Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Name: Kaimen Rigor review — Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.
Item: Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.
Rating: 96
Author: Alpha1

Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O'Reilly EM, Meyerhardt JA

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Kaimen Rigor review — 2.25★ (Weak), 0 critical, 2 high issues for “Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.”

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

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Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

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DOI

10.1056/NEJMoa2403991

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Paper source

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

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 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is progression-free survival (PFS) by blinded independent central review, which is a surrogate for overall survival. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking PFS to a meaningful clinical outcome in this setting. Overall survival data are immature and not significantly different.
“The primary endpoint was progression-free survival by blinded independent central review.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found · partly checked 06Copyedit5 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a rigorously designed and well-reported phase 3 clinical trial with strong methodology across most dimensions. The main weakness is the lack of a clear data availability statement and repository deposit, which is a common but important reporting gap.

Both reviewers independently scored all eight dimensions and agreed on all statuses, with only minor differences in evidence detail. The study type is interventional, consistent across reviewers. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded from scoring.

Numerical inconsistencies

1 finding · worst low

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.

Internal contradictions in the reported numbersAssessed

Recomputed 4 tests: 4 consistent, 0 inconsistent; 2 recomputed directly from the reported test statistics, 2 via agent-written checks.

Overstated conclusions

1 finding · worst high

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.

Efficacy rests on an unvalidated surrogate endpointAssessed

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

Premise concern: surrogate not validated for clinical benefit.

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

1 finding · 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.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior work on NET pathogenesis, antiangiogenic agents, and a phase II trial of cabozantinib, establishing the premise. The rationale linking cabozantinib's mechanism to NET treatment is clear. Limitations of prior research are implicitly addressed by the trial design, though not explicitly discussed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on NET treatment and cabozantinib's activity, and provides a logical rationale for the trial.

Evidence

“Cabozantinib is an oral small-molecule inhibitor of multiple tyrosine kinases including VEGF receptors, MET, AXL, and RET. Clinical activity of cabozantinib was demonstrated in a phase II trial that enrolled patients with advanced epNET or pNET.”

Introduction ¶1Find in source

“Based on these results, we conducted a randomized, double-blinded, placebo-controlled study to evaluate the efficacy of cabozantinib in patients with previously treated, progressive epNET or pNET (CABINET; Alliance A021602).”

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

PASSReviewer 2· 90% conf

The introduction establishes a clear scientific rationale for testing cabozantinib in NET, citing prior evidence of antiangiogenic activity and a phase II trial, and the hypothesis follows logically.

Evidence

paraphrase[Introduction, paragraph 2]

“Antiangiogenic agents targeting vascular endothelial growth factor (VEGF) and its receptors have demonstrated activity in the treatment of NET. ... Clinical activity of cabozantinib was demonstrated in a phase II trial that enrolled patients with advanced epNET or pNET.”

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

Randomization method (2:1 ratio) and stratification factors are described. Blinding is double-blinded with BICR. Power analysis is detailed with target sample sizes and hazard ratios. Inclusion/exclusion criteria are pre-specified. Outlier handling is not explicitly described, but the analysis population (ITT) and missing data approach are defined. Controls are appropriate (placebo). Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with clear randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Trial Design and Treatments]

“Within each cohort, patients were randomly assigned in a 2:1 ratio to receive cabozantinib or placebo. Randomization was stratified by concurrent somatostatin analogue use and primary tumor site...”

“Patients continued blinded treatment until disease progression, unacceptable toxicity, or withdrawal of consent.”

MethodsFind in source

paraphrase[Methods, Statistical Analysis]

“The trial was designed with targeted sample sizes of 210 and 185 patients in the epNET and pNET cohorts, respectively, to provide 90% power using stratified one-sided log-rank tests to detect true hazard ratios of 0.583 and 0.568...”

PASSReviewer 2· 95% conf

The trial design is rigorous: randomized, double-blinded, placebo-controlled, with a pre-specified sample size, stratification, and a clear primary endpoint assessed by blinded independent central review.

Evidence

paraphrase[Methods, Trial Design and Treatments]

“Patients continued blinded treatment until disease progression, unacceptable toxicity, or withdrawal of consent.”

MethodsFind in source

paraphrase[Methods, Statistical Analysis]

Sex is reported for both cohorts. Age and health status (ECOG PS) are reported. Demographics are comprehensive. 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 (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported for both cohorts, including age, sex, ECOG performance status, and tumor characteristics.

Evidence

“Female Sex, n (%) | 74 (55) | 31 (45)”

Table 1AFind in source

“Age, years, median (range) | 66 (28–86) | 66 (30–82)”

Table 1AFind in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported for both cohorts, including age, sex, ECOG performance status, tumor grade, and prior therapies.

Evidence

“Female Sex, n (%) | 74 (55) | 31 (45)”

Table 1AFind in source

“Age, years, median (range) | 66 (28–86) | 66 (30–82)”

Table 1AFind in source

The protocol was approved by the NCI central IRB. Written informed consent was obtained from all participants. The trial was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and consent are clearly documented, including IRB approval, informed consent, and regulatory compliance.

Evidence

“The protocol was approved by the NCI central institutional review board (CIRB).”

MethodsFind in source

“All participants provided written informed consent before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial reports approval by the NCI central IRB, adherence to the Declaration of Helsinki and ICH-GCP, and written informed consent from all participants.

Evidence

“The protocol was approved by the NCI central institutional review board (CIRB).”

MethodsFind in source

“All participants provided written informed consent before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines.”

MethodsFind in source

Cabozantinib is named with dose and regimen. The placebo is described. Statistical software is not explicitly named, but the analysis methods are described. No other biological/chemical resources are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (cabozantinib) is adequately identified, and statistical software is identified.

Evidence

“Patients received cabozantinib (60 mg) or placebo orally once daily.”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational product (cabozantinib) is identified with dose and regimen, and the trial registration number is provided. No other key biological resources are applicable.

Evidence

“Patients received cabozantinib (60 mg) or placebo orally once daily.”

MethodsFind in source

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

FundingFind in source

Tests are named (stratified log-rank, Cox regression, chi-square). Assumptions are handled by design (stratified Cox). Exact p-values are reported (p<0.001). Effect sizes with CIs are reported. Software is not explicitly identified. Data presentation includes Kaplan-Meier curves and tables with per-group n. Mathematical plausibility checks are not applicable for large-N continuous outcomes.

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· 90% conf

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

Evidence

“Hazard ratios (HR) were estimated through stratified Cox regression models and stratified log-rank tests calculated using stratification factors at randomization per the protocol design.”

Statistical analysisFind in source

“stratified HR = 0.38, 95% CI: 0.25–0.59; p<0.001”

ResultsFind in source

“Median progression-free survival was 8.4 months (95% CI: 7.6–12.7 months) with cabozantinib and 3.9 months (95% CI: 3.0–5.7 months) with placebo.”

ResultsFind in source

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals reported. The analysis follows the intention-to-treat principle and uses stratified Cox models and log-rank tests.

Evidence

“Hazard ratios (HR) were estimated through stratified Cox regression models and stratified log-rank tests calculated using stratification factors at randomization per the protocol design.”

Statistical analysisFind in source

“stratified HR = 0.38, 95% CI: 0.25–0.59; p<0.001”

ResultsFind in source

“Median progression-free survival was 8.4 months (95% CI: 7.6–12.7 months) with cabozantinib and 3.9 months (95% CI: 3.0–5.7 months) with placebo.”

ResultsFind in source

The paper mentions that the protocol is available at NEJM.org, but does not provide a clear data availability statement for the clinical data. No repository deposit or accession numbers are provided. Code sharing is not applicable as no bespoke code is described.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement is present but vague, and no data repository or code sharing is mentioned.

Evidence

“The protocol is available at nejm.org (https://nejm.org)”

Supplementary materialFind in source

absence[Whole paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

The paper does not include a data availability statement, and no data or code repositories are mentioned. This is a common omission in clinical trial publications but is still a reporting gap.

Evidence

absence[Entire paper]

No data availability statement is present.

Methods are detailed enough for replication. Trial registration number is provided (NCT03375320). Reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like structure. All pre-specified outcomes are reported. Limitations are discussed. Conclusions are proportional. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent with detailed methods, trial registration, and discussion of limitations.

Evidence

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

Supplementary materialFind in source

“The early termination of the trial based on interim analysis results could potentially lead to overestimation of treatment effect.”

Discussion ¶3Find in source

paraphrase[Funding section]

“Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882...”

PASSReviewer 2· 90% conf

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

Evidence

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

FundingFind in source

“The early termination of the trial based on interim analysis results could potentially lead to overestimation of treatment effect.”

Discussion ¶3Find in source

paraphrase[Funding section]

“Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 ... Also supported in part by Exelixis.”

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

Broken references and links

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.

Checked 31 references by DOI: 28 verified — 3 no DOI (shown, not verified).

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and methodologically sound, with no major integrity concerns. An informed reader should weigh the minor reporting gaps (data availability, statistical software identification, reporting guideline) and the early termination of the trial as potential limitations, but these do not undermine the core findings.

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying how de-identified patient data can be accessed (e.g., via the Alliance or a data-sharing platform like Vivli) and any conditions.
The current statement is vague or absent, and a clear data availability statement is expected for clinical trial publications.
2.
HIGHdata code
Deposit the statistical analysis code (e.g., SAS or R scripts) in a public repository with a DOI to enhance reproducibility.
Sharing analysis code improves transparency and allows independent verification of the reported results.
3.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or cover letter, and include the CONSORT flow diagram in the supplement.
Explicitly stating reporting guideline adherence demonstrates transparency and completeness.
4.
MEDIUMstatistics
Identify the statistical software (e.g., SAS version, R version) used for analyses in the Statistical Analysis section.
Naming the software version is a standard reporting requirement and aids reproducibility.
5.
MEDIUMreporting
Clarify the handling of misallocated patients in the primary analysis (e.g., sensitivity analysis) in the Statistical Analysis section.
The paper mentions misallocation of patients between cohorts, and clarifying the analysis approach would improve transparency.
6.
LOWcopyedit
Fix the inconsistent formatting of percentage ranges in the Abstract (e.g., change '62–65%' to '62%–65%').
Consistent formatting improves readability and professionalism.
7.
LOWcopyedit
Clarify whether '111 progression events by BICR' refers to the number of events or the number of patients with events in the Results section.
Ambiguity in event counting could confuse readers.
8.
LOWcopyedit
Specify the journal policy or provide a reference for the statement 'Two-sided P values are reported in accordance with Journal policy' in the Methods.
Clarifying the policy reference improves transparency.

Full text (36,681 chars)Analyzed: Aug 16, 2026

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Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Read full text (PMC)

DOI

10.1056/NEJMoa2403991

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Record fingerprint

2090ac9cbc0d2cc8e6cdd86a1d33755f7ebaeb1115e8024608ffa5eda9db203a

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

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is progression-free survival (PFS) by blinded independent central review, which is a surrogate for overall survival. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking PFS to a meaningful clinical outcome in this setting. Overall survival data are immature and not significantly different.
“The primary endpoint was progression-free survival by blinded independent central review.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found · partly checked 06Copyedit5 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 4 tests: 4 consistent, 0 inconsistent; 2 recomputed directly from the reported test statistics, 2 via agent-written checks.

Overstated conclusions

1 finding · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed

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

Premise concern: surrogate not validated for clinical benefit.

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior research on NET treatment and cabozantinib's activity, and provides a logical rationale for the trial.

Evidence

Introduction ¶1Find in source

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

PASSReviewer 2· 90% conf

The introduction establishes a clear scientific rationale for testing cabozantinib in NET, citing prior evidence of antiangiogenic activity and a phase II trial, and the hypothesis follows logically.

Evidence

paraphrase[Introduction, paragraph 2]

Introduction ¶2Find in source

absence[Introduction]

Limitations of prior research are not explicitly discussed.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with clear randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Trial Design and Treatments]

“Patients continued blinded treatment until disease progression, unacceptable toxicity, or withdrawal of consent.”

MethodsFind in source

paraphrase[Methods, Statistical Analysis]

PASSReviewer 2· 95% conf

Evidence

paraphrase[Methods, Trial Design and Treatments]

“Patients continued blinded treatment until disease progression, unacceptable toxicity, or withdrawal of consent.”

MethodsFind in source

paraphrase[Methods, Statistical Analysis]

Sex is reported for both cohorts. Age and health status (ECOG PS) are reported. Demographics are comprehensive. 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 (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported for both cohorts, including age, sex, ECOG performance status, and tumor characteristics.

Evidence

“Female Sex, n (%) | 74 (55) | 31 (45)”

Table 1AFind in source

“Age, years, median (range) | 66 (28–86) | 66 (30–82)”

Table 1AFind in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported for both cohorts, including age, sex, ECOG performance status, tumor grade, and prior therapies.

Evidence

“Female Sex, n (%) | 74 (55) | 31 (45)”

Table 1AFind in source

“Age, years, median (range) | 66 (28–86) | 66 (30–82)”

Table 1AFind in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and consent are clearly documented, including IRB approval, informed consent, and regulatory compliance.

Evidence

“The protocol was approved by the NCI central institutional review board (CIRB).”

MethodsFind in source

“All participants provided written informed consent before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial reports approval by the NCI central IRB, adherence to the Declaration of Helsinki and ICH-GCP, and written informed consent from all participants.

Evidence

“The protocol was approved by the NCI central institutional review board (CIRB).”

MethodsFind in source

“All participants provided written informed consent before enrollment.”

MethodsFind in source

“The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation 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 identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (cabozantinib) is adequately identified, and statistical software is identified.

Evidence

“Patients received cabozantinib (60 mg) or placebo orally once daily.”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational product (cabozantinib) is identified with dose and regimen, and the trial registration number is provided. No other key biological resources are applicable.

Evidence

“Patients received cabozantinib (60 mg) or placebo orally once daily.”

MethodsFind in source

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

FundingFind 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· 90% conf

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

Evidence

“Hazard ratios (HR) were estimated through stratified Cox regression models and stratified log-rank tests calculated using stratification factors at randomization per the protocol design.”

Statistical analysisFind in source

“stratified HR = 0.38, 95% CI: 0.25–0.59; p<0.001”

ResultsFind in source

“Median progression-free survival was 8.4 months (95% CI: 7.6–12.7 months) with cabozantinib and 3.9 months (95% CI: 3.0–5.7 months) with placebo.”

ResultsFind in source

PASSReviewer 2· 90% conf

Evidence

“Hazard ratios (HR) were estimated through stratified Cox regression models and stratified log-rank tests calculated using stratification factors at randomization per the protocol design.”

Statistical analysisFind in source

“stratified HR = 0.38, 95% CI: 0.25–0.59; p<0.001”

ResultsFind in source

“Median progression-free survival was 8.4 months (95% CI: 7.6–12.7 months) with cabozantinib and 3.9 months (95% CI: 3.0–5.7 months) with placebo.”

ResultsFind in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement is present but vague, and no data repository or code sharing is mentioned.

Evidence

“The protocol is available at nejm.org (https://nejm.org)”

Supplementary materialFind in source

absence[Whole paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

The paper does not include a data availability statement, and no data or code repositories are mentioned. This is a common omission in clinical trial publications but is still a reporting gap.

Evidence

absence[Entire paper]

No data availability statement is present.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent with detailed methods, trial registration, and discussion of limitations.

Evidence

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

Supplementary materialFind in source

“The early termination of the trial based on interim analysis results could potentially lead to overestimation of treatment effect.”

Discussion ¶3Find in source

paraphrase[Funding section]

“Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882...”

PASSReviewer 2· 90% conf

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

Evidence

“Trial registration number: NCT03375320 (https://clinicaltrials.gov/ct2/show/NCT03375320)”

FundingFind in source

“The early termination of the trial based on interim analysis results could potentially lead to overestimation of treatment effect.”

Discussion ¶3Find in source

paraphrase[Funding section]

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

Broken references and links

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.

Checked 31 references by DOI: 28 verified — 3 no DOI (shown, not verified).

Copyediting

5 minor

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

No major wording or formatting errors. 5 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying how de-identified patient data can be accessed (e.g., via the Alliance or a data-sharing platform like Vivli) and any conditions.
The current statement is vague or absent, and a clear data availability statement is expected for clinical trial publications.
2.
HIGHdata code
Deposit the statistical analysis code (e.g., SAS or R scripts) in a public repository with a DOI to enhance reproducibility.
Sharing analysis code improves transparency and allows independent verification of the reported results.
3.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or cover letter, and include the CONSORT flow diagram in the supplement.
Explicitly stating reporting guideline adherence demonstrates transparency and completeness.
4.
MEDIUMstatistics
Identify the statistical software (e.g., SAS version, R version) used for analyses in the Statistical Analysis section.
Naming the software version is a standard reporting requirement and aids reproducibility.
5.
MEDIUMreporting
Clarify the handling of misallocated patients in the primary analysis (e.g., sensitivity analysis) in the Statistical Analysis section.
The paper mentions misallocation of patients between cohorts, and clarifying the analysis approach would improve transparency.
6.
LOWcopyedit
Fix the inconsistent formatting of percentage ranges in the Abstract (e.g., change '62–65%' to '62%–65%').
Consistent formatting improves readability and professionalism.
7.
LOWcopyedit
Clarify whether '111 progression events by BICR' refers to the number of events or the number of patients with events in the Results section.
Ambiguity in event counting could confuse readers.
8.
LOWcopyedit
Specify the journal policy or provide a reference for the statement 'Two-sided P values are reported in accordance with Journal policy' in the Methods.
Clarifying the policy reference improves transparency.

Full text (36,681 chars)Analyzed: Aug 16, 2026