d42-021e-4d90-ad5b-0f32f0f389df is authoritative.
How this rating was calculated
Started at 5★ — no deductions. Nothing the checks ran surfaced a material problem.
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted phase 3 randomized open-label trial with rigorous design, clear reporting of ethics, resources, and statistical methods, and a transparent data-sharing statement. The main weaknesses are minor: lack of explicit reporting guideline citation, no power analysis for the exploratory biomarker analysis, and a few typographical errors in the discussion and figure legends.
Both reviewers independently scored all dimensions as pass with high confidence, and their evidence was consistent. The study type is interventional (phase 3 RCT). Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded from scoring. The statistics verification covered only a subset of tests; the rest remain unverified.
Numerical inconsistencies
None foundValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
Checked — nothing surfaced.
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p = .002 · recomputed p = .004Reviewer 1Check the p-value for the association between Tcell inf GEP and OS in the pembrolizumab plus axitinib arm.
“Tcell inf GEP | 2.03 × 10 −6 (+) | 1.41 × 10 −5 (+) | 0.002 (+) | 0.741 | 0.464 | 0.547”
Taken as given: The p-value is two-sided.; The test statistic is a standard normal Z derived from the Cox model.; The Z value is approximately 2.88, which is not directly reported but inferred from the p-value.Method: Converted the reported p-value to a Z-score using the inverse normal CDF.How we recomputed it: pZ(2.88)
Overstated conclusions
None foundConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
Checked — nothing surfaced.
12 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewer 1Pembrolizumab plus axitinib showed sustained benefits in OS, PFS, and ORR compared to sunitinib.The reported hazard ratios and response rates directly support this claim.Evidence: OS HR 0.84 (95% CI 0.71-0.99), PFS HR 0.69 (95% CI 0.59-0.81), ORR 60.6% vs 39.6%.
“Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81) and ORR (60.6% versus 39.6%) compared to sunitinib.”
AbstractFind in source - supportedReviewer 1An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS, PFS, and ORR within the pembrolizumab plus axitinib arm.The reported p-values support the association.Evidence: P = 0.002 for OS, P < 0.0001 for PFS and ORR.
“An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm.”
AbstractFind in source - supportedReviewer 1An angiogenesis signature was positively associated with OS within the pembrolizumab plus axitinib arm and with OS, PFS, and ORR within the sunitinib arm.The reported p-values support the associations.Evidence: P = 0.004 for OS in pembrolizumab+axitinib; P < 0.0001 for OS, P < 0.001 for PFS, P = 0.002 for ORR in sunitinib.
“An angiogenesis signature was positively associated with OS ( P = 0.004) within the pembrolizumab plus axitinib arm and with OS ( P < 0.0001), PFS ( P < 0.001) and ORR ( P = 0.002) within the sunitinib arm.”
AbstractFind in source - supportedReviewer 1PD-L1 CPS was only associated (negatively) with OS within the sunitinib arm.The reported p-value supports the association.Evidence: P = 0.025 for OS in sunitinib arm.
“Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm ( P = 0.025).”
AbstractFind in source - supportedReviewer 1PBRM1 mutation had a positive association with ORR within the pembrolizumab plus axitinib arm.The reported p-value and response rates support the association.Evidence: P = 0.002; ORR 71.4% vs 52.3%.
“Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR ( P = 0.002) within the pembrolizumab plus axitinib arm.”
AbstractFind in source - supportedReviewer 1Within the sunitinib arm, OS was positively associated with VHL and PBRM1 mutations and negatively associated with BAP1 mutation.The reported p-values support the associations.Evidence: P = 0.040 for VHL, P = 0.010 for PBRM1, P = 0.019 for BAP1.
“Within the sunitinib arm, OS was positively associated with VHL (von Hippel–Lindau tumor suppressor gene) ( P = 0.040) and PBRM1 ( P = 0.010) mutations and was negatively associated with BAP1 ( BRCA1- associated protein 1) mutation ( P = 0.019).”
AbstractFind in source - supportedReviewer 1Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC.The clinical benefit is supported by the efficacy results, and the biomarker information is supported by the exploratory analyses.Evidence: Efficacy results and biomarker associations as reported.
“Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC.”
AbstractFind in source - supportedReviewer 2Pembrolizumab plus axitinib shows sustained OS benefit over sunitinib at 5 years.The reported HR of 0.84 with 95% CI 0.71-0.99 supports a sustained benefit, though the CI upper bound is close to 1.Evidence: OS HR 0.84 (95% CI 0.71-0.99) from the abstract and results.
“Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99)”
AbstractFind in source - supportedReviewer 2Tcell inf GEP is positively associated with clinical outcomes in the pembrolizumab plus axitinib arm.The paper reports significant associations with ORR, PFS, and OS, with p-values <0.05.Evidence: Table 2 shows Tcell inf GEP p-values: ORR 2.03e-6, PFS 1.41e-5, OS 0.002.
“In the pembrolizumab plus axitinib arm, higher Tcell inf GEP was associated with improved ORR ( P < 0.0001), PFS ( P < 0.0001) and OS ( P = 0.002)”
ResultsFind in source - supportedReviewer 2Angiogenesis signature is positively associated with outcomes in the sunitinib arm.The paper reports significant associations with ORR, PFS, and OS in the sunitinib arm.Evidence: Table 2 shows angiogenesis p-values: ORR 0.002, PFS 5.66e-4, OS 1.69e-7.
“For the angiogenesis signature, a positive association was observed only with OS ( P = 0.004) in the pembrolizumab plus axitinib arm, and there was a positive association with ORR ( P = 0.002), PFS ( P < 0.001) and OS ( P < 0.001) in the sunitinib arm”
ResultsFind in source - supportedReviewer 2PD-L1 CPS is not a predictive marker for pembrolizumab plus axitinib.The paper reports no significant association between PD-L1 CPS and outcomes in the pembrolizumab plus axitinib arm.Evidence: Table 2 shows PD-L1 CPS p-values >0.05 for all outcomes in the pembrolizumab plus axitinib arm.
“No association was observed between continuous PD-L1 CPS and clinical outcomes for pembrolizumab plus axitinib ( P > 0.05)”
ResultsFind in source - supportedReviewer 2PBRM1 mutation is positively associated with ORR in the pembrolizumab plus axitinib arm.The paper reports a significant association with ORR (P=0.002) and higher ORR in mutant vs wild-type.Evidence: Extended Data Table 3 and Extended Data Fig. 3 show PBRM1 mutation associated with ORR (P=0.002).
“The PBRM1 mutation was positively associated with the ORR within the pembrolizumab plus axitinib arm, with significantly higher rates in the PBRM1 mutant than in the wild-type subgroup (71.4% versus 52.3%; P = 0.002)”
ResultsFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary efficacy claim is based on hard clinical outcomes: overall survival (OS) and progression-free survival (PFS) from a phase 3 randomized trial. These are direct clinical endpoints, not surrogates. The biomarker analyses (Tcell inf GEP, angiogenesis signature, PD-L1 CPS, mutations) are exploratory and not the primary basis for the efficacy claim.
“Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81) and ORR (60.6% versus 39.6%) compared to sunitinib.”
- ADEQUATEEffect sizeThe effect sizes are clinically meaningful: median OS improved from 40.8 to 47.2 months (HR 0.84), median PFS from 11.1 to 15.7 months (HR 0.69), and ORR increased from 39.6% to 60.6%. These are substantial differences in hard endpoints, and the hazard ratios are statistically significant with confidence intervals excluding 1.0.
“The median OS was 47.2 months in the pembrolizumab plus axitinib arm and 40.8 months in the sunitinib arm (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99). Median PFS was 15.7 months in the pembrolizumab plus axitinib arm and 11.1 months in the sunitinib arm (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites prior phase 3 trials (IMmotion151, JAVELIN Renal 101, CheckMate 9ER) and discusses their limitations, including confounding due to different drugs. The rationale for the biomarker analysis is logically linked to the need for predictive biomarkers. The paper acknowledges limitations of prior research and addresses them through a prespecified exploratory analysis.
“Studies to evaluate predictive and prognostic biomarkers in metastatic RCC have been largely derived from phase 3 studies (for example, IMmotion151, JAVELIN Renal 101 and CheckMate 9ER) in which similar mechanisms (for example, PD-L1 inhibitor plus VEGF-TKI) but different drugs were evaluated as frontline therapy – . Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”
“Here we report the final clinical data after 5 years of follow-up from KEYNOTE-426 and the results of a prespecified exploratory biomarker analysis that was conducted to determine whether molecular determinants relevant to the underlying disease biology are associated with clinical outcomes (ORR, PFS and OS) for pembrolizumab plus axitinib and for sunitinib in participants with advanced clear cell RCC.”
“Studies to evaluate predictive and prognostic biomarkers in metastatic RCC have been largely derived from phase 3 studies (for example, IMmotion151, JAVELIN Renal 101 and CheckMate 9ER) in which similar mechanisms (for example, PD-L1 inhibitor plus VEGF-TKI) but different drugs were evaluated as frontline therapy – . Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”
“Here we report the final clinical data after 5 years of follow-up from KEYNOTE-426 and the results of a prespecified exploratory biomarker analysis that was conducted to determine whether molecular determinants relevant to the underlying disease biology are associated with clinical outcomes (ORR, PFS and OS) for pembrolizumab plus axitinib and for sunitinib in participants with advanced clear cell RCC.”
Randomization method and unit are reported (1:1 ratio, stratified by IMDC risk and region). The open-label design is explicitly stated, which is acceptable for this trial type. Power analysis is not reported for the exploratory biomarker analysis, but the primary trial was previously powered; the exploratory nature is acknowledged. Inclusion/exclusion criteria are described. Outlier handling is not explicitly described, but the analysis population is defined. Controls are inherent in the randomized comparator arm. Independent replication is not applicable for a single pivotal trial.
“Participants were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg intravenously once every 3 weeks for up to 35 cycles (~2 years) plus axitinib 5 mg by mouth twice daily continuously or sunitinib 50 mg by mouth once daily for 4 weeks on and 2 weeks off, continuously. Randomization was stratified according to the IMDC risk group (favorable versus intermediate versus poor risk) and by geographic region (North America versus Western Europe versus rest of the world).”
“Because the trial outcome was previously defined as positive and the present analysis is exploratory, no formal hypothesis testing was performed in the present analysis.”
“Participants were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg intravenously once every 3 weeks for up to 35 cycles (~2 years) plus axitinib 5 mg by mouth twice daily continuously or sunitinib 50 mg by mouth once daily for 4 weeks on and 2 weeks off, continuously. Randomization was stratified according to the IMDC risk group (favorable versus intermediate versus poor risk) and by geographic region (North America versus Western Europe versus rest of the world).”
“Because the trial outcome was previously defined as positive and the present analysis is exploratory, no formal hypothesis testing was performed in the present analysis.”
Sex is reported (male/female percentages) and both sexes are enrolled, so sex_justified is not applicable. Age is reported as median and range. Demographics include region, IMDC risk, sarcomatoid features, PD-L1 CPS, and metastatic sites. Species/strain and housing conditions are not applicable for human subjects.
“Age, median (range), years | 62.0 (30–89) | 61.0 (26–90) | | <65 years | 260 (60.2) | 278 (64.8) | | Sex | | Male | 308 (71.3) | 320 (74.6) | | Female | 124 (28.7) | 109 (25.4)”
“Age, median (range), years | 62.0 (30–89) | 61.0 (26–90) | | <65 years | 260 (60.2) | 278 (64.8) | | Sex | | Male | 308 (71.3) | 320 (74.6) | | Female | 124 (28.7) | 109 (25.4) |”
The paper states the trial was approved by appropriate institutional review boards and regulatory agencies, and written informed consent was provided by all participants. This satisfies both irb_ethics_statement and informed_consent. Regulatory compliance is stated via Good Clinical Practice. IACUC is not applicable for a human trial.
“The trial was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Written informed consent was provided by all participants before enrollment.”
“The trial was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Written informed consent was provided by all participants before enrollment.”
The drugs are named with manufacturer (Merck) and dosing regimen. The PD-L1 IHC assay (22C3 pharmDx, Agilent) is identified. Software tools (OmicSoft Array Suite version 9, SAS version 9.4, R version 4.2.1) are identified with versions. Antibodies, cell lines, mycoplasma, and organisms are not applicable for this human trial.
“Participants were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg intravenously once every 3 weeks for up to 35 cycles (~2 years) plus axitinib 5 mg by mouth twice daily continuously or sunitinib 50 mg by mouth once daily for 4 weeks on and 2 weeks off, continuously.”
“Statistical analyses were performed in SAS version 9.4 and R version 4.2.1 software.”
“PD-L1 expression was centrally determined using the PD-L1 IHC 22C3 pharmDx (Agilent Technologies).”
“Raw reads were processed using a customized data analysis pipeline in OmicSoft Array Suite version 9 (Qiagen) .”
Tests are named (Cox proportional hazards, logistic regression, Kaplan-Meier, Miettinen and Nurminen). Assumptions are handled by design (Cox model, stratified). Exact p-values are reported for many biomarker associations (e.g., P = 0.002). Effect sizes with CIs are reported for OS and PFS. Software is identified. Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility is not applicable for large-N continuous outcomes.
“To estimate the magnitude of the treatment difference (that is, hazard ratio) between the treatment arms, we used a stratified Cox proportional hazards model with the Efron method for handling ties.”
“An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm.”
“To estimate the magnitude of the treatment difference (that is, hazard ratio) between the treatment arms, we used a stratified Cox proportional hazards model with the Efron method for handling ties.”
“An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm.”
The data availability statement names the MSD data-sharing website and describes the process for requesting data, including a committee review and data-sharing agreement. This is a concrete managed-access route, so it is adequate. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”
“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”
Trial registration is provided (NCT02853331). Methods are detailed enough for replication. A reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like reporting with a flow diagram. All outcomes are reported, including negative results. Limitations are discussed in the Discussion. Conclusions are proportional, acknowledging the exploratory nature. Funding and COI are disclosed.
“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”
“However, the prespecified exploratory biomarker analysis from the KEYNOTE-426 trial is limited by the small sample sizes of some of the subgroups and the lack of statistical power and (or) multiplicity adjustments for association analysis of some biomarkers, hindering definitive conclusions.”
“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”
“However, the prespecified exploratory biomarker analysis from the KEYNOTE-426 trial is limited by the small sample sizes of some of the subgroups and the lack of statistical power and (or) multiplicity adjustments for association analysis of some biomarkers, hindering definitive conclusions.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 49 references by DOI: 36 verified — 13 no DOI (shown, not verified).
- NO DOIKeytruda (pembrolizumab injection), for intravenous use. Package insert.No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEAU guidelines on renal cell carcinomaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancerNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIBiomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma (aRCC)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOI1694MO Novel serum glycoproteomic biomarkers predict response to nivolumab plus cabozantinib (NIVO+CABO) versus sunitinib (SUN) in advanced RCC (aRCC): analysis from CheckMate 9ERNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIKIM-1 as a circulating biomarker in metastatic RCC: post-hoc analysis of JAVELIN Renal 101No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEvaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC): post-hoc analysis of CheckMate 214No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAssociation of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIImmunomodulatory effects of tyrosine kinase inhibitors (TKIs) in renal cell carcinoma (RCC) patientsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): final follow-up results from the CheckMate 9ER trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIBiomarker-driven prospective clinical trial in renal cell carcinoma: developing machine learning models to allocate patients to treatment arms using RNA sequencingNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISAMETA: a phase III study of savolitinib + durvalumab vs sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinomaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGuidance for industry: clinical trial endpoints for the approval of cancer drugs and biologicsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- datahttps://clinicaltrials.gov/study/NCT02853331LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://externaldatasharing-msd.com/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly typo, consistency.
- MINORtypoDiscussion, paragraph 6“pressent dataset”→ present datasetTypographical error.
- MINORtypoDiscussion, paragraph 6“PRRM1 mutation”→ PBRM1 mutationInconsistent abbreviation.
- MINORconsistencyExtended Data Fig. 3 legend“von Lindau-Hippel tumor suppressor gene”→ von Hippel-Lindau tumor suppressor geneIncorrect name.
- MINORconsistencyExtended Data Fig. 4 legend“von Lindau-Hippel tumor suppressor gene”→ von Hippel-Lindau tumor suppressor geneIncorrect gene name.
The published work is robust and well-reported; an informed reader should weigh the exploratory nature of the biomarker analyses and the lack of explicit reporting guideline citation as minor limitations. No erratum is warranted for the copyedit typos, but the authors may consider issuing a correction for the gene name errors (PRRM1→PBRM1, von Lindau-Hippel→von Hippel-Lindau) to maintain accuracy.
- 1.MEDIUMcopyeditIn the Discussion, paragraph 6, correct the typo 'pressent dataset' to 'present dataset'.Typographical error undermines professionalism.
- 2.MEDIUMcopyeditIn the Discussion, paragraph 6, correct 'PRRM1 mutation' to 'PBRM1 mutation'.Incorrect gene abbreviation could mislead readers.
- 3.MEDIUMcopyeditIn Extended Data Fig. 3 and Fig. 4 legends, correct 'von Lindau-Hippel tumor suppressor gene' to 'von Hippel-Lindau tumor suppressor gene'.Incorrect gene name in figure legends is a factual error.
- 4.MEDIUMreportingIn the Methods or Reporting Summary, explicitly state adherence to the CONSORT reporting guideline.Both reviewers noted the reporting guideline is not explicitly cited; explicit adherence strengthens transparency.
- 5.MEDIUMreportingIn the Methods, add a statement that the exploratory biomarker analysis was not formally powered, and provide the sample size rationale for the biomarker population.Power analysis is not reported for the exploratory analysis; clarifying this helps readers interpret the findings.
- 6.LOWreportingIn the Methods, describe how outliers in biomarker data were handled, or state that no outliers were excluded.Outlier handling is not explicitly described; transparency about this is important for reproducibility.
- 7.LOWdata codeIn the Data Availability section, consider providing accession numbers for the sequencing data (e.g., in a repository) if possible, while maintaining patient privacy.Providing accession numbers would enhance data accessibility, though managed access is acceptable for patient data.
- 8.LOWstatisticsIn the Results, consider reporting confidence intervals for all biomarker effect estimates, not just p-values.Confidence intervals provide more information than p-values alone and aid interpretation.
- 9.LOWreportingIn the Discussion, address the potential for multiplicity in the biomarker analyses more explicitly, even though adjustments were made.Explicit discussion of multiplicity would strengthen the interpretation of exploratory findings.
- 10.LOWreportingIn the Methods, provide more detail on the RNA sequencing quality control criteria and the number of samples excluded for each reason.Detailed QC criteria improve reproducibility and transparency.
- 11.LOWreportingIn the Results, consider presenting the biomarker data in a forest plot to facilitate comparison across biomarkers and arms.Forest plots would improve visual comparison of effect sizes across biomarkers.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.