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: 59
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.

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Kaimen Rigor review — 3.75★ (Adequate), 0 critical, 8 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 10, 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)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingStudy design partially met−0.25★
ReportingBiological variables partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: lowEngine: 7.29.0Source: full text

Findings by category

01ArithmeticNone found 02OverreachNone found 03AuthenticityNone found 504DisclosureReporting gaps 05AvailabilityNone found 06Copyedit9 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 paper presents a robust long-term follow-up of a phase 3 clinical trial, with a strong scientific premise, well-described statistical analyses, and high reporting transparency. However, several methodological and reporting details, particularly regarding study design, biological variables, ethical approvals, and data/code availability, are inadequately specified.

This evaluation synthesized three independent reviewer runs and a copyedit report. Reviewers largely agreed on the strengths but diverged on the completeness of reporting in several dimensions. My synthesis weighed the specific evidence provided by each reviewer, prioritizing concrete omissions over general statements. The statistics component recomputed 4 reported tests consistently, but this covers only a subset of the reported statistics.

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 4 tests: 4 consistent, 0 inconsistent; 4 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

5 findings · worst medium

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.

Biological variables underreported (sex, age, strain)Assessed
Data/code availability incompleteAssessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions3 pass · 5 warn

The abstract and introduction cite the initial KEYNOTE-426 results, IMmotion151, JAVELIN Renal 101, CheckMate 9ER, among others. It acknowledges the need for durable outcomes and predictive biomarkers, addressing limitations of prior biomarker studies such as confounding from different drugs. The hypothesis follows from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on PD-1/VEGFR-TKI combinations and biomarker studies, and provides a logical rationale for the long-term follow-up and biomarker analyses.

Evidence

paraphrase[Introduction, paragraph 1]

“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.”

“Because the treatment duration of pembrolizumab is limited to 2 years, it is important to assess the long-term durability of clinical outcomes.”

Introduction ¶2Find in source

“Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶1Find in source

PASSReviewer 2· 95% conf

The paper thoroughly cites prior work, establishes a clear rationale for long-term follow-up and biomarker analysis, and discusses limitations of previous studies.

Evidence

paraphrase[Introduction, paragraph 1]

“Because the treatment duration of pembrolizumab is limited to 2 years, it is important to assess the long-term durability of clinical outcomes. There is an unmet need for biomarkers that are predictive of patient outcomes after using available first-line treatment options in RCC.”

“Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶2Find in source

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific foundation by citing prior work, providing a logical rationale, and addressing limitations of prior research.

Evidence

“At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC).”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

“extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶2Find in source

Randomization method is not explicitly stated (only 'randomly assigned' with stratification). Blinding is described as 'open-label' but no rationale for the open-label design is provided. No a priori sample size calculation is reported in this paper. Inclusion/exclusion criteria and ITT analysis population are adequately defined.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous: randomized, open-label, with stratification, prespecified endpoints, and a statistical analysis plan for the biomarker analyses.

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.”

“The biomarker analysis followed a statistical analysis plan written before merging of the clinical data with biomarker assessment, specifying where statistical testing would be used and what biomarker cutoffs defined the subgroups for treatment arm comparisons.”

Statistical analysisFind in source

WARNReviewer 2· 85% conf

The study design is a randomized open-label trial, but several methodological details are insufficiently reported, such as the randomization method, blinding rationale, and a priori power analysis, leading to a warning.

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.”

paraphrase[Methods, Statistical analysis]

“The paper does not mention a sample size calculation; it states that the present analysis is exploratory and no formal hypothesis testing was performed.”

WARNReviewer 3· 80% conf

The study design is reported but lacks details on randomization method, blinding rationale, and power analysis, while inclusion/exclusion criteria and analysis population are adequately defined.

Evidence

MethodsFind in source

paraphrase[Methods, 'Inclusion and ethics']

“KEYNOTE-426 (NCT02853331) is a randomized, open-label, phase 3 trial”

“eligible participants were adults with newly diagnosed stage IV or recurrent clear cell RCC who had not previously received systemic therapy for advanced disease. Participants had a Karnofsky Performance Scale score of 70% or higher at baseline, one or more measurable lesions per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the investigator and a tumor sample available for biomarker assessment.”

MethodsFind in source

Table 1 reports sex (male/female) and age (median and range). Health status is not reported in Table 1 (only eligibility criteria of KPS >=70). Weight is not reported. Race/ethnicity and comorbidities are not reported.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key biological variables (sex, age, disease characteristics) are reported in the baseline table, and the biomarker analysis includes relevant tumor molecular features.

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

“Participants had a Karnofsky Performance Scale score of 70% or higher at baseline, one or more measurable lesions per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the investigator and a tumor sample available for biomarker assessment.”

MethodsFind in source

“Region of enrollment | | North America | 104 (24.1) | 103 (24.0) | | Western Europe | 106 (24.5) | 104 (24.2) | | Rest of the world | 222 (51.4) | 222 (51.7) |”

Table 1Find in source

WARNReviewer 2· 90% conf

Sex is reported, but age is reported without weight or health status, and demographics lack race/ethnicity and comorbidities, leading to inadequate reporting.

Evidence

paraphrase[Table 1]

“Sex: Male 308 (71.3%), Female 124 (28.7%)”

paraphrase[Table 1]

“Age, median (range), years: 62.0 (30–89)”

absence[Table 1 and Methods]

Race/ethnicity and comorbidities are not reported.

WARNReviewer 3· 70% conf

Sex is reported adequately, but age, weight, and health status are incompletely reported, and demographics lack race/ethnicity and comorbidities.

Evidence

paraphrase[Table 1]

“Male 308 (71.3%) | Female 124 (28.7%)”

paraphrase[Table 1]

“Age, median (range), years: 62.0 (30–89)”

paraphrase[Table 1]

“Table 1 includes age, sex, region, IMDC risk group, sarcomatoid features, PD-L1 CPS, number of organs with metastases, and most common sites of metastasis. No race/ethnicity or comorbidities.”

The paper states the trial was approved by 'appropriate institutional review boards' but does not name the specific body or provide a protocol number. Written informed consent and Good Clinical Practice compliance are stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial reports ethics approval by institutional review boards, written informed consent, and compliance with 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

WARNReviewer 2· 90% conf

Ethics approval is mentioned but not named specifically, and the regulatory compliance statement is adequate, but the vague IRB statement and lack of protocol number result in a warning.

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.”

MethodsFind in source

“Written informed consent was provided by all participants before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of Good Clinical Practice”

MethodsFind in source

WARNReviewer 3· 95% conf

Informed consent and regulatory compliance are adequately reported, but the ethics approval statement is vague (no named IRB or protocol number).

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.”

MethodsFind in source

“Written informed consent was provided by all participants before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of Good Clinical Practice”

MethodsFind in source

Pembrolizumab, axitinib, and sunitinib are named with dose and regimen but the manufacturer is not stated. The PD-L1 IHC assay is identified with vendor. Software tools (SAS, R, OmicSoft, etc.) are identified with versions. No custom code repository is provided.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (pembrolizumab, axitinib, sunitinib) are identified with doses and regimens, and the PD-L1 IHC assay and software tools are named.

Evidence

MethodsFind in source

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

MethodsFind in source

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

Statistical analysisFind in source

WARNReviewer 2· 85% conf

The investigational drugs are identified with dose and regimen but not with manufacturer/source, and custom code is not shared, while software tools are adequately identified.

Evidence

“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.”

MethodsFind in source

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

Statistical analysisFind in source

absence[Data availability section]

No custom code repository is provided.

WARNReviewer 3· 75% conf

Software tools are well identified, but the investigational drugs are not identified with manufacturer/source, and sequencing data are not deposited in a public repository.

Evidence

MethodsFind in source

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

Statistical analysisFind in source

The paper uses Cox proportional hazards, logistic regression, Kaplan-Meier, and Miettinen-Nurminen methods. P-values are reported exactly (e.g., P = 0.002, P < 0.0001). Hazard ratios with 95% CIs are given. Software versions are stated. Data presentation includes KM curves, forest plots, and CONSORT diagram. No mathematical inconsistencies were detected.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are well described, including tests, models, and software. P-values are reported exactly for many analyses, and effect sizes with confidence intervals are provided for primary outcomes.

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

“Tcell inf GEP | 2.03 × 10 −6 (+) | 1.41 × 10 −5 (+) | 0.002 (+) | 0.741 | 0.464 | 0.547”

Table 2Find in source

“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)”

ResultsFind in source

PASSReviewer 2· 90% conf

Statistical tests are named, exact p-values are reported, effect sizes with confidence intervals are provided, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

Statistical analysisFind in source

“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)”

ResultsFind in source

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

Statistical analysisFind in source

PASSReviewer 3· 90% conf

Statistical tests are named, assumptions are handled by standard methods, effect sizes with CIs are reported, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

paraphrase[Methods, 'Statistical analysis']

“We used the Kaplan–Meier method to estimate OS, PFS and DOR in each treatment 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. The stratified Miettinen and Nurminen method, with weights proportional to the stratum size, was used for comparison of ORR between the treatment arms.”

“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)”

ResultsFind in source

paraphrase[Table 2]

“Tcell inf GEP: ORR P = 2.03 × 10^−6 (+), PFS P = 1.41 × 10^−5 (+), OS P = 0.002 (+)”

The paper provides a detailed data availability statement via the MSD data-sharing website. However, no repository deposit or accession numbers for RNA-seq/WES data are mentioned, and custom analysis code is not shared.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed data availability statement describes a managed-access process for clinical data, which is appropriate for patient-level data.

Evidence

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

Data availabilityFind in source

WARNReviewer 2· 85% conf

A data availability statement with a concrete platform (MSD data-sharing website) is provided, and a procedure for accessing genetic data is described, but custom code is not shared.

Evidence

paraphrase[Data availability section]

“Merck Sharp & Dohme (MSD) ... is committed to providing qualified scientific researchers access to anonymized data ... The MSD data-sharing website (https://externaldatasharing-msd.com/) outlines the process and requirements for submitting a data request.”

“Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts”

Data availabilityFind in source

absence[Data availability section and Methods]

No custom code is shared.

WARNReviewer 3· 90% conf

A data availability statement with a concrete mechanism for requesting data is provided, but sequencing data are not deposited in a public repository and code is not shared.

Evidence

paraphrase[Data availability section]

“Merck Sharp & Dohme (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. The MSD data-sharing website (https://externaldatasharing-msd.com/) outlines the process and requirements for submitting a data request.”

absence[Data availability section]

No repository deposit for sequencing data.

absence[Data availability section]

No code sharing.

The paper includes a CONSORT diagram, trial registration number, detailed methods, and a limitations paragraph. All primary and secondary outcomes are reported. Funding source and competing interests are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: methods are detailed, trial registration is provided, limitations are discussed, conclusions are proportional, 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

“B.I.R. reports receiving writing support for the present paper from Merck Sharp & Dohme (MSD); payment to his institution for clinical trial research from MSD; and consulting fees from MSD.”

Competing interestsFind in source

PASSReviewer 2· 90% conf

The paper is well-structured, includes trial registration, reports all outcomes, discusses limitations, and provides proportional conclusions, though it does not explicitly reference a reporting guideline.

Evidence

“ClinicalTrials.gov identifier: NCT02853331”

AbstractFind in source

“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 ¶5Find in source

“Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA”

FundingFind in source

PASSReviewer 3· 95% conf

Methods are complete, the trial is registered, a CONSORT diagram is included, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331”

AbstractFind in source

“Fig. 1 CONSORT diagram.”

Figure 1Find in source

“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.”

DiscussionFind 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).

3 data/code links checked; 3 live.

Copyediting

9 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 9 minor suggestions below.

9 copyedit issues flagged: mostly typo, consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

This published work demonstrates a generally robust methodology, but an informed reader should be aware of the reporting gaps in study design details, participant demographics, ethical approval specifics, and the lack of public deposition for sequencing data and analysis code. These issues, along with several minor copyedit errors, suggest that a formal erratum or a more detailed supplementary information document would enhance the paper's completeness and reproducibility for future researchers.

1.
HIGHreporting
In the Methods section, specify the exact randomization method used (e.g., computer-generated random sequence, block sizes) to enhance reproducibility.
The specific method of random sequence generation is a critical detail for assessing the rigor of a randomized controlled trial.
2.
HIGHreporting
In the Methods section, provide a rationale for the open-label design of the trial.
Explaining why blinding was not feasible or appropriate is important for transparency in clinical trial design.
3.
HIGHreporting
In the Methods section, include an a priori sample size or power calculation for the exploratory biomarker analyses, or explicitly state that these analyses were not formally powered.
Clarity on power analysis is crucial for interpreting the statistical significance and generalizability of exploratory findings.
4.
HIGHreporting
In Table 1 or a supplementary table, report additional demographic details such as weight, race/ethnicity, and key comorbidities.
Comprehensive demographic reporting is essential for assessing the generalizability and potential disparities in clinical trial results.
5.
HIGHethics
In the Methods section under 'Inclusion and ethics', name the specific institutional review board(s) that approved the trial and provide the protocol number.
Specific identification of ethics approvals enhances transparency and traceability of ethical oversight.
6.
HIGHrigor
In the Methods section, state the manufacturer/source for each investigational drug (pembrolizumab, axitinib, sunitinib).
Identifying the source of key reagents is fundamental for reproducibility and proper attribution.
7.
HIGHdata code
Deposit the RNA-seq and WES data in a public repository (e.g., GEO, dbGaP) and provide accession numbers in the Data Availability section.
Public deposition of sequencing data is crucial for data transparency, re-analysis, and reproducibility of biomarker findings.
8.
HIGHdata code
Share any custom analysis code in a public repository (e.g., GitHub, Zenodo) with a permanent identifier and include the link in the Data Availability section.
Sharing custom code is essential for computational reproducibility and allows other researchers to verify or build upon the analyses.
9.
MEDIUMreporting
In the Methods section, add a statement on how outliers were handled in the biomarker analyses, or clarify that no outliers were excluded.
Explicitly stating outlier handling procedures improves transparency and allows for critical evaluation of data processing.
10.
MEDIUMreporting
In the Methods section, add a brief note on the verification of statistical assumptions (e.g., proportional hazards) for the Cox models.
Reporting on assumption checks for statistical models enhances the credibility of the analysis.
11.
LOWcopyedit
Correct all instances of 'pressent' to 'present' in the Discussion section.
Typographical errors detract from the professionalism and readability of the manuscript.
12.
LOWcopyedit
Correct all instances of 'PRRM1' to 'PBRM1' in the Discussion section.
Accurate gene nomenclature is essential for scientific precision and clarity.
13.
LOWcopyedit
Ensure consistent naming of the 'von Hippel-Lindau tumor suppressor gene' throughout the manuscript, especially in Extended Data Fig. 4-7.
Consistency in terminology improves readability and avoids confusion.
14.
LOWcopyedit
In Extended Data Table 3, footnote, correct 'In the axitinib arm' to 'In the sunitinib arm'.
Accuracy in table footnotes is important for correct interpretation of data.
15.
LOWcopyedit
Revise the sentence in Discussion, paragraph 4, to improve clarity and correct the run-on structure.
Clear and grammatically correct sentences enhance the overall quality of writing.

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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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Issued Aug 10, 2026Engine 7.29.0

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Kaimen Rigor review

Kaimen Rigor reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingStudy design partially met−0.25★
ReportingBiological variables partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: lowEngine: 7.29.0Source: full text

Findings by category

01ArithmeticNone found 02OverreachNone found 03AuthenticityNone found 504DisclosureReporting gaps 05AvailabilityNone found 06Copyedit9 minor suggestions

Numerical inconsistencies

None found

Checked — nothing surfaced.

Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 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

5 findings · worst medium

Biological variables underreported (sex, age, strain)Assessed
Data/code availability incompleteAssessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions3 pass · 5 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

paraphrase[Introduction, paragraph 1]

“Because the treatment duration of pembrolizumab is limited to 2 years, it is important to assess the long-term durability of clinical outcomes.”

Introduction ¶2Find in source

“Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶1Find in source

PASSReviewer 2· 95% conf

The paper thoroughly cites prior work, establishes a clear rationale for long-term follow-up and biomarker analysis, and discusses limitations of previous studies.

Evidence

paraphrase[Introduction, paragraph 1]

“Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶2Find in source

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific foundation by citing prior work, providing a logical rationale, and addressing limitations of prior research.

Evidence

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 2]

“extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

Introduction ¶2Find in source

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous: randomized, open-label, with stratification, prespecified endpoints, and a statistical analysis plan for the biomarker analyses.

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.”

Statistical analysisFind in source

WARNReviewer 2· 85% conf

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.”

paraphrase[Methods, Statistical analysis]

“The paper does not mention a sample size calculation; it states that the present analysis is exploratory and no formal hypothesis testing was performed.”

WARNReviewer 3· 80% conf

The study design is reported but lacks details on randomization method, blinding rationale, and power analysis, while inclusion/exclusion criteria and analysis population are adequately defined.

Evidence

MethodsFind in source

paraphrase[Methods, 'Inclusion and ethics']

“KEYNOTE-426 (NCT02853331) is a randomized, open-label, phase 3 trial”

MethodsFind in source

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key biological variables (sex, age, disease characteristics) are reported in the baseline table, and the biomarker analysis includes relevant tumor molecular features.

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

MethodsFind in source

“Region of enrollment | | North America | 104 (24.1) | 103 (24.0) | | Western Europe | 106 (24.5) | 104 (24.2) | | Rest of the world | 222 (51.4) | 222 (51.7) |”

Table 1Find in source

WARNReviewer 2· 90% conf

Sex is reported, but age is reported without weight or health status, and demographics lack race/ethnicity and comorbidities, leading to inadequate reporting.

Evidence

paraphrase[Table 1]

“Sex: Male 308 (71.3%), Female 124 (28.7%)”

paraphrase[Table 1]

“Age, median (range), years: 62.0 (30–89)”

absence[Table 1 and Methods]

Race/ethnicity and comorbidities are not reported.

WARNReviewer 3· 70% conf

Sex is reported adequately, but age, weight, and health status are incompletely reported, and demographics lack race/ethnicity and comorbidities.

Evidence

paraphrase[Table 1]

“Male 308 (71.3%) | Female 124 (28.7%)”

paraphrase[Table 1]

“Age, median (range), years: 62.0 (30–89)”

paraphrase[Table 1]

“Table 1 includes age, sex, region, IMDC risk group, sarcomatoid features, PD-L1 CPS, number of organs with metastases, and most common sites of metastasis. No race/ethnicity or comorbidities.”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial reports ethics approval by institutional review boards, written informed consent, and compliance with Good Clinical Practice.

Evidence

MethodsFind in source

WARNReviewer 2· 90% conf

Ethics approval is mentioned but not named specifically, and the regulatory compliance statement is adequate, but the vague IRB statement and lack of protocol number result in a warning.

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.”

MethodsFind in source

“Written informed consent was provided by all participants before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of Good Clinical Practice”

MethodsFind in source

WARNReviewer 3· 95% conf

Informed consent and regulatory compliance are adequately reported, but the ethics approval statement is vague (no named IRB or protocol number).

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.”

MethodsFind in source

“Written informed consent was provided by all participants before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of Good Clinical Practice”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (pembrolizumab, axitinib, sunitinib) are identified with doses and regimens, and the PD-L1 IHC assay and software tools are named.

Evidence

MethodsFind in source

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

MethodsFind in source

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

Statistical analysisFind in source

WARNReviewer 2· 85% conf

The investigational drugs are identified with dose and regimen but not with manufacturer/source, and custom code is not shared, while software tools are adequately identified.

Evidence

MethodsFind in source

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

Statistical analysisFind in source

absence[Data availability section]

No custom code repository is provided.

WARNReviewer 3· 75% conf

Software tools are well identified, but the investigational drugs are not identified with manufacturer/source, and sequencing data are not deposited in a public repository.

Evidence

MethodsFind in source

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

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

Statistical analysisFind in source

“Tcell inf GEP | 2.03 × 10 −6 (+) | 1.41 × 10 −5 (+) | 0.002 (+) | 0.741 | 0.464 | 0.547”

Table 2Find in source

“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)”

ResultsFind in source

PASSReviewer 2· 90% conf

Statistical tests are named, exact p-values are reported, effect sizes with confidence intervals are provided, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

Statistical analysisFind in source

“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)”

ResultsFind in source

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

Statistical analysisFind in source

PASSReviewer 3· 90% conf

Statistical tests are named, assumptions are handled by standard methods, effect sizes with CIs are reported, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

paraphrase[Methods, 'Statistical analysis']

“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)”

ResultsFind in source

paraphrase[Table 2]

“Tcell inf GEP: ORR P = 2.03 × 10^−6 (+), PFS P = 1.41 × 10^−5 (+), OS P = 0.002 (+)”

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

A detailed data availability statement describes a managed-access process for clinical data, which is appropriate for patient-level data.

Evidence

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

Data availabilityFind in source

WARNReviewer 2· 85% conf

A data availability statement with a concrete platform (MSD data-sharing website) is provided, and a procedure for accessing genetic data is described, but custom code is not shared.

Evidence

paraphrase[Data availability section]

Data availabilityFind in source

absence[Data availability section and Methods]

No custom code is shared.

WARNReviewer 3· 90% conf

A data availability statement with a concrete mechanism for requesting data is provided, but sequencing data are not deposited in a public repository and code is not shared.

Evidence

paraphrase[Data availability section]

absence[Data availability section]

No repository deposit for sequencing data.

absence[Data availability section]

No code sharing.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: methods are detailed, trial registration is provided, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

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

AbstractFind in source

Discussion ¶8Find in source

“B.I.R. reports receiving writing support for the present paper from Merck Sharp & Dohme (MSD); payment to his institution for clinical trial research from MSD; and consulting fees from MSD.”

Competing interestsFind in source

PASSReviewer 2· 90% conf

Evidence

“ClinicalTrials.gov identifier: NCT02853331”

AbstractFind in source

Discussion ¶5Find in source

“Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA”

FundingFind in source

PASSReviewer 3· 95% conf

Methods are complete, the trial is registered, a CONSORT diagram is included, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT02853331”

AbstractFind in source

“Fig. 1 CONSORT diagram.”

Figure 1Find in source

DiscussionFind 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).

3 data/code links checked; 3 live.

Copyediting

9 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 9 minor suggestions below.

9 copyedit issues flagged: mostly typo, consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
In the Methods section, specify the exact randomization method used (e.g., computer-generated random sequence, block sizes) to enhance reproducibility.
The specific method of random sequence generation is a critical detail for assessing the rigor of a randomized controlled trial.
2.
HIGHreporting
In the Methods section, provide a rationale for the open-label design of the trial.
Explaining why blinding was not feasible or appropriate is important for transparency in clinical trial design.
3.
HIGHreporting
In the Methods section, include an a priori sample size or power calculation for the exploratory biomarker analyses, or explicitly state that these analyses were not formally powered.
Clarity on power analysis is crucial for interpreting the statistical significance and generalizability of exploratory findings.
4.
HIGHreporting
In Table 1 or a supplementary table, report additional demographic details such as weight, race/ethnicity, and key comorbidities.
Comprehensive demographic reporting is essential for assessing the generalizability and potential disparities in clinical trial results.
5.
HIGHethics
In the Methods section under 'Inclusion and ethics', name the specific institutional review board(s) that approved the trial and provide the protocol number.
Specific identification of ethics approvals enhances transparency and traceability of ethical oversight.
6.
HIGHrigor
In the Methods section, state the manufacturer/source for each investigational drug (pembrolizumab, axitinib, sunitinib).
Identifying the source of key reagents is fundamental for reproducibility and proper attribution.
7.
HIGHdata code
Deposit the RNA-seq and WES data in a public repository (e.g., GEO, dbGaP) and provide accession numbers in the Data Availability section.
Public deposition of sequencing data is crucial for data transparency, re-analysis, and reproducibility of biomarker findings.
8.
HIGHdata code
Share any custom analysis code in a public repository (e.g., GitHub, Zenodo) with a permanent identifier and include the link in the Data Availability section.
Sharing custom code is essential for computational reproducibility and allows other researchers to verify or build upon the analyses.
9.
MEDIUMreporting
In the Methods section, add a statement on how outliers were handled in the biomarker analyses, or clarify that no outliers were excluded.
Explicitly stating outlier handling procedures improves transparency and allows for critical evaluation of data processing.
10.
MEDIUMreporting
In the Methods section, add a brief note on the verification of statistical assumptions (e.g., proportional hazards) for the Cox models.
Reporting on assumption checks for statistical models enhances the credibility of the analysis.
11.
LOWcopyedit
Correct all instances of 'pressent' to 'present' in the Discussion section.
Typographical errors detract from the professionalism and readability of the manuscript.
12.
LOWcopyedit
Correct all instances of 'PRRM1' to 'PBRM1' in the Discussion section.
Accurate gene nomenclature is essential for scientific precision and clarity.
13.
LOWcopyedit
Ensure consistent naming of the 'von Hippel-Lindau tumor suppressor gene' throughout the manuscript, especially in Extended Data Fig. 4-7.
Consistency in terminology improves readability and avoids confusion.
14.
LOWcopyedit
In Extended Data Table 3, footnote, correct 'In the axitinib arm' to 'In the sunitinib arm'.
Accuracy in table footnotes is important for correct interpretation of data.
15.
LOWcopyedit
Revise the sentence in Discussion, paragraph 4, to improve clarity and correct the run-on structure.
Clear and grammatically correct sentences enhance the overall quality of writing.

Full text (70,578 chars)Analyzed: Aug 10, 2026