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: Adcurare Rigor Record — 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: Adcurare

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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Adcurare Rigor Review — 2.5★ (Weak), 0 critical, 10 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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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 6, 2026

Adcurare Rigor Review

Rigor Reviewed

2.5 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
CitationsCitations & links (capped) ×5−1★
ReportingEthical approvals partially met−0.25★
ReportingData & code availability partially met−0.25★

Citations & links are capped at −1★ combined, however many are flagged.

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced5 types

Data/code availability incomplete
Ethics/consent reporting incomplete
Internal contradictions in the reported numbers
Other integrity concern
References not resolvable to a published paper

This Adcurare Rigor Review uses AI 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.

The manuscript reports a long-term follow-up and biomarker analysis from a phase 3 RCT with a strong scientific premise and generally transparent reporting. The main weaknesses are incomplete reporting of study design details (randomization method, power analysis, outlier handling), an unnamed ethics committee, missing manufacturer identification for key drugs, absent effect sizes for continuous biomarker associations, and no data/code sharing for generated sequencing data.

Three independent reviewers (all AI) evaluated the full manuscript text. The verification component's statistics check recomputed 5 reported tests consistently; the remaining statistical results (the majority of biomarker p-values) were not machine-verified. 5 references could not be found in Crossref/OpenAlex — they should be re-checked; none were retracted. The copyedit pass identified 11 issues (1 major: a label inconsistency in Extended Data Table 3).

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

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

2 integrity concerns flagged (0 high).

Reporting

Eight Dimensions6 pass · 2 warn

Prior work on pembrolizumab plus axitinib and need for long-term data and biomarkers is cited. A logical rationale linking the premise to the objectives is provided, and limitations of prior research (e.g., extrapolation from other trials) are acknowledged, though not systematically mitigated.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific foundation by citing relevant prior work and logically linking the premise to the study objectives.

Evidence

direct quote[Introduction, paragraph 1]

“KEYNOTE-426 was the first trial of a PD-1 inhibitor and VEGFR-TKI combination in the first-line treatment setting and, therefore, has the longest follow-up duration of any combination of a PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor and a TKI.”

direct quote[Introduction, paragraph 2]

“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.”

direct quote[Introduction, paragraph 2]

“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.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise by citing prior work on the combination therapy and identifying the unmet need for long-term data and predictive biomarkers.

Evidence

direct quote[Introduction, paragraph 1]

direct quote[Introduction, paragraph 2]

direct quote[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”

PASSReviewer 3· 95% conf

The scientific premise is well-established. Prior work is cited (KEYNOTE-426, IMmotion151, JAVELIN Renal 101, CheckMate 9ER), the rationale for long-term follow-up and biomarker analysis is clear, and limitations of prior research are acknowledged.

Evidence

direct quote[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… were evaluated as frontline therapy. Thus, extrapolation of these data to define predictive biomarkers in frontline therapy for advanced RCC is potentially confounded.”

direct quote[Introduction, last paragraph]

direct quote[Discussion, paragraph 11]

“A strength of the biomarker analysis is that the populations included a high proportion of the treated population in each arm; therefore, inferences drawn from these respective datasets are largely representative of the KEYNOTE-426 trial population.”

Randomization method (1:1 ratio) and stratification factors (IMDC risk group, geographic region) are reported. The unit of randomization is the participant. Blinding is not applicable as the trial is open-label, which is stated. A priori power analysis is not reported for the exploratory biomarker analyses, but the primary efficacy analysis was previously positive. Inclusion/exclusion criteria are described in detail. Outlier handling is not explicitly discussed, but the analysis population definitions (ITT, treated, evaluable) are clear. Controls are inherent in the comparator arm (sunitinib). Independent replication is not applicable for a single pivotal trial. For a human RCT, the applicable sub-criteria are randomization_method, randomization_unit, blinding_levels, power_analysis, inclusion_exclusion, and outlier_handling (mapped to analysis population). All are adequate except power_analysis (not reported for the exploratory analysis) and outlier_handling (not explicitly reported).

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design is generally rigorous, with adequate randomization, blinding description, inclusion/exclusion criteria, and handling of analysis populations. However, a power analysis is not reported for the present exploratory analysis.

Evidence

direct quote[Methods, Trial design, participants and treatments]

“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).”

direct quote[Abstract]

“open-label, randomized, phase 3 KEYNOTE-426 trial”

direct quote[Methods, Trial design, participants and treatments]

“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.”

PASSReviewer 2· 90% conf

The study design is rigorous for a phase 3 trial, with clear randomization, stratification, and prespecified analyses, though blinding is not applicable (open-label) and power analysis is not reported for the exploratory biomarker component.

Evidence

direct quote[Methods, Trial design, participants and treatments]

“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).”

direct quote[Methods, Inclusion and ethics]

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

direct quote[Methods, Trial design, participants and treatments]

“In brief, 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.”

WARNReviewer 3· 90% conf

The study is a well-conducted phase 3 RCT, but several design elements are underreported: the randomization method is not specified beyond stating it was stratified, blinding is open-label without justification, no a priori power analysis is reported for the current follow-up/biomarker analyses, and outlier handling is not addressed.

Evidence

direct quote[Methods, 'Trial design, participants and treatments']

“Participants were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg intravenously once every 3 weeks… plus axitinib… or sunitinib… Randomization was stratified according to the IMDC risk group… and by geographic region.”

direct quote[Methods, 'Inclusion and ethics']

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

direct quote[Methods, 'Statistical analysis']

“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 in Table 1 (71.3% male, 28.7% female in the pembrolizumab+axitinib arm). Age is reported as median and range. Health status is captured via Karnofsky Performance Scale score and IMDC risk group. Demographics include age, sex, region, and disease characteristics (IMDC risk, sarcomatoid features, PD-L1 CPS, number of metastases). Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 75% conf

Sex and demographics are well reported, but weight is missing from the age/weight/health criterion, leading to a borderline pass.

Evidence

direct quote[Table 1]

“Male 308 (71.3) 320 (74.6) Female 124 (28.7) 109 (25.4)”

direct quote[Table 1 and Methods]

“Age, median (range), years 62.0 (30–89) 61.0 (26–90)”

direct quote[Table 1]

“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)”

PASSReviewer 2· 95% conf

Biological variables are well-reported for a human clinical trial, including age, sex, and key disease characteristics.

Evidence

direct quote[Table 1]

“Sex | Male 308 (71.3) | 320 (74.6) | Female 124 (28.7) | 109 (25.4)”

direct quote[Table 1]

“Age, median (range), years | 62.0 (30–89) | 61.0 (26–90)”

direct quote[Table 1]

“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)”

PASSReviewer 3· 95% conf

Biological variables are well-reported. Sex, age, health status (KPS), and detailed demographics (IMDC risk, region, metastases sites, prior therapy) are provided in Table 1. Both sexes are included, so sex justification is not applicable. Species/strain and housing conditions are not applicable.

Evidence

direct quote[Results, paragraph 1 and Table 1]

“Male: 308 (71.3%) Female: 124 (28.7%) (pembrolizumab plus axitinib arm)”

direct quote[Table 1]

“Age, median (range), years: 62.0 (30–89) (pembrolizumab plus axitinib arm)”

direct quote[Table 1]

“Region of enrollment, IMDC risk group, Sarcomatoid features, PD-L1 CPS, No. of organs with metastases, Most common sites of metastasis, Previous radiotherapy, Previous nephrectomy”

The paper states that the trial was approved by 'appropriate institutional review boards' but does not name a specific body. Written informed consent is explicitly mentioned. Compliance with Good Clinical Practice is stated. Since a named IRB is missing, this dimension is scored as warn.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Informed consent and regulatory compliance are adequately reported, but the ethics statement does not name a specific IRB, making it inadequate.

Evidence

direct quote[Methods, Inclusion and ethics]

“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.”

direct quote[Methods, Inclusion and ethics]

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

direct quote[Methods, Inclusion and ethics]

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

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported: the trial was approved by institutional review boards, participants provided written informed consent, and compliance with Good Clinical Practice is stated.

Evidence

direct quote[Methods, Inclusion and ethics]

“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.”

direct quote[Abstract and Methods]

“ClinicalTrials.gov identifier: NCT02853331”

WARNReviewer 3· 85% conf

Ethical compliance is reported but the ethics committee approval statement does not name a specific approving body, which is considered inadequate. Informed consent is adequately reported (written). Regulatory compliance (GCP) is stated.

Evidence

direct quote[Methods, 'Inclusion and ethics']

“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.”

direct quote[Methods, 'Inclusion and ethics']

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

direct quote[Methods, 'Inclusion and ethics']

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

For a clinical trial of a drug, the investigational products are the key resources. Pembrolizumab, axitinib, and sunitinib are named, and the manufacturer (Merck Sharp & Dohme) is implied. The PD-L1 IHC assay is identified (22C3 pharmDx, Agilent Technologies). Software tools are identified: OmicSoft Array Suite version 9, SAS version 9.4, R version 4.2.1, Picard version 1.114, Genome Analysis Toolkit version 2. Antibodies, cell lines, mycoplasma testing, and organisms are not applicable. Reagents_identified is scored against the investigational products and is adequate. Software_tools_identified is adequate.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Investigational products and software are adequately identified. The PD-L1 IHC assay is identified but without catalog number, leading to a partially adequate rating.

Evidence

direct quote[Methods, Trial design, participants and treatments]

“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.”

direct quote[Methods, Statistical analysis]

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

direct quote[Table 1 footnote]

“PD-L1 IHC 22C3 pharmDx (Agilent Technologies)”

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational products (pembrolizumab, axitinib, sunitinib) are named with manufacturer, and software tools are identified with versions.

Evidence

direct quote[Methods, Trial design, participants and treatments]

direct quote[Methods, Assessments]

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

direct quote[Methods, Statistical analysis]

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

WARNReviewer 3· 85% conf

The investigational drugs (pembrolizumab, axitinib, sunitinib) are named with dose and regimen but manufacturer/source is not provided for axitinib and sunitinib, making reagent identification inadequate. Software tools are well-identified. Other resource categories (antibodies, cell lines, etc.) are not applicable.

Evidence

direct quote[Methods, 'Trial design, participants and treatments']

“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”

direct quote[Table 1 footnote]

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

direct quote[Methods, 'Assessments' and 'Statistical analysis']

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

Tests are named (Cox proportional hazards, logistic regression, Kaplan-Meier, Miettinen and Nurminen method). Exact p-values are reported (e.g., 2.03 × 10^-6). Effect sizes (hazard ratios) and 95% confidence intervals are provided. Software is identified (SAS 9.4, R 4.2.1). Data presentation includes Kaplan-Meier curves, forest plots, and tables with per-group n. Assumptions_verified is not explicitly reported, but for a large clinical trial using Cox models, this is acceptable. 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 verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are well described, exact p-values and effect sizes with CIs are reported, software is identified. Assumption verification is not explicitly reported, but this is acceptable for a large clinical trial using standard methods.

Evidence

direct quote[Table 2]

“Tcell inf GEP 2.03 × 10^−6 (+)”

direct quote[Abstract]

“hazard ratio: 0.84; 95% confidence interval: 0.71–0.99”

direct quote[Methods, Statistical analysis]

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

PASSReviewer 2· 90% conf

Statistical analysis is rigorous: tests are named, exact p-values are reported, effect sizes with confidence intervals are provided, and software is identified. Assumptions are not explicitly verified but are standard for Cox models. Data presentation includes Kaplan-Meier curves and forest plots.

Evidence

direct quote[Table 2]

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

direct quote[Results, Efficacy outcomes]

“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)”

direct quote[Methods, Statistical analysis]

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

PASSReviewer 3· 90% conf

Statistical tests are named (Cox, logistic, Kaplan-Meier, Miettinen-Nurminen). Exact p-values and HRs with 95% CIs are reported for primary and subgroup analyses. Software is identified. Data presentation is adequate with K-M curves and forest plots. However, assumptions verification (e.g., proportional hazards) is not explicitly discussed, and effect sizes with CIs are not provided for the continuous biomarker associations (only p-values).

Evidence

direct quote[Results, 'Efficacy outcomes' and Table 2]

“median OS was 47.2 months… (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99). Median PFS was 15.7 months… (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81).”

direct quote[Table 2]

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

absence[Methods, 'Statistical analysis']

Assumption verification is not mentioned.

The data availability statement describes a process for requesting anonymized clinical trial data from MSD, which is adequate for patient-level data. However, the biomarker data (RNA-seq, WES) are not deposited in a public repository (e.g., GEO, dbGaP) with accession numbers, which is a gap. Custom code is not shared. For a clinical trial with biomarker data, repository_deposit and accession_numbers are applicable for the non-identifiable genomic data, and code_sharing is applicable for the custom analysis pipeline.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement with a concrete access route is provided, but no raw data are deposited in a public repository, no accession numbers are given, and no custom code is shared. Thus, some-but-not-all applicable criteria are adequate.

Evidence

direct quote[Data availability section]

“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 or accession numbers are mentioned.

absence[Data availability section]

No code sharing is mentioned.

WARNReviewer 2· 85% conf

A data availability statement is present and describes a managed-access process, but no repository deposit or accession numbers are provided for the biomarker data (RNA-seq, WES), and code is not shared.

Evidence

direct quote[Data availability section]

“Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co., 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.”

absence[Data availability section]

No repository deposit or accession numbers for biomarker data.

absence[Data availability section]

No code sharing statement.

WARNReviewer 3· 85% conf

A data availability statement is present and describes a concrete managed-access process via the MSD data-sharing website, which is adequate for patient-level data. However, the RNA sequencing and whole-exome sequencing data generated in this study are not deposited in a public repository, and no code is shared, which are expected for biomarker analyses.

Evidence

direct quote[Data availability section]

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

absence[Data availability section]

Sequencing data are not deposited in a public repository.

absence[Data availability section]

Code is not shared.

Methods are detailed and replicable. The trial is registered (NCT02853331). A Nature Portfolio Reporting Summary is available. All pre-specified outcomes are reported, including non-significant results. Limitations are discussed in the Discussion. Conclusions are proportional to the data. Funding and competing interests are fully 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· 95% conf

The paper provides complete methods, trial registration, a reporting summary, transparent reporting of all outcomes (including negative results), a limitations discussion, proportional conclusions, and funding/COI statements.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov identifier: NCT02853331”

direct quote[Discussion, paragraph 6]

“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”

direct quote[Funding and Competing interests sections]

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

PASSReviewer 2· 90% conf

Reporting is transparent: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. A reporting guideline is not explicitly referenced but the paper follows CONSORT-like structure.

Evidence

direct quote[Abstract and Methods]

“ClinicalTrials.gov identifier: NCT02853331”

direct quote[Discussion, paragraph 8]

“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.”

direct quote[Funding and Competing interests sections]

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

PASSReviewer 3· 95% conf

The manuscript is well-structured with comprehensive methods, trial registration (NCT02853331), transparent reporting of all outcomes (including negative biomarker results), a CONSORT flow diagram, discussion of limitations, proportional conclusions, and detailed funding/COI statements. The only minor gap is that a reporting guideline is not formally cited (though a CONSORT diagram is present).

Evidence

direct quote[Abstract]

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

direct quote[Figure 1 legend]

“Fig. 1 CONSORT diagram.”

direct quote[Discussion, paragraph 11]

“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.”

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

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

Reproducibility

3 data/code links checked; 3 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

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

1.
HIGHother
Correction: in Extended Data Table 3 footnote, change 'axitinib arm' to 'sunitinib arm' to match the table header.
This is a factual inconsistency — the table describes sunitinib-arm results, not axitinib — that reviewers and editors will catch and question.
2.
HIGHreporting
In the Methods (Inclusion and ethics), name a specific IRB/ethics committee (e.g., 'the trial was approved by Western Institutional Review Board, protocol number XXX') rather than 'appropriate institutional review boards'.
A generic statement without a named body is considered insufficient by most journals and all three reviewers flagged this as missing.
3.
HIGHdata code
Deposit RNA-seq and whole-exome sequencing data in a controlled-access repository (e.g., dbGaP, EGA, GEO) and add accession numbers to the Data availability section.
These data are the basis for the biomarker analyses; without public deposition, the analyses cannot be independently verified — a core reproducibility requirement.
4.
HIGHstatistics
In Table 2 and the main text, report effect sizes (e.g., hazard ratios or odds ratios per 1-SD increase) with 95% confidence intervals for all continuous biomarker associations, not only p-values and direction signs.
P-values alone do not convey magnitude or precision; effect sizes with CIs are expected for all regression-based associations and are missing from the biomarker results.
5.
HIGHdata code
Share custom analysis code (OmicSoft pipeline scripts, R scripts for biomarker models) in a public repository (GitHub, Zenodo) with a persistent DOI, and add the link to the Data availability section.
No custom code is currently shared, preventing full reproducibility of the biomarker analyses.
6.
HIGHreporting
In the Methods or Acknowledgements, explicitly cite the CONSORT 2010 statement (or STROBE for the biomarker component) and state that reporting follows this guideline.
Although a CONSORT flow diagram is present, the formal guideline citation is missing, which is a standard expectation for clinical trial papers.
7.
HIGHstatistics
Add a brief statement in the Methods (Statistical analysis) verifying the proportional hazards assumption for Cox models (e.g., 'The proportional hazards assumption was assessed using Schoenfeld residuals and was satisfied').
Assumption verification is not currently reported; this is a standard reviewer request for time-to-event analyses.
8.
HIGHstatistics
Add an a priori power analysis or sample-size justification for the exploratory biomarker analyses, or explicitly state that the sample size was determined by the parent trial and that the analysis is post hoc/exploratory with no formal power.
No power analysis is provided; reviewers and readers will want to know whether the study had adequate statistical power for the biomarker comparisons, especially for subgroups.
9.
HIGHstatistics
Describe how outliers in biomarker data (e.g., gene expression values, mutation calls) were identified and handled in the Methods (Statistical analysis or Assessments).
Outlier handling is not mentioned anywhere; this is a standard methodological detail expected for genomic analyses.
10.
HIGHreporting
Specify the random sequence generation method (e.g., 'computer-generated random numbers with permuted blocks and a 1:1 allocation ratio, stratified by ...') in the Methods.
The method of randomization is not described beyond stating 'randomly assigned in a 1:1 ratio', which is insufficient for a trial report.
11.
MEDIUMreporting
Provide a brief rationale for the open-label design in the Methods (e.g., 'Given the known toxicity profiles of TKIs and the requirement for dose modifications, blinding was not feasible.')
The open-label design is stated but not justified; explicit acknowledgment of why blinding was not used strengthens design transparency.
12.
MEDIUMreporting
In the Methods (Trial design, participants and treatments), explicitly state the manufacturer/source (company, city, country) for axitinib and sunitinib.
Investigational drugs are core reagents; their source should be identified for replicability, as is standard for clinical trial reports.
13.
MEDIUMreporting
In Table 1 or Methods, include baseline weight (mean ± SD or median with range) of participants to complete the age/weight/health status reporting.
Weight is a standard demographic variable in clinical trials and its absence is a minor reporting gap.
14.
MEDIUMreporting
In the Data availability section, specify the expected timeframe for data access upon request (e.g., 'Data will be shared within 6 months of an approved request').
The current managed-access statement does not indicate how long data access takes, which would help prospective users.
15.
LOWcopyedit
Across the Discussion and Extended Data figures, correct 'pressent' to 'present' and 'PRRM1' to 'PBRM1'; correct 'von Lindau-Hippel' to 'von Hippel-Lindau' in figure legends and table footnotes.
These are typographical errors that affect readability and accuracy of gene/entity names.
16.
LOWcopyedit
In Table 2 footnote, use consistent ASCII plus/minus signs or matched Unicode symbols for '+' and '−' indicators without mixing quote styles.
Minor punctuation inconsistency that a copyeditor would flag.
17.
LOWstatistics
In the Discussion, explicitly acknowledge that the lack of a pre-registered analysis plan for the biomarker component (beyond the parent trial SAP) may affect reproducibility, and consider registering the plan retrospectively.
Weakens the strength of the exploratory claims; pre-registration would strengthen the biomarker findings.
18.
LOWdata code
Verify the 5 references flagged as 'not_found_in_registry' (CheckMate 9ER biomarker analysis, KIM-1 JAVELIN, KEYNOTE-427, TKIs immunomodulatory effects, CheckMate 9ER final follow-up) as they may be mis-cited, preprints, or conference abstracts — correct or add missing identifiers.
These references could not be located in standard registries; while not retracted, their absence is a potential integrity concern that should be resolved before submission.

Full text (72,141 chars)Analyzed: Jul 6, 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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10.1038/s41591-025-03867-5

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Issued Jul 6, 2026Engine 7.6.0

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