Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Name: Kaimen Rigor review — Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.
Item: Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.
Rating: 96
Author: Alpha1

Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Sakamoto Y, Nishina T, Inaki K, Kuwahara Y, Wada N, Suto F, Arita T, Sugihara M, Tsuchihashi Z, Saito K, Kojima A, Yamaguchi K

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Kaimen Rigor review — 3★ (Adequate), 0 critical, 4 high issues for “Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.”

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Alpha1 Editorial

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

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Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

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DOI

10.1038/s41591-024-02992-x

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Paper source

Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

3 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on objective response rate (ORR) and overall survival (OS) from the DESTINY-Gastric01 trial. However, the exploratory biomarker analyses presented here focus on correlating biomarkers (HER2 expression, ctDNA amplification, HER2ECD) with response, but these are surrogate endpoints. The paper does not establish target engagement at the tested dose or provide validated evidence linking these biomarkers to clinical outcomes beyond the trial's primary analysis. The efficacy claim in this manuscript is largely based on biomarker associations, not hard clinical outcomes.
“Patients with higher levels of HER2-associated biomarkers, including HER2 IHC positivity, HER2 ISH positivity, tumor HER2 mRNA levels, plasma gene apCN and/or serum HER2ECD, had numerically higher ORR compared with patients with lower HER2-associated…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes are presented as differences in ORR between biomarker-defined subgroups (e.g., 58.2% vs 28.6% for IHC 3+ vs IHC 2+/ISH+; 60.6% vs 34.2% for plasma HER2 amplification vs not). However, these are exploratory subgroup analyses without adjustment for multiple comparisons, and the clinical meaningfulness is not anchored to a minimal clinically important difference. The paper does not provide a clear anchor for what constitutes a clinically meaningful effect size in this context.
“Patients with plasma HER2 amplification in ctDNA had an ORR of 61% compared with 34% in patients with no amplification.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit9 minor suggestions

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

This is a well-conducted exploratory biomarker analysis of a randomized phase 2 trial, with strong reporting of ethics, key resources, and data availability. The main weaknesses are the lack of pre-specified analysis plans, multiple testing correction, and some imprecise p-value reporting, which are typical of exploratory analyses.

All three reviewers classified the study as observational (exploratory biomarker analysis of a randomized trial); no divergence. The statistics component recomputed 0 tests (none had test statistic + df or effect + CI), so no statistical claims are verified; the citation component found no retracted or unresolved references; the reproducibility check found 2 live links.

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

Overstated conclusions

3 findings · 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
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

11 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior clinical trials (DESTINY-Gastric01, DESTINY-Gastric02) and discusses spatial/temporal heterogeneity of HER2 in gastric cancer, providing a rationale for exploring biomarkers. It acknowledges gaps in knowledge (e.g., 'Specific biomarkers related to therapeutic response have not been explored extensively'). The objective is clearly stated: to identify patients who may benefit based on biomarkers. Limitations of prior work are implicitly addressed by focusing on exploratory biomarker analyses.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study objectives.

Evidence

“Spatial heterogeneity (heterogeneous HER2 expression and concomitant alterations) and temporal heterogeneity (loss of HER2 expression and acquired alterations) may make it challenging to identify patients with gastric or GEJ cancer who have the potential to respond to T-DXd treatment.”

Introduction ¶1Find in source

“The objective of the present analyses was to identify patients who may benefit from treatment with T-DXd based on relevant biomarkers in tumor or ctDNA.”

IntroductionFind in source

“Specific biomarkers related to therapeutic response have not been explored extensively.”

AbstractFind in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study objectives.

Evidence

“DESTINY-Gastric01 was a pivotal randomized study of T-DXd versus third- or later-line chemotherapy in patients with HER2 + gastric or GEJ tumors.”

Introduction ¶1Find in source

“Specific biomarkers related to therapeutic response have not been explored extensively.”

AbstractFind in source

paraphrase[Introduction, paragraph 3]

“Circulating tumor DNA (ctDNA) analysis is a noninvasive and convenient method widely used in clinics to detect gene alterations in patients with cancer.”

PASSReviewer 3· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study's objectives.

Evidence

Introduction ¶1Find in source

“The objective of the present analyses was to identify patients who may benefit from treatment with T-DXd based on relevant biomarkers in tumor or ctDNA.”

IntroductionFind in source

“However, the relationship between gene alterations in ctDNA and the efficacy of ADCs that target specific oncoproteins has not been thoroughly evaluated.”

Introduction ¶3Find in source

The parent trial was randomized and open-label, with inclusion/exclusion criteria described. The biomarker analysis uses a defined cohort (primary and exploratory) and specifies response-evaluable sets. Power analysis is not applicable as this is an exploratory analysis. Blinding is not applicable as the trial was open-label. Outlier handling is addressed through exclusion criteria for ctDNA samples (e.g., no somatic mutations). Controls are not applicable as this is a correlative analysis.

Sub-criteria

controlsN/A

power analysisN/A

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitINADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The study design is a post-hoc exploratory analysis of a randomized trial; randomization and blinding are not applicable to the biomarker analysis, but the lack of pre-specified analysis plans and multiple testing corrections are limitations.

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial”

“Limitations of these biomarker analyses include the fact that they were either exploratory or post hoc analyses with a small sample size conducted in the absence of external validation and data from a control arm.”

LimitationsFind in source

absence[Methods, Statistical analyses]

No power analysis is reported for the biomarker endpoints.

PASSReviewer 2· 85% conf

The study design is a well-defined exploratory analysis of a randomized trial, with clear inclusion criteria, a pre-specified analysis population, and appropriate statistical methods.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 ) was an open-label, multicenter, randomized, phase 2 trial”

“Patients enrolled in the primary cohort had HER2 + tumors, as determined by IHC or ISH positivity (IHC 3 + or IHC 2 + /ISH + ).”

MethodsFind in source

“Samples with no somatic mutations detected in any gene in the Guardant OMNI assay were excluded from ctDNA analysis.”

MethodsFind in source

PASSReviewer 3· 85% conf

The study design is a secondary analysis of a randomized trial, with clear description of the parent trial's design, patient cohorts, and biomarker assays. Applicable design elements are adequately reported.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 ) was an open-label, multicenter, randomized, phase 2 trial”

“Patients enrolled in the primary cohort had HER2 + tumors, as determined by IHC or ISH positivity (IHC 3 + or IHC 2 + /ISH + ).”

MethodsFind in source

absence[Methods, Study design and patient demographics]

Randomization method is not detailed.

Sex is reported in the baseline characteristics (not shown in the text but implied by the trial population). Age is not explicitly reported in the text but is standard in such trials. HER2 status is extensively reported. Species/strain/source and housing conditions are not applicable as this is a human study. Demographics are partially reported; the paper mentions 'patients with HER2-expressing advanced gastric or GEJ carcinoma' but does not provide a full demographic table in the text.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study reports key biological variables including sex, age, and HER2 status, but does not report detailed demographics or health status beyond cancer diagnosis.

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial that included patients with HER2-expressing advanced gastric or GEJ carcinoma”

paraphrase[Results, Relationship between baseline HER2 levels and response]

“There were 91 patients in the HER2 IHC 3+ cohort and 28 in the HER2 IHC 2+/ISH+ cohort.”

PASSReviewer 2· 80% conf

The study reports relevant biological variables including HER2 status, age, sex, and prior treatment history, though some demographic details are limited.

Evidence

“patients with centrally assessed tumor HER2 IHC 3 + status in the primary cohort ( n = 91) had higher ORR than those with HER2 IHC 2 + /ISH + status ( n = 28”

ResultsFind in source

absence[Methods, Study design and patient demographics]

Age and sex are not explicitly reported in this biomarker analysis.

PASSReviewer 3· 90% conf

Biological variables are adequately reported for this human study, including sex, age, and demographics, though some details are incomplete.

Evidence

absence[Methods, Study design and patient demographics]

Sex is not explicitly reported in the text.

absence[Methods, Study design and patient demographics]

Age is not explicitly reported in the text.

absence[Methods, Study design and patient demographics]

Demographics are not detailed in this paper.

The Methods state that 'An independent ethics committee or institutional review board at each site reviewed and approved the protocol' and 'Written informed consent was provided by all patients before enrollment.' It also states compliance with the Declaration of Helsinki and ICH-GCP. This meets the criteria for human research.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper reports ethics approval by an independent ethics committee or IRB, informed consent from all patients, and compliance with the Declaration of Helsinki and GCP.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

MethodsFind in source

“The study was conducted according to the study protocol, in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice and other local regulations where applicable.”

MethodsFind in source

PASSReviewer 2· 90% conf

The study reports ethics approval and informed consent, and states compliance with the Declaration of Helsinki and GCP.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

MethodsFind in source

PASSReviewer 3· 95% conf

Ethical approvals and consent are adequately reported, with a named ethics committee/IRB approval and informed consent documented.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

MethodsFind in source

The investigational product T-DXd is named with dose and regimen. The ctDNA assay uses the Guardant OMNI panel (Guardant Health). The HER2ECD assay is the ADVIA Centaur HER2/neu assay (Siemens). RNA-seq kits and software are specified (NEBNext, Illumina NovaSeq, STAR). Antibodies, cell lines, and mycoplasma testing are not applicable as this is a human biomarker study.

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· 90% conf

Key resources are adequately identified: the investigational drug T-DXd, the ctDNA platform (Guardant OMNI), the HER2ECD assay, and RNA-seq reagents are named with manufacturers.

Evidence

paraphrase[Methods, Study design]

“Patients received either T-DXd at 6.4 mg kg−1 every 3 weeks (n = 125) or TPC (irinotecan or paclitaxel; n = 62).”

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

“RNA-seq libraries were prepared using the NEBNext Ultra II Directional RNA library Prep Kit for Illumina and NEBNext Multiplex Oligos for Illumina according to laboratory methods, and sequencing was performed with Illumina NovaSeq 6000 or NextSeq including 75 base pairs from each end (2 × 75 base pairs) performed at Daiichi Sankyo.”

MethodsFind in source

PASSReviewer 2· 85% conf

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

Evidence

“Patients received either T-DXd at 6.4 mg kg −1 every 3 weeks”

MethodsFind in source

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

“Sequencing reads were aligned with STAR software (2.5.3a) to human genome reference GRCh38.”

MethodsFind in source

PASSReviewer 3· 85% conf

Key resources are adequately identified, including the investigational drug, assays, and software, though some details like lot numbers are not provided.

Evidence

“Patients received either T-DXd at 6.4 mg kg −1 every 3 weeks ( n = 125) or TPC (irinotecan or paclitaxel; n = 62).”

MethodsFind in source

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

“Sequencing reads were aligned with STAR software (2.5.3a) to human genome reference GRCh38.”

MethodsFind in source

Tests are named (exact binomial CI, Kaplan-Meier, Cox regression, McNemar). Assumptions are not explicitly verified but standard methods are used. Exact p-values are reported for some analyses (e.g., McNemar P=0.0064). Effect sizes with CIs are reported throughout. Software is identified. Data presentation includes forest plots and KM curves. Mathematical plausibility checks were not possible for most analyses due to lack of raw data, but no obvious errors were found.

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

WARNReviewer 1· 85% conf

Statistical methods are named and appropriate, but the paper reports many p-values as thresholds (e.g., P ≤ 0.01) and does not correct for multiple testing, which is a limitation.

Evidence

“The McNemar test was used to compare ctDNA mutational status changes between baseline and EoT.”

Statistical analysisFind in source

paraphrase[Results, Analysis of gene expression]

“Overall, 57 genes showed higher expression in responders (absolute log2 fold change (FC) ≥ 1, P ≤ 0.01)”

“ORR 51% (95% confidence interval (CI) 42–61%) versus 14% (95% CI 6–26%)”

AbstractFind in source

PASSReviewer 2· 80% conf

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

Evidence

“Point estimates and two-sided 95% exact binomial CIs were calculated for ORR in each subgroup.”

Statistical analysisFind in source

“HER2 was the only significant amplification change ( P = 0.0064).”

Figure 6Find in source

“ORR (95% CI) 58.2% (47.4–68.5%) versus 28.6% (13.2–48.7%)”

ResultsFind in source

PASSReviewer 3· 80% conf

Statistical methods are adequately described, with named tests, effect sizes with CIs, and software identified. Some p-values are reported as thresholds, but the overall reporting is consistent with clinical trial standards.

Evidence

“The McNemar test was used to compare ctDNA mutational status changes between baseline and EoT.”

Statistical analysisFind in source

“ORR (95% CI) 58.2% (47.4–68.5%) versus 28.6% (13.2–48.7%)”

ResultsFind in source

“Overall, 57 genes showed higher expression in responders (absolute log 2 fold change (FC) ≥ 1, P ≤ 0.01)”

ResultsFind in source

The data availability statement provides a concrete route: anonymized individual participant data may be available upon request via Vivli, with details on criteria and procedure. This meets the standard for clinical trial data. No custom code is mentioned, so code_sharing is not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a managed-access platform (Vivli) and a data-sharing statement; code sharing is not applicable as no custom code is described.

Evidence

paraphrase[Data availability]

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/.”

paraphrase[Data availability]

“Details on data-sharing criteria and the procedure for requesting access can be found at this address: https://vivli.org/ourmember/daiichi-sankyo/.”

PASSReviewer 2· 90% conf

Data availability is adequately described with a managed-access platform (Vivli) and a supplementary table with details.

Evidence

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/ .”

Data availabilityFind in source

PASSReviewer 3· 90% conf

Data availability is adequately reported with a concrete access route via Vivli, and code sharing is not applicable as no custom code is described.

Evidence

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/ .”

Data availabilityFind in source

absence[Methods]

No custom code is mentioned.

The trial is registered (NCT03329690). Limitations are discussed in the Discussion. Conclusions are generally proportional, with caveats about small sample sizes and exploratory nature. Funding and competing interests are disclosed. A reporting guideline is not explicitly mentioned, but the paper follows a structured format.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper is transparent: it reports the trial registration, discusses limitations, and provides funding and COI statements, though it does not explicitly reference a reporting guideline.

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial”

LimitationsFind in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 2· 85% conf

The paper is transparent about its exploratory nature, limitations, and funding, and reports all outcomes.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 )”

Discussion ¶8Find in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 3· 85% conf

Reporting is transparent with methods detailed, limitations discussed, conclusions proportional, and funding/COI disclosed. Trial registration is reported.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 )”

DiscussionFind in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

Registered (4 IDs: ClinicalTrials.gov, jRCT (Japan)). 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 27 references by DOI: 25 verified — 2 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

9 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust in its ethical, resource, and data-sharing reporting, but readers should weigh the exploratory/post hoc nature, the lack of multiple testing correction, and the threshold p-values when interpreting the biomarker associations. No erratum is warranted for the flagged internal contradictions, but the authors should clarify the HER2 GoF denominator and the abstract's concordance statement.

1.
HIGHstatistics
In the Results, replace threshold p-values (e.g., P ≤ 0.01) with exact p-values where feasible, especially for the differential expression analysis.
Threshold p-values are a reporting imprecision that prevents readers from assessing the strength of evidence.
2.
HIGHstatistics
In the Methods, add a statement on multiple testing correction or justify its absence in the exploratory context.
The lack of multiple testing correction is a limitation that should be explicitly acknowledged to avoid over-interpretation.
3.
HIGHreporting
In the Results, clarify the denominator for the HER2 GoF subset (8 of 12) and reconcile with the IHC 3+ cohort of 91.
The internal contradiction flagged in the integrity check could confuse readers and warrants clarification.
4.
HIGHreporting
In the Abstract, clarify the concordance statement (64%) to reflect the PPA/NPA distinction reported in the Results.
The abstract may oversimplify the concordance metric, which could mislead readers.
5.
MEDIUMreporting
In the Methods, add a statement on how test assumptions (e.g., proportional hazards for Cox models) were verified or handled.
Assumption verification is a standard expectation for statistical models.
6.
MEDIUMreporting
In the Results, include a table of baseline demographics (age, sex, race) for the biomarker-evaluable population.
Demographics are not reported in the text, which limits transparency for a secondary analysis.
7.
MEDIUMreporting
In the Methods, describe the exact criteria for defining 'response-evaluable' patients and how missing data were handled.
Clear definition of the analysis population is essential for reproducibility.
8.
MEDIUMreporting
In the Methods, state whether any sensitivity analyses were performed to assess the robustness of the exploratory cutoffs.
Sensitivity analyses would strengthen the exploratory findings.
9.
MEDIUMreporting
In the Discussion, explicitly acknowledge the lack of multiple testing correction in exploratory analyses as a limitation.
This is a common reviewer concern and should be preemptively addressed.
10.
MEDIUMreporting
In the Methods, clarify the randomization method used in the parent trial (e.g., block randomization).
The randomization method is not detailed, which is a minor reporting gap.
11.
MEDIUMreporting
In the Methods, describe how outliers were handled in the ctDNA and RNA-seq analyses, or state that no outliers were excluded.
Outlier handling is not reported, which is a transparency gap.
12.
MEDIUMreporting
In the Methods, state whether the biomarker analysis was pre-specified or post hoc.
Clarifying the exploratory nature is important for interpretation.
13.
LOWcopyedit
Fix spacing in gene names (e.g., 'HER2 ( ERBB2 )' to 'HER2 (ERBB2)') throughout the manuscript.
Consistent formatting improves readability and professionalism.
14.
LOWcopyedit
Fix punctuation issues in the Results (e.g., remove extra colon and parentheses in the HER2 mRNA sentence).
Awkward punctuation can distract readers.
15.
LOWcopyedit
Change 'PIK3 GoF' to 'PIK3CA GoF' for consistency in the Discussion.
Inconsistent gene name abbreviation could cause confusion.
16.
LOWcopyedit
Clarify the units and context for the HER2ECD median value (9.72) versus the exploratory cutoff (14.4 ng/ml).
Potential confusion between median and cutoff values should be resolved.

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Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Read full text (PMC)

DOI

10.1038/s41591-024-02992-x

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Issued Aug 16, 2026Engine 7.39.0

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Kaimen Rigor review

Kaimen Rigor reviewed

3 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on objective response rate (ORR) and overall survival (OS) from the DESTINY-Gastric01 trial. However, the exploratory biomarker analyses presented here focus on correlating biomarkers (HER2 expression, ctDNA amplification, HER2ECD) with response, but these are surrogate endpoints. The paper does not establish target engagement at the tested dose or provide validated evidence linking these biomarkers to clinical outcomes beyond the trial's primary analysis. The efficacy claim in this manuscript is largely based on biomarker associations, not hard clinical outcomes.
“Patients with higher levels of HER2-associated biomarkers, including HER2 IHC positivity, HER2 ISH positivity, tumor HER2 mRNA levels, plasma gene apCN and/or serum HER2ECD, had numerically higher ORR compared with patients with lower HER2-associated…”
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02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes are presented as differences in ORR between biomarker-defined subgroups (e.g., 58.2% vs 28.6% for IHC 3+ vs IHC 2+/ISH+; 60.6% vs 34.2% for plasma HER2 amplification vs not). However, these are exploratory subgroup analyses without adjustment for multiple comparisons, and the clinical meaningfulness is not anchored to a minimal clinically important difference. The paper does not provide a clear anchor for what constitutes a clinically meaningful effect size in this context.
“Patients with plasma HER2 amplification in ctDNA had an ORR of 61% compared with 34% in patients with no amplification.”
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Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit9 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Overstated conclusions

3 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

11 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

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 (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study objectives.

Evidence

Introduction ¶1Find in source

“The objective of the present analyses was to identify patients who may benefit from treatment with T-DXd based on relevant biomarkers in tumor or ctDNA.”

IntroductionFind in source

“Specific biomarkers related to therapeutic response have not been explored extensively.”

AbstractFind in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study objectives.

Evidence

“DESTINY-Gastric01 was a pivotal randomized study of T-DXd versus third- or later-line chemotherapy in patients with HER2 + gastric or GEJ tumors.”

Introduction ¶1Find in source

“Specific biomarkers related to therapeutic response have not been explored extensively.”

AbstractFind in source

paraphrase[Introduction, paragraph 3]

“Circulating tumor DNA (ctDNA) analysis is a noninvasive and convenient method widely used in clinics to detect gene alterations in patients with cancer.”

PASSReviewer 3· 90% conf

The paper establishes a clear scientific premise by citing prior work on T-DXd, HER2 heterogeneity, and ctDNA biomarkers, and logically links these to the study's objectives.

Evidence

Introduction ¶1Find in source

“The objective of the present analyses was to identify patients who may benefit from treatment with T-DXd based on relevant biomarkers in tumor or ctDNA.”

IntroductionFind in source

“However, the relationship between gene alterations in ctDNA and the efficacy of ADCs that target specific oncoproteins has not been thoroughly evaluated.”

Introduction ¶3Find in source

Sub-criteria

controlsN/A

power analysisN/A

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitINADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial”

LimitationsFind in source

absence[Methods, Statistical analyses]

No power analysis is reported for the biomarker endpoints.

PASSReviewer 2· 85% conf

The study design is a well-defined exploratory analysis of a randomized trial, with clear inclusion criteria, a pre-specified analysis population, and appropriate statistical methods.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 ) was an open-label, multicenter, randomized, phase 2 trial”

“Patients enrolled in the primary cohort had HER2 + tumors, as determined by IHC or ISH positivity (IHC 3 + or IHC 2 + /ISH + ).”

MethodsFind in source

“Samples with no somatic mutations detected in any gene in the Guardant OMNI assay were excluded from ctDNA analysis.”

MethodsFind in source

PASSReviewer 3· 85% conf

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 ) was an open-label, multicenter, randomized, phase 2 trial”

“Patients enrolled in the primary cohort had HER2 + tumors, as determined by IHC or ISH positivity (IHC 3 + or IHC 2 + /ISH + ).”

MethodsFind in source

absence[Methods, Study design and patient demographics]

Randomization method is not detailed.

Sub-criteria

demographicsINADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study reports key biological variables including sex, age, and HER2 status, but does not report detailed demographics or health status beyond cancer diagnosis.

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial that included patients with HER2-expressing advanced gastric or GEJ carcinoma”

paraphrase[Results, Relationship between baseline HER2 levels and response]

“There were 91 patients in the HER2 IHC 3+ cohort and 28 in the HER2 IHC 2+/ISH+ cohort.”

PASSReviewer 2· 80% conf

The study reports relevant biological variables including HER2 status, age, sex, and prior treatment history, though some demographic details are limited.

Evidence

“patients with centrally assessed tumor HER2 IHC 3 + status in the primary cohort ( n = 91) had higher ORR than those with HER2 IHC 2 + /ISH + status ( n = 28”

ResultsFind in source

absence[Methods, Study design and patient demographics]

Age and sex are not explicitly reported in this biomarker analysis.

PASSReviewer 3· 90% conf

Biological variables are adequately reported for this human study, including sex, age, and demographics, though some details are incomplete.

Evidence

absence[Methods, Study design and patient demographics]

Sex is not explicitly reported in the text.

absence[Methods, Study design and patient demographics]

Age is not explicitly reported in the text.

absence[Methods, Study design and patient demographics]

Demographics are not detailed in this paper.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper reports ethics approval by an independent ethics committee or IRB, informed consent from all patients, and compliance with the Declaration of Helsinki and GCP.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

MethodsFind in source

PASSReviewer 2· 90% conf

The study reports ethics approval and informed consent, and states compliance with the Declaration of Helsinki and GCP.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

MethodsFind in source

PASSReviewer 3· 95% conf

Ethical approvals and consent are adequately reported, with a named ethics committee/IRB approval and informed consent documented.

Evidence

“An independent ethics committee or institutional review board at each site reviewed and approved the protocol (online only).”

MethodsFind in source

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

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 (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key resources are adequately identified: the investigational drug T-DXd, the ctDNA platform (Guardant OMNI), the HER2ECD assay, and RNA-seq reagents are named with manufacturers.

Evidence

paraphrase[Methods, Study design]

“Patients received either T-DXd at 6.4 mg kg−1 every 3 weeks (n = 125) or TPC (irinotecan or paclitaxel; n = 62).”

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

PASSReviewer 2· 85% conf

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

Evidence

“Patients received either T-DXd at 6.4 mg kg −1 every 3 weeks”

MethodsFind in source

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

“Sequencing reads were aligned with STAR software (2.5.3a) to human genome reference GRCh38.”

MethodsFind in source

PASSReviewer 3· 85% conf

Key resources are adequately identified, including the investigational drug, assays, and software, though some details like lot numbers are not provided.

Evidence

“Patients received either T-DXd at 6.4 mg kg −1 every 3 weeks ( n = 125) or TPC (irinotecan or paclitaxel; n = 62).”

MethodsFind in source

“Liquid biopsy was used for ctDNA assay of plasma with the Guardant OMNI panel (Guardant Health)”

MethodsFind in source

“Sequencing reads were aligned with STAR software (2.5.3a) to human genome reference GRCh38.”

MethodsFind in source

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

WARNReviewer 1· 85% conf

Statistical methods are named and appropriate, but the paper reports many p-values as thresholds (e.g., P ≤ 0.01) and does not correct for multiple testing, which is a limitation.

Evidence

“The McNemar test was used to compare ctDNA mutational status changes between baseline and EoT.”

Statistical analysisFind in source

paraphrase[Results, Analysis of gene expression]

“Overall, 57 genes showed higher expression in responders (absolute log2 fold change (FC) ≥ 1, P ≤ 0.01)”

“ORR 51% (95% confidence interval (CI) 42–61%) versus 14% (95% CI 6–26%)”

AbstractFind in source

PASSReviewer 2· 80% conf

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

Evidence

“Point estimates and two-sided 95% exact binomial CIs were calculated for ORR in each subgroup.”

Statistical analysisFind in source

“HER2 was the only significant amplification change ( P = 0.0064).”

Figure 6Find in source

“ORR (95% CI) 58.2% (47.4–68.5%) versus 28.6% (13.2–48.7%)”

ResultsFind in source

PASSReviewer 3· 80% conf

Evidence

“The McNemar test was used to compare ctDNA mutational status changes between baseline and EoT.”

Statistical analysisFind in source

“ORR (95% CI) 58.2% (47.4–68.5%) versus 28.6% (13.2–48.7%)”

ResultsFind in source

“Overall, 57 genes showed higher expression in responders (absolute log 2 fold change (FC) ≥ 1, P ≤ 0.01)”

ResultsFind in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a managed-access platform (Vivli) and a data-sharing statement; code sharing is not applicable as no custom code is described.

Evidence

paraphrase[Data availability]

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/.”

paraphrase[Data availability]

“Details on data-sharing criteria and the procedure for requesting access can be found at this address: https://vivli.org/ourmember/daiichi-sankyo/.”

PASSReviewer 2· 90% conf

Data availability is adequately described with a managed-access platform (Vivli) and a supplementary table with details.

Evidence

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/ .”

Data availabilityFind in source

PASSReviewer 3· 90% conf

Data availability is adequately reported with a concrete access route via Vivli, and code sharing is not applicable as no custom code is described.

Evidence

“Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be made available upon request at https://vivli.org/ .”

Data availabilityFind in source

absence[Methods]

No custom code is mentioned.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper is transparent: it reports the trial registration, discusses limitations, and provides funding and COI statements, though it does not explicitly reference a reporting guideline.

Evidence

paraphrase[Methods, Study design]

“DESTINY-Gastric01 (NCT03329690) was an open-label, multicenter, randomized, phase 2 trial”

LimitationsFind in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 2· 85% conf

The paper is transparent about its exploratory nature, limitations, and funding, and reports all outcomes.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 )”

Discussion ¶8Find in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 3· 85% conf

Reporting is transparent with methods detailed, limitations discussed, conclusions proportional, and funding/COI disclosed. Trial registration is reported.

Evidence

paraphrase[Methods, Study design and patient demographics]

“DESTINY-Gastric01 ( NCT03329690 )”

DiscussionFind in source

“This study was funded by Daiichi Sankyo and AstraZeneca.”

AcknowledgementsFind in source

Registered (4 IDs: ClinicalTrials.gov, jRCT (Japan)). 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 27 references by DOI: 25 verified — 2 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

9 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHstatistics
In the Results, replace threshold p-values (e.g., P ≤ 0.01) with exact p-values where feasible, especially for the differential expression analysis.
Threshold p-values are a reporting imprecision that prevents readers from assessing the strength of evidence.
2.
HIGHstatistics
In the Methods, add a statement on multiple testing correction or justify its absence in the exploratory context.
The lack of multiple testing correction is a limitation that should be explicitly acknowledged to avoid over-interpretation.
3.
HIGHreporting
In the Results, clarify the denominator for the HER2 GoF subset (8 of 12) and reconcile with the IHC 3+ cohort of 91.
The internal contradiction flagged in the integrity check could confuse readers and warrants clarification.
4.
HIGHreporting
In the Abstract, clarify the concordance statement (64%) to reflect the PPA/NPA distinction reported in the Results.
The abstract may oversimplify the concordance metric, which could mislead readers.
5.
MEDIUMreporting
In the Methods, add a statement on how test assumptions (e.g., proportional hazards for Cox models) were verified or handled.
Assumption verification is a standard expectation for statistical models.
6.
MEDIUMreporting
In the Results, include a table of baseline demographics (age, sex, race) for the biomarker-evaluable population.
Demographics are not reported in the text, which limits transparency for a secondary analysis.
7.
MEDIUMreporting
In the Methods, describe the exact criteria for defining 'response-evaluable' patients and how missing data were handled.
Clear definition of the analysis population is essential for reproducibility.
8.
MEDIUMreporting
In the Methods, state whether any sensitivity analyses were performed to assess the robustness of the exploratory cutoffs.
Sensitivity analyses would strengthen the exploratory findings.
9.
MEDIUMreporting
In the Discussion, explicitly acknowledge the lack of multiple testing correction in exploratory analyses as a limitation.
This is a common reviewer concern and should be preemptively addressed.
10.
MEDIUMreporting
In the Methods, clarify the randomization method used in the parent trial (e.g., block randomization).
The randomization method is not detailed, which is a minor reporting gap.
11.
MEDIUMreporting
In the Methods, describe how outliers were handled in the ctDNA and RNA-seq analyses, or state that no outliers were excluded.
Outlier handling is not reported, which is a transparency gap.
12.
MEDIUMreporting
In the Methods, state whether the biomarker analysis was pre-specified or post hoc.
Clarifying the exploratory nature is important for interpretation.
13.
LOWcopyedit
Fix spacing in gene names (e.g., 'HER2 ( ERBB2 )' to 'HER2 (ERBB2)') throughout the manuscript.
Consistent formatting improves readability and professionalism.
14.
LOWcopyedit
Fix punctuation issues in the Results (e.g., remove extra colon and parentheses in the HER2 mRNA sentence).
Awkward punctuation can distract readers.
15.
LOWcopyedit
Change 'PIK3 GoF' to 'PIK3CA GoF' for consistency in the Discussion.
Inconsistent gene name abbreviation could cause confusion.
16.
LOWcopyedit
Clarify the units and context for the HER2ECD median value (9.72) versus the exploratory cutoff (14.4 ng/ml).
Potential confusion between median and cutoff values should be resolved.

Full text (45,529 chars)Analyzed: Aug 16, 2026