Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

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.

Name: Kaimen Rigor review — 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.
Item: 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.
Rating: 100
Author: Alpha1

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

Paper source

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Kaimen Rigor review — 5★ (Exemplary), 0 critical, 0 high issues for “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.”

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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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.

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DOI

10.1038/s41591-025-03867-5

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

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.

Paper source

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.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

5 / 5

Exemplary — no material problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — no deductions. Nothing the checks ran surfaced a material problem.

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Findings by category

01ArithmeticNone found 02OverreachNone found 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit4 minor suggestions

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 found

Values 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.

Overstated conclusions

None found

Conclusions 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.

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

Data authenticity concerns

None found

An 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 found

Required 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.

Eight Dimensions8 pass

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.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior trials and identifying an unmet need for predictive biomarkers in RCC.

Evidence

“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.”

Introduction ¶1Find in source

“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.”

Introduction ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior trials and explaining the rationale for long-term follow-up and biomarker exploration.

Evidence

Introduction ¶1Find in source

Introduction ¶2Find in source

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.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous with randomization, stratification, and prespecified analyses; blinding is not applicable due to open-label design, which is stated.

Evidence

“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).”

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

“KEYNOTE-426 ( NCT02853331 ) is a randomized, open-label, phase 3 trial conducted across 129 medical centers globally.”

“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.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The trial design is rigorous with clear randomization, stratification, and prespecified analyses; blinding is not applicable due to open-label design, which is stated.

Evidence

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

“KEYNOTE-426 ( NCT02853331 ) is a randomized, open-label, phase 3 trial conducted across 129 medical centers globally.”

“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.”

Statistical analysisFind in source

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.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, and other demographics are reported in the baseline table; species/strain and housing are not applicable for a human trial.

Evidence

“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)”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial: sex, age, and demographics are provided; species/strain and housing are not applicable.

Evidence

“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) |”

Table 1Find in source

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.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are reported; the trial was approved by institutional review boards and conducted per Good Clinical Practice.

Evidence

“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.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported: the trial was approved by institutional review boards and regulatory agencies, and written informed consent was obtained.

Evidence

MethodsFind in source

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.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (pembrolizumab, axitinib, sunitinib) are identified with doses and regimens; software tools are identified with versions.

Evidence

MethodsFind in source

“Statistical analyses were performed in SAS version 9.4 and R version 4.2.1 software.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational products (pembrolizumab, axitinib, sunitinib) are named with dosing, and the PD-L1 IHC assay is specified; software tools are identified.

Evidence

“PD-L1 expression was centrally determined using the PD-L1 IHC 22C3 pharmDx (Agilent Technologies).”

MethodsFind in source

“Raw reads were processed using a customized data analysis pipeline in OmicSoft Array Suite version 9 (Qiagen) .”

MethodsFind in source

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.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described; p-values are reported exactly for many analyses, and effect sizes with CIs are provided.

Evidence

“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.”

Statistical analysisFind in source

“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

PASSReviewer 2· 85% conf

Statistical methods are appropriate and well described; p-values are reported exactly for many analyses, and effect sizes with confidence intervals are provided.

Evidence

Statistical analysisFind in source

AbstractFind in source

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.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed data availability statement provides a concrete managed-access route via the MSD data-sharing website; code sharing is not applicable as no custom code is described.

Evidence

“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete managed-access mechanism via MSD's data-sharing website; code sharing is not applicable as no custom code is mentioned.

Evidence

“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”

Data availabilityFind in source

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.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”

AbstractFind in source

“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.”

Discussion ¶8Find in source

PASSReviewer 2· 90% conf

Reporting is transparent: trial registration is provided, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”

AbstractFind in source

Discussion ¶8Find in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

References 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).

2 data/code links checked; 2 live.

Copyediting

4 minor

Wording, 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.

Kaimen Rigor Action ItemsFinal pass before journal submission

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.
MEDIUMcopyedit
In the Discussion, paragraph 6, correct the typo 'pressent dataset' to 'present dataset'.
Typographical error undermines professionalism.
2.
MEDIUMcopyedit
In the Discussion, paragraph 6, correct 'PRRM1 mutation' to 'PBRM1 mutation'.
Incorrect gene abbreviation could mislead readers.
3.
MEDIUMcopyedit
In 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.
MEDIUMreporting
In 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.
MEDIUMreporting
In 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.
LOWreporting
In 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 code
In 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.
LOWstatistics
In 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.
LOWreporting
In 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.
LOWreporting
In 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.
LOWreporting
In 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.

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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.

Read full text (PMC)

DOI

10.1038/s41591-025-03867-5

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Record fingerprint

058db712162e2e3ad310fbd68b5a12d2e244b657dd5050fce6e053c1f05ac1c9

Verify via API

Issued Aug 15, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

5 / 5

Exemplary — no material problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — no deductions. Nothing the checks ran surfaced a material problem.

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Findings by category

01ArithmeticNone found 02OverreachNone found 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit4 minor suggestions

Numerical inconsistencies

None found

Checked — nothing surfaced.

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

None found

Checked — nothing surfaced.

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

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior trials and identifying an unmet need for predictive biomarkers in RCC.

Evidence

Introduction ¶1Find in source

Introduction ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior trials and explaining the rationale for long-term follow-up and biomarker exploration.

Evidence

Introduction ¶1Find in source

Introduction ¶2Find in source

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingINADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous with randomization, stratification, and prespecified analyses; blinding is not applicable due to open-label design, which is stated.

Evidence

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

“KEYNOTE-426 ( NCT02853331 ) is a randomized, open-label, phase 3 trial conducted across 129 medical centers globally.”

“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.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The trial design is rigorous with clear randomization, stratification, and prespecified analyses; blinding is not applicable due to open-label design, which is stated.

Evidence

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

“KEYNOTE-426 ( NCT02853331 ) is a randomized, open-label, phase 3 trial conducted across 129 medical centers globally.”

“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.”

Statistical analysisFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, and other demographics are reported in the baseline table; species/strain and housing are not applicable for a human trial.

Evidence

“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)”

Table 1Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial: sex, age, and demographics are provided; species/strain and housing are not applicable.

Evidence

“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) |”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are reported; the trial was approved by institutional review boards and conducted per Good Clinical Practice.

Evidence

MethodsFind in source

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported: the trial was approved by institutional review boards and regulatory agencies, and written informed consent was obtained.

Evidence

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (pembrolizumab, axitinib, sunitinib) are identified with doses and regimens; software tools are identified with versions.

Evidence

MethodsFind in source

“Statistical analyses were performed in SAS version 9.4 and R version 4.2.1 software.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational products (pembrolizumab, axitinib, sunitinib) are named with dosing, and the PD-L1 IHC assay is specified; software tools are identified.

Evidence

“PD-L1 expression was centrally determined using the PD-L1 IHC 22C3 pharmDx (Agilent Technologies).”

MethodsFind in source

“Raw reads were processed using a customized data analysis pipeline in OmicSoft Array Suite version 9 (Qiagen) .”

MethodsFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described; p-values are reported exactly for many analyses, and effect sizes with CIs are provided.

Evidence

Statistical analysisFind in source

AbstractFind in source

PASSReviewer 2· 85% conf

Statistical methods are appropriate and well described; p-values are reported exactly for many analyses, and effect sizes with confidence intervals are provided.

Evidence

Statistical analysisFind in source

AbstractFind in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed data availability statement provides a concrete managed-access route via the MSD data-sharing website; code sharing is not applicable as no custom code is described.

Evidence

“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete managed-access mechanism via MSD's data-sharing website; code sharing is not applicable as no custom code is mentioned.

Evidence

“The MSD data-sharing website ( https://externaldatasharing-msd.com/ ) outlines the process and requirements for submitting a data request.”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”

AbstractFind in source

Discussion ¶8Find in source

PASSReviewer 2· 90% conf

Reporting is transparent: trial registration is provided, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331 (https://clinicaltrials.gov/study/NCT02853331) .”

AbstractFind in source

Discussion ¶8Find in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

References 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).

2 data/code links checked; 2 live.

Copyediting

4 minor

Wording, 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.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMcopyedit
In the Discussion, paragraph 6, correct the typo 'pressent dataset' to 'present dataset'.
Typographical error undermines professionalism.
2.
MEDIUMcopyedit
In the Discussion, paragraph 6, correct 'PRRM1 mutation' to 'PBRM1 mutation'.
Incorrect gene abbreviation could mislead readers.
3.
MEDIUMcopyedit
In 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.
MEDIUMreporting
In 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.
MEDIUMreporting
In 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.
LOWreporting
In 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 code
In 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.
LOWstatistics
In 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.
LOWreporting
In 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.
LOWreporting
In 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.
LOWreporting
In 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.

Full text (70,578 chars)Analyzed: Aug 15, 2026