Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.

Name: Kaimen Rigor review — Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.
Item: Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.
Rating: 100
Author: Alpha1

Herbst RS, John T, Grohé C, Goldman JW, Kato T, Laktionov K, Bonanno L, Tiseo M, Majem M, Dómine M, Ahn MJ, Kowalski DM, Pérol M, Sriuranpong V, Özgüroğlu M, Bhetariya P, Markovets A, Rukazenkov Y, Muldoon C, Robichaux J, Hartmaier R, Tsuboi M, Wu YL

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Kaimen Rigor review — 3.25★ (Adequate), 0 critical, 1 high issue for “Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.

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DOI

10.1038/s41591-025-03577-y

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.

Paper source

Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

3.25 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
LinksDead data/code link−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on the combined endpoint of DFS or MRD events, where MRD (molecular residual disease) is a surrogate biomarker. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking MRD detection to the clinical outcome of disease-free survival in this setting. The claim that MRD monitoring may identify patients who could benefit from longer adjuvant osimertinib is speculative and requires clinical confirmation.
“MRD detection could potentially identify patients who may benefit from longer adjuvant osimertinib, although this requires clinical confirmation.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size for the combined DFS or MRD event-free rate at 36 months is 86% versus 36% (HR 0.23), but this is based on a surrogate endpoint (MRD) and lacks an anchor to a minimal clinically important difference or a validated clinical outcome. The magnitude of the effect on the surrogate is not sufficient to establish clinical meaningfulness without validation.
“DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15–0.36)).”
Find in source
03Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 105AvailabilityBroken references and links 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 is a well-conducted post hoc exploratory analysis of the ADAURA trial, with clear scientific premise, rigorous design leveraging a randomized double-blind trial, and transparent reporting. The main weaknesses are minor: lack of explicit reporting guideline reference, some software versions not fully specified, and a few copyedit issues.

The reviewers disagreed on study type (observational vs. interventional); I adopted 'observational' because the paper is a post hoc analysis of existing trial data without a new intervention. The analysis is exploratory and not pre-specified, so power analysis and exact p-values are not applicable. The statistics verification covered only 3 tests; the rest are unverified but not flagged as inconsistent.

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 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks.

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

7 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

Prior work is extensively cited, including the primary ADAURA results, MRD studies in early-stage NSCLC, and the rationale for longer adjuvant treatment. The premise that MRD could predict recurrence and identify patients who may benefit from extended osimertinib is logically linked to the study objectives. Limitations of prior research (e.g., small sample sizes, non-biomarker-selected populations) are acknowledged and addressed by the larger, biomarker-selected ADAURA cohort.

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 by citing prior work on MRD in early-stage NSCLC and the ADAURA trial, and provides a logical rationale for the study.

Evidence

“Several studies in patients with early-stage NSCLC who have undergone curative intent treatment support the use of tumor-informed MRD assays to predict radiographic clinical recurrence – .”

Introduction ¶3Find in source

“We performed an exploratory analysis to investigate whether plasma-based, tumor-informed MRD analysis could predict disease recurrence during and after adjuvant treatment, in a patient cohort ( n = 220) from ADAURA.”

IntroductionFind in source

“Due to low tumor burden, and a concomitant low fraction of ctDNA in patients with early-stage disease, robust detection of ctDNA can be challenging.”

Introduction ¶3Find in source

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise by citing prior work on osimertinib efficacy, MRD in NSCLC, and the rationale for exploring MRD to predict recurrence and guide treatment duration.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Adjuvant osimertinib for a duration of 3 years is recommended for resected EGFRm stage IB–IIIA NSCLC, based on results from the phase 3 ADAURA trial... A trend toward an increased DFS event rate was observed after completion of 3 years of osimertinib treatment, suggesting that some patients may benefit from a longer treatment duration... Several studies in patients with early-stage NSCLC who have undergone curative intent treatment support the use of tumor-informed MRD assays to predict radiographic clinical recurrence.”

“Although studies are limited, these data suggest the potential utility of tumor-informed MRD assays to monitor MRD in early-stage NSCLC.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 5]

Randomization method (1:1, stratified by stage, EGFR mutation, race) and unit (patient) are reported. Blinding (double-blind) is stated. Inclusion/exclusion criteria are detailed. Power analysis was not performed for this exploratory MRD analysis, but the sample size is justified by comparison to prior studies. Replicate distinction and controls are not applicable for this human clinical trial. Outlier handling is not explicitly addressed for MRD, but the analysis population is defined. Independent replication is not applicable as this is a single trial analysis.

Sub-criteria

controlsN/A

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingNOT REPORTED

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 a post hoc analysis of a randomized trial, with clear inclusion/exclusion criteria and appropriate statistical methods, though it is not a new interventional design.

Evidence

“Full details of the phase 3, double-blind, placebo-controlled ADAURA trial have been reported previously”

MethodsFind in source

“Of 682 patients randomized in ADAURA, 239 (35%) had available matched tumor, germline DNA and plasma samples for development and testing of tumor-specific RaDaR panels at the time of data cut-off (DCO)”

ResultsFind in source

“This analysis of MRD is a post hoc exploratory analysis separate from the prespecified primary and secondary endpoints of the ADAURA study.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous, leveraging a randomized, double-blind, placebo-controlled trial with clear inclusion/exclusion criteria and a pre-specified analysis plan for the primary endpoints, though the MRD analysis is post hoc.

Evidence

paraphrase[Methods, ADAURA trial design]

“Patients were stratified per disease stage (IB, II or IIIA), EGFR mutation type (Ex19del or L858R) and race (Asian or non-Asian), and then randomized 1:1 to receive osimertinib (80 mg QD) or placebo.”

paraphrase[Methods, ADAURA trial design]

“Full details of the phase 3, double-blind, placebo-controlled ADAURA trial have been reported previously.”

paraphrase[Methods, Statistical analysis]

“No statistical methods were used to predetermine sample sizes but our sample sizes are larger than those in refs. 24,25,26 or similar to those in ref. 27 as reported in relevant previous studies.”

Sex and age are reported for the overall ADAURA population and the MRD analysis set. Demographics (age, sex, race, disease stage, smoking status) are provided in Extended Data Tables. Sex is reported for both sexes, so justification for single-sex is not applicable. Age and health status (WHO performance status) are reported. Species/strain/source 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

Biological variables such as sex, age, disease stage, and EGFR mutation subtype are reported for the MRD analysis set and overall population.

Evidence

“A breakdown of biological sex and age is provided for each treatment arm of the overall ADAURA population (Extended Data Table ), the MRD analysis patient set by study group from ADAURA (Extended Data Table )”

MethodsFind in source

“Demographics, disease characteristics and outcomes were generally similar between patients in the MRD analysis set ( n = 220) and overall ADAURA population ( N = 682; Extended Data Table ).”

ResultsFind in source

PASSReviewer 2· 95% conf

Biological variables are adequately reported, including sex, age, disease stage, and EGFR mutation type, though race is reported but not fully justified for the MRD subset.

Evidence

paraphrase[Extended Data Table 2]

“Extended Data Table 2 Baseline demographics, disease characteristics, and outcomes for the MRD analysis set (n = 220) and full ADAURA patient population (N = 682)”

paraphrase[Extended Data Table 2]

“Extended Data Table 2 includes columns for 'Sex', 'Age', 'Race', 'Smoking history'.”

“a World Health Organization performance status of 0 or 1.”

MethodsFind in source

The Methods section states that the ADAURA protocol was approved by relevant ethics committees and institutional review boards, and that all patients provided written informed consent. It also states compliance with the Declaration of Helsinki and ICH-GCP guidelines. This is a human study, so IACUC is not applicable.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper reports ethics approval from relevant committees, informed consent from all patients, and compliance with the Declaration of Helsinki and ICH-GCP.

Evidence

paraphrase[Methods, Inclusion and ethics]

“The ADAURA protocol and amendments were approved by the relevant ethics committees. ... All patients provided written informed consent.”

“The trial was conducted in accordance with the provisions of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, applicable regulatory requirements and the trial sponsor’s (AstraZeneca) policy on bioethics and human samples”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported, including ethics committee approval, informed consent, and regulatory compliance.

Evidence

“The ADAURA protocol and amendments were approved by the relevant ethics committees.”

MethodsFind in source

“All patients provided written informed consent.”

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

Osimertinib is identified as the investigational product with dose and regimen. The RaDaR MRD assay is described with reference to prior publication. Software tools (bcbio-nextgen, bwa, VarDict, snpEff, Seq2C, SAS) are identified with versions and/or URLs. Antibodies, cell lines, mycoplasma testing, and organisms are not applicable for this clinical trial.

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

The investigational product (osimertinib) is identified, and the MRD assay (RaDaR) is described with vendor and methodology, though some software versions are not fully specified.

Evidence

“randomized 1:1 to receive osimertinib (80 mg QD) or placebo”

MethodsFind in source

“RaDaR MRD analysis (NeoGenomics) was performed as outlined in ref.”

MethodsFind in source

“FASTQ files were processed using pipeline software bcbio-nextgen (10.5281/zenodo.3564938). Reads were aligned to the hg38 reference using bwa mem v.0.7.17.”

MethodsFind in source

PASSReviewer 2· 95% conf

Key resources are adequately identified, including the investigational drug (osimertinib), the MRD assay (RaDaR), and software tools.

Evidence

paraphrase[Methods, ADAURA trial design]

“randomized 1:1 to receive osimertinib (80 mg QD) or placebo.”

paraphrase[Methods, MRD detection]

“RaDaR MRD analysis (NeoGenomics) was performed as outlined in ref. 28.”

paraphrase[Methods, Genomic analysis at baseline]

“FASTQ files were processed using pipeline software bcbio-nextgen (10.5281/zenodo.3564938). Reads were aligned to the hg38 reference using bwa mem v.0.7.17. Variant calling was performed using VarDict v.1.8.2... Copy number analysis... was performed using Seq2C (https://github.com/AstraZeneca-NGS/Seq2C).”

Statistical tests are named (log-rank, Cox proportional hazards). Exact p-values are reported for the primary ADAURA analysis (e.g., P < 0.001 for OS), but for the MRD analysis, p-values are not generated as it is post hoc. Effect sizes (HR) with 95% CIs are reported throughout. Software (SAS v.9.4M7) is identified. Data presentation includes Kaplan-Meier curves and swimmer plots. Assumptions for Cox models are not explicitly verified, but this is standard for large trials. Mathematical plausibility checks are not applicable for continuous outcomes and model-derived statistics.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported; p-values are not reported for the main analyses as they are exploratory.

Evidence

paraphrase[Methods, Statistical analysis]

“DFS for the MRD analysis set was analyzed using a log-rank test stratified by disease stage ... HR for the combined endpoint of DFS or MRD events in the osimertinib versus placebo group was calculated using an unadjusted Cox proportional hazards model”

“DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15–0.36)).”

AbstractFind in source

“These analyses were not included in the statistical analysis plan (SAP) and therefore P values have not been generated .”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

Statistical analysis is rigorous, with named tests, exact p-values where applicable, effect sizes with confidence intervals, and software identified. The analysis is appropriate for the exploratory nature of the study.

Evidence

paraphrase[Methods, Statistical analysis]

“DFS for the MRD analysis set was analyzed using a log-rank test stratified by disease stage... HR for the combined endpoint of DFS or MRD events in the osimertinib versus placebo group was calculated using an unadjusted Cox proportional hazards model.”

paraphrase[Introduction, paragraph 1]

“an overall hazard ratio (HR) for death of 0.49 (95.03% confidence interval (CI) 0.34–0.70; P < 0.001).”

“The DFS and MRD event-free rate at 36 months on treatment was 86% (95% CI, 78–92) versus 36% (95% CI, 27–45) with an overall HR of 0.23 (95% CI, 0.15–0.36) for osimertinib versus placebo.”

ResultsFind in source

A data availability statement is present, explaining that clinical data are not publicly available due to privacy, but can be requested via AstraZeneca's data sharing policy or through Vivli. This is adequate for a clinical trial with patient-level data. Repository deposit and accession numbers are not applicable for the clinical data, but the hg38 reference is cited. Code sharing is not applicable as the analysis used standard software.

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 clearly stated with a managed-access route via AstraZeneca's data sharing policy and Vivli, which is appropriate for patient-level data.

Evidence

“Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure . Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org”

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data availability is adequately addressed with a clear statement and a mechanism for data access, though the data are not publicly deposited due to patient privacy.

Evidence

paraphrase[Data availability]

“To protect the privacy and confidentiality of patients in this study, clinical data are not made publicly available in a repository or in the supplementary material. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org.”

paraphrase[Data availability]

“hg38 reference: NCBI RefSeq assembly (v.GCF_000001405.40).”

The trial is registered (NCT02511106). Methods are detailed enough for replication. Limitations are discussed (e.g., subset analysis, assay sensitivity). Conclusions are proportional, noting the need for prospective validation. Funding and competing interests are disclosed. A reporting guideline is not explicitly referenced, but the Nature Portfolio reporting summary is linked.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The paper is transparent about its exploratory nature, reports limitations, and provides funding and COI statements; trial registration is provided.

Evidence

“ClinicalTrials.gov identifier: NCT02511106 (https://clinicaltrials.gov/study/NCT02511106) .”

AbstractFind in source

“Key limitations of the MRD analysis were that only a subset of patients from ADAURA were assessed for MRD due to restrictions on sample availability, and the limited clinical sensitivity (65%) of the tissue-informed RaDaR MRD panels.”

Discussion ¶8Find in source

“Research support for the exploratory MRD analysis of the ADAURA study ( NCT02511106 ) was supported by AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Reporting is transparent, with a registered trial, detailed methods, limitations discussed, and conclusions proportional to the evidence.

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov identifier: NCT02511106 (https://clinicaltrials.gov/study/NCT02511106).”

Discussion ¶7Find in source

“Prospective studies to understand the optimal frequency of MRD monitoring following adjuvant treatment completion and the appropriate clinical interventions following MRD detection are warranted before this can be applied routinely to the real-world clinical setting.”

DiscussionFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

1 finding · worst medium

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.

Dead data/code linksRecomputed

Checked 45 references by DOI: 43 verified — 2 no DOI (shown, not verified).

9 of 10 data/code links checked; 8 live, 1 dead; 1 not probed.

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, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the exploratory nature of the MRD analysis, the subset of patients analyzed, and the limited clinical sensitivity of the assay. Minor copyedit issues and a dead link in the data availability should be corrected in any erratum or revision.

1.
HIGHdata code
Fix the dead link found in the data availability section (reproducibility check found 1 dead link among 10 checked).
A broken link in the data availability statement undermines the reproducibility of the paper.
2.
MEDIUMreporting
Add an explicit reference to a reporting guideline (e.g., CONSORT or STROBE) in the Methods or Reporting Summary.
Explicitly referencing a reporting guideline enhances transparency and is expected by many journals.
3.
MEDIUMstatistics
Add a statement verifying proportional hazards assumptions for the Cox models used in the MRD analysis.
Verifying model assumptions strengthens the statistical rigor of the analysis.
4.
MEDIUMreporting
Clarify the exact criteria for 'MRD detected' in the Methods, including the preset threshold and how it was defined during analytical development.
Clear definition of the primary outcome is essential for reproducibility and interpretation.
5.
MEDIUMreporting
Include a CONSORT-style flow diagram for the MRD analysis set to improve clarity on patient selection.
A flow diagram helps readers understand how the subset of 220 patients was derived from the 682 randomized.
6.
MEDIUMreporting
Provide a brief justification for the sample size of the MRD analysis set, even if post hoc, referencing the feasibility of assay development.
Justifying the sample size, even post hoc, addresses potential concerns about statistical power.
7.
MEDIUMreporting
Clarify whether the MRD analysis was pre-specified in a statistical analysis plan or is entirely post hoc, and if post hoc, note the number of exploratory analyses performed.
Transparency about the exploratory nature and multiplicity of analyses is important for interpretation.
8.
MEDIUMreporting
Add a note on whether any sensitivity analyses were performed to assess the impact of missing samples on MRD detection rates.
Sensitivity analyses would strengthen the robustness of the findings given the subset analysis.
9.
MEDIUMreporting
In the Discussion, explicitly acknowledge the potential for lead-time bias in the MRD lead-time analysis and discuss its implications.
Acknowledging lead-time bias is important for interpreting the clinical utility of MRD monitoring.
10.
LOWcopyedit
Fix the typographical error in the Results section: change '5% CI' to '95% CI'.
Correcting this typo prevents misinterpretation of the confidence interval.
11.
LOWcopyedit
Rephrase the sentence in Methods, Statistical analysis: 'DFS events that did not occur within two scheduled visits (plus visit window) of the last evaluable assessment (or randomization) were censored and therefore excluded in the number of events.' to improve clarity.
The current phrasing is awkward and could be misinterpreted.
12.
LOWcopyedit
Ensure the footnote 'Percentages may not total to 100 due to rounding' is consistently applied to all tables with percentages.
Consistency in table footnotes is a standard editorial requirement.
13.
LOWreporting
Provide the full list of participating ethics committees or IRBs in the supplementary material for completeness.
Listing the ethics committees enhances transparency for a multi-center trial.
14.
LOWdata code
Consider making the analysis code for the MRD detection algorithm available in a public repository to enhance reproducibility.
Sharing code would allow independent verification of the MRD detection pipeline.
15.
LOWreporting
Provide exact p-values for the subgroup analyses (e.g., TP53 status) where feasible, even if exploratory, to aid interpretation.
Exact p-values, when available, provide more information than threshold-only reporting.
16.
LOWreporting
Clarify the definition of 'MRD event' in the context of the combined endpoint to avoid ambiguity.
A clear definition of the combined endpoint is necessary for accurate interpretation.

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Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.

Read full text (PMC)

DOI

10.1038/s41591-025-03577-y

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Record fingerprint

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Verify via API

Issued Aug 15, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

3.25 / 5

Adequate — real issues to address

Observational Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
LinksDead data/code link−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on the combined endpoint of DFS or MRD events, where MRD (molecular residual disease) is a surrogate biomarker. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking MRD detection to the clinical outcome of disease-free survival in this setting. The claim that MRD monitoring may identify patients who could benefit from longer adjuvant osimertinib is speculative and requires clinical confirmation.
“MRD detection could potentially identify patients who may benefit from longer adjuvant osimertinib, although this requires clinical confirmation.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size for the combined DFS or MRD event-free rate at 36 months is 86% versus 36% (HR 0.23), but this is based on a surrogate endpoint (MRD) and lacks an anchor to a minimal clinically important difference or a validated clinical outcome. The magnitude of the effect on the surrogate is not sufficient to establish clinical meaningfulness without validation.
“DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15–0.36)).”
Find in source
03Declared data/code link does not resolve
mediumAvailabilityrecomputedFull detail
Dead link — nothing to verify.
“https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 105AvailabilityBroken references and links 06Copyedit3 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks.

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

7 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 (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior work on MRD in early-stage NSCLC and the ADAURA trial, and provides a logical rationale for the study.

Evidence

“Several studies in patients with early-stage NSCLC who have undergone curative intent treatment support the use of tumor-informed MRD assays to predict radiographic clinical recurrence – .”

Introduction ¶3Find in source

IntroductionFind in source

“Due to low tumor burden, and a concomitant low fraction of ctDNA in patients with early-stage disease, robust detection of ctDNA can be challenging.”

Introduction ¶3Find in source

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise by citing prior work on osimertinib efficacy, MRD in NSCLC, and the rationale for exploring MRD to predict recurrence and guide treatment duration.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Although studies are limited, these data suggest the potential utility of tumor-informed MRD assays to monitor MRD in early-stage NSCLC.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 5]

Sub-criteria

controlsN/A

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingNOT REPORTED

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 a post hoc analysis of a randomized trial, with clear inclusion/exclusion criteria and appropriate statistical methods, though it is not a new interventional design.

Evidence

“Full details of the phase 3, double-blind, placebo-controlled ADAURA trial have been reported previously”

MethodsFind in source

ResultsFind in source

“This analysis of MRD is a post hoc exploratory analysis separate from the prespecified primary and secondary endpoints of the ADAURA study.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

Evidence

paraphrase[Methods, ADAURA trial design]

“Full details of the phase 3, double-blind, placebo-controlled ADAURA trial have been reported previously.”

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· 90% conf

Biological variables such as sex, age, disease stage, and EGFR mutation subtype are reported for the MRD analysis set and overall population.

Evidence

MethodsFind in source

“Demographics, disease characteristics and outcomes were generally similar between patients in the MRD analysis set ( n = 220) and overall ADAURA population ( N = 682; Extended Data Table ).”

ResultsFind in source

PASSReviewer 2· 95% conf

Biological variables are adequately reported, including sex, age, disease stage, and EGFR mutation type, though race is reported but not fully justified for the MRD subset.

Evidence

paraphrase[Extended Data Table 2]

“Extended Data Table 2 Baseline demographics, disease characteristics, and outcomes for the MRD analysis set (n = 220) and full ADAURA patient population (N = 682)”

paraphrase[Extended Data Table 2]

“Extended Data Table 2 includes columns for 'Sex', 'Age', 'Race', 'Smoking history'.”

“a World Health Organization performance status of 0 or 1.”

MethodsFind 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

The paper reports ethics approval from relevant committees, informed consent from all patients, and compliance with the Declaration of Helsinki and ICH-GCP.

Evidence

paraphrase[Methods, Inclusion and ethics]

“The ADAURA protocol and amendments were approved by the relevant ethics committees. ... All patients provided written informed consent.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported, including ethics committee approval, informed consent, and regulatory compliance.

Evidence

“The ADAURA protocol and amendments were approved by the relevant ethics committees.”

MethodsFind in source

“All patients provided written informed consent.”

MethodsFind in source

paraphrase[Methods, Inclusion and ethics]

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

The investigational product (osimertinib) is identified, and the MRD assay (RaDaR) is described with vendor and methodology, though some software versions are not fully specified.

Evidence

“randomized 1:1 to receive osimertinib (80 mg QD) or placebo”

MethodsFind in source

“RaDaR MRD analysis (NeoGenomics) was performed as outlined in ref.”

MethodsFind in source

“FASTQ files were processed using pipeline software bcbio-nextgen (10.5281/zenodo.3564938). Reads were aligned to the hg38 reference using bwa mem v.0.7.17.”

MethodsFind in source

PASSReviewer 2· 95% conf

Key resources are adequately identified, including the investigational drug (osimertinib), the MRD assay (RaDaR), and software tools.

Evidence

paraphrase[Methods, ADAURA trial design]

“randomized 1:1 to receive osimertinib (80 mg QD) or placebo.”

paraphrase[Methods, MRD detection]

“RaDaR MRD analysis (NeoGenomics) was performed as outlined in ref. 28.”

paraphrase[Methods, Genomic analysis at baseline]

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported; p-values are not reported for the main analyses as they are exploratory.

Evidence

paraphrase[Methods, Statistical analysis]

“DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15–0.36)).”

AbstractFind in source

“These analyses were not included in the statistical analysis plan (SAP) and therefore P values have not been generated .”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

Evidence

paraphrase[Methods, Statistical analysis]

“DFS for the MRD analysis set was analyzed using a log-rank test stratified by disease stage... HR for the combined endpoint of DFS or MRD events in the osimertinib versus placebo group was calculated using an unadjusted Cox proportional hazards model.”

paraphrase[Introduction, paragraph 1]

“an overall hazard ratio (HR) for death of 0.49 (95.03% confidence interval (CI) 0.34–0.70; P < 0.001).”

“The DFS and MRD event-free rate at 36 months on treatment was 86% (95% CI, 78–92) versus 36% (95% CI, 27–45) with an overall HR of 0.23 (95% CI, 0.15–0.36) for osimertinib versus placebo.”

ResultsFind in source

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 clearly stated with a managed-access route via AstraZeneca's data sharing policy and Vivli, which is appropriate for patient-level data.

Evidence

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data availability is adequately addressed with a clear statement and a mechanism for data access, though the data are not publicly deposited due to patient privacy.

Evidence

paraphrase[Data availability]

“hg38 reference: NCBI RefSeq assembly (v.GCF_000001405.40).”

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The paper is transparent about its exploratory nature, reports limitations, and provides funding and COI statements; trial registration is provided.

Evidence

“ClinicalTrials.gov identifier: NCT02511106 (https://clinicaltrials.gov/study/NCT02511106) .”

AbstractFind in source

Discussion ¶8Find in source

“Research support for the exploratory MRD analysis of the ADAURA study ( NCT02511106 ) was supported by AstraZeneca.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Reporting is transparent, with a registered trial, detailed methods, limitations discussed, and conclusions proportional to the evidence.

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov identifier: NCT02511106 (https://clinicaltrials.gov/study/NCT02511106).”

Discussion ¶7Find in source

DiscussionFind in source

Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

1 finding · worst medium

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.

Dead data/code linksRecomputed

Checked 45 references by DOI: 43 verified — 2 no DOI (shown, not verified).

9 of 10 data/code links checked; 8 live, 1 dead; 1 not probed.

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, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Fix the dead link found in the data availability section (reproducibility check found 1 dead link among 10 checked).
A broken link in the data availability statement undermines the reproducibility of the paper.
2.
MEDIUMreporting
Add an explicit reference to a reporting guideline (e.g., CONSORT or STROBE) in the Methods or Reporting Summary.
Explicitly referencing a reporting guideline enhances transparency and is expected by many journals.
3.
MEDIUMstatistics
Add a statement verifying proportional hazards assumptions for the Cox models used in the MRD analysis.
Verifying model assumptions strengthens the statistical rigor of the analysis.
4.
MEDIUMreporting
Clarify the exact criteria for 'MRD detected' in the Methods, including the preset threshold and how it was defined during analytical development.
Clear definition of the primary outcome is essential for reproducibility and interpretation.
5.
MEDIUMreporting
Include a CONSORT-style flow diagram for the MRD analysis set to improve clarity on patient selection.
A flow diagram helps readers understand how the subset of 220 patients was derived from the 682 randomized.
6.
MEDIUMreporting
Provide a brief justification for the sample size of the MRD analysis set, even if post hoc, referencing the feasibility of assay development.
Justifying the sample size, even post hoc, addresses potential concerns about statistical power.
7.
MEDIUMreporting
Clarify whether the MRD analysis was pre-specified in a statistical analysis plan or is entirely post hoc, and if post hoc, note the number of exploratory analyses performed.
Transparency about the exploratory nature and multiplicity of analyses is important for interpretation.
8.
MEDIUMreporting
Add a note on whether any sensitivity analyses were performed to assess the impact of missing samples on MRD detection rates.
Sensitivity analyses would strengthen the robustness of the findings given the subset analysis.
9.
MEDIUMreporting
In the Discussion, explicitly acknowledge the potential for lead-time bias in the MRD lead-time analysis and discuss its implications.
Acknowledging lead-time bias is important for interpreting the clinical utility of MRD monitoring.
10.
LOWcopyedit
Fix the typographical error in the Results section: change '5% CI' to '95% CI'.
Correcting this typo prevents misinterpretation of the confidence interval.
11.
LOWcopyedit
Rephrase the sentence in Methods, Statistical analysis: 'DFS events that did not occur within two scheduled visits (plus visit window) of the last evaluable assessment (or randomization) were censored and therefore excluded in the number of events.' to improve clarity.
The current phrasing is awkward and could be misinterpreted.
12.
LOWcopyedit
Ensure the footnote 'Percentages may not total to 100 due to rounding' is consistently applied to all tables with percentages.
Consistency in table footnotes is a standard editorial requirement.
13.
LOWreporting
Provide the full list of participating ethics committees or IRBs in the supplementary material for completeness.
Listing the ethics committees enhances transparency for a multi-center trial.
14.
LOWdata code
Consider making the analysis code for the MRD detection algorithm available in a public repository to enhance reproducibility.
Sharing code would allow independent verification of the MRD detection pipeline.
15.
LOWreporting
Provide exact p-values for the subgroup analyses (e.g., TP53 status) where feasible, even if exploratory, to aid interpretation.
Exact p-values, when available, provide more information than threshold-only reporting.
16.
LOWreporting
Clarify the definition of 'MRD event' in the context of the combined endpoint to avoid ambiguity.
A clear definition of the combined endpoint is necessary for accurate interpretation.

Full text (67,453 chars)Analyzed: Aug 15, 2026