Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Name: Kaimen Rigor review — Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.
Item: Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.
Rating: 59
Author: Alpha1

Powles T, Chang YH, Yamamoto Y, Munoz J, Reyes-Cosmelli F, Peer A, Cohen G, Yu EY, Lorch A, Bavle A, Homet Moreno B, Markensohn J, Edmondson M, Chen C, Cristescu R, Peña C, Lunceford J, Gunduz S

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Kaimen Rigor review — 4.25★ (Strong), 0 critical, 3 high issues for “Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.”

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Powles T, Chang YH, Yamamoto Y, Munoz J, Reyes-Cosmelli F, Peer A, Cohen G, Yu EY, Lorch A, Bavle A, Homet Moreno B, Markensohn J, Edmondson M, Chen C, Cristescu R, Peña C, Lunceford J, Gunduz S

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DOI

10.1038/s41591-024-03091-7

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122164fad4adbe5168eb26c48c4f36ba77ca3ada61155a439cc4444c0fe8e9d4

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Issued Aug 16, 2026Engine 7.39.0

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Powles T, Chang YH, Yamamoto Y, Munoz J, Reyes-Cosmelli F, Peer A, Cohen G, Yu EY, Lorch A, Bavle A, Homet Moreno B, Markensohn J, Edmondson M, Chen C, Cristescu R, Peña C, Lunceford J, Gunduz S

Paper source

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×3−0.25★

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

Biggest issues

01Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
87.2% is unattainable for n=130 (nearest: 86.9, 87.7%)
“87.2% of patients in the chemotherapy arm”
Baseline ctDNA positivity in chemothera…Find in source
02Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
11.5% is unattainable for n=115 (nearest: 11.3, 12.2%)
“11.5% of patients in the pembrolizumab arm”
ctDNA clearance at C2 in pembrolizumab…Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
41.2% is unattainable for n=123 (nearest: 40.7, 41.5%)
“41.2% of patients in the chemotherapy arm”
ctDNA clearance at C2 in chemotherapy a…Find in source

Findings by category

201ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit3 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 retrospective exploratory biomarker analysis of the KEYNOTE-361 trial is methodologically sound, with a clear premise, rigorous design, and transparent reporting. Minor reporting gaps include unspecified statistical software, unverified model assumptions, and lack of explicit outlier handling, but these do not undermine the core findings.

Both reviewers classified the study as interventional (retrospective biomarker substudy of an RCT); no disagreement. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification covered only a subset of tests; the 3 inconsistent results are not detailed and do not constitute demonstrable errors.

Numerical inconsistencies

2 findings · worst medium

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.

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

3 printed percentages that do not match their own count.

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.

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

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 thoroughly reviews prior ctDNA research in urothelial carcinoma and other cancers, acknowledging mixed results and gaps. The rationale for evaluating ctDNA in metastatic urothelial carcinoma is well-articulated, and the study objectives follow logically from the cited evidence. Limitations of prior research are addressed by the study design and analysis plan.

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 with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“ctDNA has been shown to have a role in reflecting response to treatment in solid tumors as well as potential prognostic implications, although varying results have been reported in the treatment of different tumor types and degrees of tumor burden.”

“Determining the utility of ctDNA as a biomarker in patients with advanced or metastatic urothelial carcinoma from KEYNOTE-361 is of interest.”

IntroductionFind in source

“This exploratory analysis was conducted per a prespecified statistical analysis plan.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Determining the utility of ctDNA as a biomarker in patients with advanced or metastatic urothelial carcinoma from KEYNOTE-361 is of interest.”

IntroductionFind in source

“We used multiple methods of ctDNA analysis to robustly test the hypothesis that immunotherapy and chemotherapy have distinct patterns of ctDNA response.”

Statistical analysisFind in source

The parent trial was randomized and open-label, with blinding of the central review for BOR. Power calculations were performed to determine sample size. Inclusion/exclusion criteria are described. Outlier handling is not explicitly discussed, but the analysis population is defined. Controls are inherent in the comparison arms. Independent replication is not applicable for this exploratory analysis.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

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· 85% conf

The study design is rigorous, with clear randomization, blinding, power analysis, and prespecified inclusion criteria, though some elements are not fully detailed.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

“BOR of complete or partial response was evaluated per RECIST v.1.1 as assessed by blinded independent central review (BICR).”

MethodsFind in source

“Before sample selection for this analysis, power calculations were performed to determine the sample size needed to ensure sufficient power for testing associations with clinical outcomes.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The study design is rigorous, with clear randomization, blinding, power analysis, and prespecified inclusion criteria, though some elements are not fully detailed.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

“BOR of complete or partial response was evaluated per RECIST v.1.1 as assessed by blinded independent central review (BICR).”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“Bootstrap sampling of data from preliminary work conducted on trials outside of KEYNOTE-361 across different settings of sample sizes suggested a design targeting 125 patients per arm could achieve 80% power after correcting for multiple testing.”

Sex of participants was self-reported and baseline characteristics are provided in Extended Data Table 1. Age and other demographics are reported. Since both sexes are enrolled, sex justification is not applicable. 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· 80% conf

Biological variables are adequately reported for a human clinical trial, including sex, age, and demographics.

Evidence

“Sex of participants was determined based on self-report.”

MethodsFind in source

“Extended Data Table 1 Baseline characteristics for the analysis-eligible population Data are n (%) except otherwise noted.”

Table 1Find in source

PASSReviewer 2· 80% conf

Biological variables are adequately reported for a human clinical trial, including sex, age, and demographics.

Evidence

“Sex of participants was determined based on self-report.”

MethodsFind in source

“Key eligibility criteria included patients aged ≥18 years with previously untreated locally advanced, unresectable or metastatic urothelial carcinoma; an ECOG PS score of 0 to 2; and one or more measurable lesions per RECIST v.1.1 by investigator assessment.”

Table 1Find in source

The study protocol was approved by the institutional review board or ethics committee at each participating institution. Written informed consent was obtained from all patients. Compliance with the Declaration of Helsinki and Good Clinical Practice is stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and consent are adequately documented.

Evidence

“The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution.”

MethodsFind in source

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

MethodsFind in source

“The study was conducted in accordance with the protocol, its amendments and the ethical principles originating from the Declaration of Helsinki and Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

“The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution.”

MethodsFind in source

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

MethodsFind in source

“The study was conducted in accordance with the protocol, its amendments and the ethical principles originating from the Declaration of Helsinki and Good Clinical Practice guidelines.”

MethodsFind in source

The investigational product pembrolizumab is identified with dose and regimen. The ctDNA assay (GuardantOMNI) and WES methods are described with vendor information. Software tools are named with versions. Antibodies, cell lines, and mycoplasma testing are not applicable as this is a clinical trial without wet-lab assays.

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· 85% conf

Key resources, including the investigational drug and assay, are adequately identified.

Evidence

“pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years)”

MethodsFind in source

“ctDNA levels were assessed using the next-generation-sequencing-based GuardantOMNI assay.”

MethodsFind in source

“WES reads were aligned to reference human genome GRCh37 by using bwa mem followed by preprocessing steps including duplicate marking, indel realignment and base recalibration with Picard (v.1.114) and GATK (Genome Analysis Toolkit, v.2)”

MethodsFind in source

PASSReviewer 2· 85% conf

Key resources are adequately identified, including the investigational product, assays, and software.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

paraphrase[Methods, Outcomes and assessments]

“Plasma ctDNA was evaluated using the GH GuardantOMNI assay and has been described previously.”

MethodsFind in source

Statistical tests are named (logistic regression, Cox proportional hazards). Assumptions are handled by design. Exact p-values are reported. Effect sizes with confidence intervals are provided for key analyses. Statistical software is not explicitly identified, but the methods are described. Data presentation includes Kaplan-Meier curves and per-group n. Mathematical plausibility checks were not possible for all analyses due to lack of raw data.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes reported.

Evidence

“Associations with BOR were evaluated separately in each arm using logistic regression. Associations with PFS and OS was evaluated using Cox proportional hazards regression.”

Statistical analysisFind in source

“change with pembrolizumab ( n = 87) was more associated with BOR ( P = 4.39 × 10 −5 ) and OS ( P = 7.07 × 10 −5 )”

AbstractFind in source

“improvements in disease-free survival (hazard ratio (HR), 0.58 (95% confidence interval (CI), 0.43–0.79))”

IntroductionFind in source

PASSReviewer 2· 80% conf

Statistical analysis is rigorous with named tests, exact p-values, and effect sizes, though some assumptions are not explicitly verified.

Evidence

“Associations with BOR were evaluated separately in each arm using logistic regression. Associations with PFS and OS was evaluated using Cox proportional hazards regression.”

Statistical analysisFind in source

“change with pembrolizumab ( n = 87) was more associated with BOR ( P = 4.39 × 10 −5 ) and OS ( P = 7.07 × 10 −5 ) than chemotherapy ( n = 102; BOR: P = 1.01 × 10 −4 ; OS: P = 0.018).”

AbstractFind in source

paraphrase[Results, Discussion]

“improvements in disease-free survival (hazard ratio (HR), 0.58 (95% confidence interval (CI), 0.43–0.79)) and OS (HR, 0.59; 95% CI, 0.41–0.86) were found with atezolizumab versus observation.”

The data availability statement provides a detailed procedure for requesting data from MSD, including a website and committee review. This is a managed-access approach appropriate for clinical trial data. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no custom 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

Data availability is adequately described with a concrete access mechanism.

Evidence

“The MSD data-sharing website ( http://engagezone.msd.com/ds_documentation.php ) 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 access route, though no code is shared.

Evidence

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

Data availabilityFind in source

The trial is registered (NCT02853305). A reporting summary is mentioned. All outcomes are reported, including negative results. Limitations are discussed in detail. Conclusions are proportional to the evidence. Funding and competing interests are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Reporting is transparent with trial registration, limitations, and funding disclosures.

Evidence

“Clinical trial registration: NCT02853305 (https://clinicaltrials.gov/study/NCT02853305)”

AbstractFind in source

“our findings are limited by a moderately sized sample from KEYNOTE-361, the retrospective nature of the analysis and that the analysis occurred only in two of the three study arms.”

Discussion ¶8Find in source

“T.P. reports receiving grants from AstraZeneca, Roche, Bristol-Myers Squibb, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai;”

Competing interests sectionFind in source

PASSReviewer 2· 85% conf

Reporting is transparent with trial registration, limitations, and funding/COI statements, though no reporting guideline is explicitly mentioned.

Evidence

“Clinical trial registration: NCT02853305 (https://clinicaltrials.gov/study/NCT02853305) .”

AbstractFind in source

“Although we strategically aimed to select a representative set of patients for this substudy, our findings are limited by a moderately sized sample from KEYNOTE-361, the retrospective nature of the analysis and that the analysis occurred only in two of the three study arms.”

DiscussionFind in source

“This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.”

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

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 32 references by DOI: 29 verified — 3 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

3 minor

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

No major wording or formatting errors. 3 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor reporting gaps (statistical software, model assumptions, outlier handling) and the unverified subset of statistics, but none warrant an erratum. The copyedit issues are trivial and do not affect scientific integrity.

1.
HIGHstatistics
In the Methods, Statistical analysis section, explicitly state the statistical software used (e.g., R version, SAS version) to enhance reproducibility.
Both reviewers flagged the absence of statistical software identification, which is a reproducibility gap.
2.
HIGHstatistics
In the Methods, Statistical analysis section, explicitly verify and report assumptions of logistic and Cox regression (e.g., proportional hazards) or state that they were checked.
Reviewer 2 noted assumptions_verified as inadequate; readers need to know model assumptions were assessed.
3.
HIGHrigor
In the Methods, explicitly describe how outliers were handled in the ctDNA metrics, or state that no outliers were excluded.
Both reviewers flagged outlier_handling as reported_but_inadequate; this is a transparency gap for the biomarker analysis.
4.
MEDIUMreporting
In the Methods or Reporting Summary, mention adherence to a reporting guideline such as CONSORT or STROBE.
Reviewer 2 noted reporting_guideline as not_reported; explicit guideline adherence strengthens transparency.
5.
MEDIUMrigor
In the Methods, specify the randomization method (e.g., block randomization, stratification factors) for the parent trial.
Reviewer 2 noted randomization_method as reported_but_inadequate; this detail is relevant for the parent trial's design.
6.
MEDIUMcopyedit
In the Abstract, correct 'tumor-uniformed maxVAF' to 'tumor-uninformed maxVAF'.
Copyedit flagged an inconsistent spelling of 'uninformed'.
7.
MEDIUMcopyedit
In Extended Data Table 1, correct 'Easter Cooperative Oncology Group' to 'Eastern Cooperative Oncology Group'.
Copyedit flagged a typo in 'Eastern'.
8.
LOWcopyedit
In Methods, Statistical analysis, rephrase 'The statistical significance was based on P values which concurrently assess the strength of the association and the number of events.' to 'Statistical significance was based on P values, which reflect both the strength of association and the number of events.'
Copyedit flagged awkward phrasing that could be clarified.
9.
LOWdata code
In the Data Availability section, consider providing a direct link to the data request portal or a specific accession number for the biomarker data if possible.
Reviewer 1 suggested this to improve accessibility, though the current statement is adequate.
10.
LOWreporting
In the Discussion, clarify the clinical implications of the lack of independent value of ctDNA changes beyond radiographic response, to avoid overinterpretation.
Reviewer 1 suggested this to ensure conclusions are not overstated.
11.
LOWrigor
In the Methods, provide more detail on the stratification sampling procedure for patient selection, including the exact variables and algorithm used.
Reviewer 1 suggested this to enhance reproducibility of the patient selection process.

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Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Powles T, Chang YH, Yamamoto Y, Munoz J, Reyes-Cosmelli F, Peer A, Cohen G, Yu EY, Lorch A, Bavle A, Homet Moreno B, Markensohn J, Edmondson M, Chen C, Cristescu R, Peña C, Lunceford J, Gunduz S

Read full text (PMC)

DOI

10.1038/s41591-024-03091-7

Share this Kaimen Rigor review

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Embed this Rigor badge

<a href="https://alpha1science.com/verify/3d8b69da-22bc-4294-b1f8-348ec51bf40a" target="_blank" rel="noopener">
  <img src="https://alpha1science.com/verify/3d8b69da-22bc-4294-b1f8-348ec51bf40a/badge" alt="Kaimen Rigor review — 4.25★ (Strong), 0 critical, 3 high issues for “Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.”" width="440" height="104" style="max-width:100%;height:auto" />
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Record fingerprint

122164fad4adbe5168eb26c48c4f36ba77ca3ada61155a439cc4444c0fe8e9d4

Verify via API

Issued Aug 16, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×3−0.25★

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

Biggest issues

01Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
87.2% is unattainable for n=130 (nearest: 86.9, 87.7%)
“87.2% of patients in the chemotherapy arm”
Baseline ctDNA positivity in chemothera…Find in source
02Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
11.5% is unattainable for n=115 (nearest: 11.3, 12.2%)
“11.5% of patients in the pembrolizumab arm”
ctDNA clearance at C2 in pembrolizumab…Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
41.2% is unattainable for n=123 (nearest: 40.7, 41.5%)
“41.2% of patients in the chemotherapy arm”
ctDNA clearance at C2 in chemotherapy a…Find in source

Findings by category

201ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit3 minor suggestions

Numerical inconsistencies

2 findings · worst medium

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

3 printed percentages that do not match their own count.

Overstated conclusions

None found

Checked — nothing surfaced.

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

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 with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Determining the utility of ctDNA as a biomarker in patients with advanced or metastatic urothelial carcinoma from KEYNOTE-361 is of interest.”

IntroductionFind in source

“This exploratory analysis was conducted per a prespecified statistical analysis plan.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Determining the utility of ctDNA as a biomarker in patients with advanced or metastatic urothelial carcinoma from KEYNOTE-361 is of interest.”

IntroductionFind in source

“We used multiple methods of ctDNA analysis to robustly test the hypothesis that immunotherapy and chemotherapy have distinct patterns of ctDNA response.”

Statistical analysisFind in source

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

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· 85% conf

The study design is rigorous, with clear randomization, blinding, power analysis, and prespecified inclusion criteria, though some elements are not fully detailed.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

“BOR of complete or partial response was evaluated per RECIST v.1.1 as assessed by blinded independent central review (BICR).”

MethodsFind in source

“Before sample selection for this analysis, power calculations were performed to determine the sample size needed to ensure sufficient power for testing associations with clinical outcomes.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The study design is rigorous, with clear randomization, blinding, power analysis, and prespecified inclusion criteria, though some elements are not fully detailed.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

“BOR of complete or partial response was evaluated per RECIST v.1.1 as assessed by blinded independent central review (BICR).”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

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· 80% conf

Biological variables are adequately reported for a human clinical trial, including sex, age, and demographics.

Evidence

“Sex of participants was determined based on self-report.”

MethodsFind in source

“Extended Data Table 1 Baseline characteristics for the analysis-eligible population Data are n (%) except otherwise noted.”

Table 1Find in source

PASSReviewer 2· 80% conf

Biological variables are adequately reported for a human clinical trial, including sex, age, and demographics.

Evidence

“Sex of participants was determined based on self-report.”

MethodsFind in source

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

Ethical approvals and consent are adequately documented.

Evidence

“The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution.”

MethodsFind in source

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

MethodsFind in source

“The study was conducted in accordance with the protocol, its amendments and the ethical principles originating from the Declaration of Helsinki and Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

“The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution.”

MethodsFind in source

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

MethodsFind in source

“The study was conducted in accordance with the protocol, its amendments and the ethical principles originating from the Declaration of Helsinki and Good Clinical Practice guidelines.”

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· 85% conf

Key resources, including the investigational drug and assay, are adequately identified.

Evidence

“pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years)”

MethodsFind in source

“ctDNA levels were assessed using the next-generation-sequencing-based GuardantOMNI assay.”

MethodsFind in source

PASSReviewer 2· 85% conf

Key resources are adequately identified, including the investigational product, assays, and software.

Evidence

paraphrase[Methods, Study design]

“Patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (~2 years) plus platinum-based chemotherapy...”

paraphrase[Methods, Outcomes and assessments]

“Plasma ctDNA was evaluated using the GH GuardantOMNI assay and has been described previously.”

MethodsFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes reported.

Evidence

“Associations with BOR were evaluated separately in each arm using logistic regression. Associations with PFS and OS was evaluated using Cox proportional hazards regression.”

Statistical analysisFind in source

“change with pembrolizumab ( n = 87) was more associated with BOR ( P = 4.39 × 10 −5 ) and OS ( P = 7.07 × 10 −5 )”

AbstractFind in source

“improvements in disease-free survival (hazard ratio (HR), 0.58 (95% confidence interval (CI), 0.43–0.79))”

IntroductionFind in source

PASSReviewer 2· 80% conf

Statistical analysis is rigorous with named tests, exact p-values, and effect sizes, though some assumptions are not explicitly verified.

Evidence

“Associations with BOR were evaluated separately in each arm using logistic regression. Associations with PFS and OS was evaluated using Cox proportional hazards regression.”

Statistical analysisFind in source

“change with pembrolizumab ( n = 87) was more associated with BOR ( P = 4.39 × 10 −5 ) and OS ( P = 7.07 × 10 −5 ) than chemotherapy ( n = 102; BOR: P = 1.01 × 10 −4 ; OS: P = 0.018).”

AbstractFind in source

paraphrase[Results, Discussion]

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

Data availability is adequately described with a concrete access mechanism.

Evidence

“The MSD data-sharing website ( http://engagezone.msd.com/ds_documentation.php ) 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 access route, though no code is shared.

Evidence

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

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Reporting is transparent with trial registration, limitations, and funding disclosures.

Evidence

“Clinical trial registration: NCT02853305 (https://clinicaltrials.gov/study/NCT02853305)”

AbstractFind in source

“our findings are limited by a moderately sized sample from KEYNOTE-361, the retrospective nature of the analysis and that the analysis occurred only in two of the three study arms.”

Discussion ¶8Find in source

Competing interests sectionFind in source

PASSReviewer 2· 85% conf

Reporting is transparent with trial registration, limitations, and funding/COI statements, though no reporting guideline is explicitly mentioned.

Evidence

“Clinical trial registration: NCT02853305 (https://clinicaltrials.gov/study/NCT02853305) .”

AbstractFind in source

DiscussionFind in source

“This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.”

AcknowledgementsFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

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 32 references by DOI: 29 verified — 3 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

3 minor

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

No major wording or formatting errors. 3 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHstatistics
In the Methods, Statistical analysis section, explicitly state the statistical software used (e.g., R version, SAS version) to enhance reproducibility.
Both reviewers flagged the absence of statistical software identification, which is a reproducibility gap.
2.
HIGHstatistics
In the Methods, Statistical analysis section, explicitly verify and report assumptions of logistic and Cox regression (e.g., proportional hazards) or state that they were checked.
Reviewer 2 noted assumptions_verified as inadequate; readers need to know model assumptions were assessed.
3.
HIGHrigor
In the Methods, explicitly describe how outliers were handled in the ctDNA metrics, or state that no outliers were excluded.
Both reviewers flagged outlier_handling as reported_but_inadequate; this is a transparency gap for the biomarker analysis.
4.
MEDIUMreporting
In the Methods or Reporting Summary, mention adherence to a reporting guideline such as CONSORT or STROBE.
Reviewer 2 noted reporting_guideline as not_reported; explicit guideline adherence strengthens transparency.
5.
MEDIUMrigor
In the Methods, specify the randomization method (e.g., block randomization, stratification factors) for the parent trial.
Reviewer 2 noted randomization_method as reported_but_inadequate; this detail is relevant for the parent trial's design.
6.
MEDIUMcopyedit
In the Abstract, correct 'tumor-uniformed maxVAF' to 'tumor-uninformed maxVAF'.
Copyedit flagged an inconsistent spelling of 'uninformed'.
7.
MEDIUMcopyedit
In Extended Data Table 1, correct 'Easter Cooperative Oncology Group' to 'Eastern Cooperative Oncology Group'.
Copyedit flagged a typo in 'Eastern'.
8.
LOWcopyedit
In Methods, Statistical analysis, rephrase 'The statistical significance was based on P values which concurrently assess the strength of the association and the number of events.' to 'Statistical significance was based on P values, which reflect both the strength of association and the number of events.'
Copyedit flagged awkward phrasing that could be clarified.
9.
LOWdata code
In the Data Availability section, consider providing a direct link to the data request portal or a specific accession number for the biomarker data if possible.
Reviewer 1 suggested this to improve accessibility, though the current statement is adequate.
10.
LOWreporting
In the Discussion, clarify the clinical implications of the lack of independent value of ctDNA changes beyond radiographic response, to avoid overinterpretation.
Reviewer 1 suggested this to ensure conclusions are not overstated.
11.
LOWrigor
In the Methods, provide more detail on the stratification sampling procedure for patient selection, including the exact variables and algorithm used.
Reviewer 1 suggested this to enhance reproducibility of the patient selection process.

Full text (61,838 chars)Analyzed: Aug 16, 2026