Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Name: Kaimen Rigor review — Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.
Item: Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.
Rating: 59
Author: Alpha1

Schuler M, Cuppens K, Plönes T, Wiesweg M, Du Pont B, Hegedus B, Köster J, Mairinger F, Darwiche K, Paschen A, Maes B, Vanbockrijck M, Lähnemann D, Zhao F, Hautzel H, Theegarten D, Hartemink K, Reis H, Baas P, Schramm A, Aigner C

Paper source

Read full text (PMC)

Embed this Rigor badge

Kaimen Rigor review — 2.75★ (Weak), 0 critical, 2 high issues for “Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.”

Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Read alongside

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Read full text (PMC)

DOI

10.1038/s41591-024-02965-0

Share this Kaimen Rigor review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://alpha1science.com/verify/7150f091-4ade-4080-8cf4-4cb9575e4d7b" target="_blank" rel="noopener">
  <img src="https://alpha1science.com/verify/7150f091-4ade-4080-8cf4-4cb9575e4d7b/badge" alt="Kaimen Rigor review — 2.75★ (Weak), 0 critical, 2 high issues for “Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Kaimen Rigor review.

Record fingerprint

2324fb14eb08b15ae5365fdc449c114248a2b8baefa1727c582f0d23470e475c

Verify via API

Issued Aug 16, 2026Engine 7.39.0

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

Alpha¹ by Kaimen

Fetching the latest research

Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Paper source

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 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

2.75 / 5

Weak — serious problems found

Interventional 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★
StatisticsPrinted percentage does not match its own count (capped) ×2−0.25★

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 pathological response (major pathological response, MPR) and radiographic response rates, which are surrogate endpoints. The study does not demonstrate target engagement at the tested dose (no PK/PD data) and does not cite validated evidence linking MPR to long-term clinical outcomes in this setting. The paper itself acknowledges limitations in assessing clinical efficacy.
“The rates of major pathological responses (MPR, ≤10% viable tumor cells) were 27% and 30% ... With a median duration of follow-up of 12 months, rates of DFS and overall survival (OS) at 12 months were 89% and 93% with nivolumab monotherapy, and 93% and 100%…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes (e.g., MPR rates of 27% and 30%) are presented without anchoring to a minimal clinically important difference or to the normal/reference value. The study is not powered for efficacy and the authors state it was not designed for formal statistical comparison. The clinical meaningfulness of these response rates is not established.
“The study was not designed for formal statistical comparison of both treatment arms. ... the moderate sample size and study design preclude formal assessment of clinical efficacy.”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
30% does not match the reported count 9/29
“and 30%”
Results
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
89% does not match the reported count 27/30
“rates of DFS and overall survival (OS) at 12 months were 89% and 93% with nivolumab monotherapy”
ResultsFind in source

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

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

This is a well-conducted and transparently reported phase 2 randomized trial with strong scientific premise, clear design, and comprehensive reporting of ethics, resources, data, and code. Minor reporting gaps include lack of explicit reporting guideline, incomplete power analysis, and some ambiguous phrasing in the abstract and results.

Both reviewers classified the study as interventional, and I adopt that classification. The evaluation covered the full text, including methods, results, and supplementary materials. Non-applicable criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification component checked only 2 tests, both inconsistent, but these are not listed in the inconsistent tests array, so they are not treated as demonstrable errors.

Numerical inconsistencies

2 findings · worst medium

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

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

2 printed percentages that do not match their own count.

Overstated conclusions

2 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

6 major claims checked against the paper's own evidence: all 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 extensively cites prior work on neoadjuvant ICI, including SWOG S1801, NEOSTAR, and CheckMate 816, and discusses the rationale for dual checkpoint blockade. It acknowledges limitations of prior studies, such as the toxicity of chemoimmunotherapy and the need for better combinations. The hypothesis logically follows from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study builds on a well-established rationale for neoadjuvant immunotherapy and dual PD-1/LAG-3 blockade, citing prior clinical and preclinical evidence.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Clinical proof-of-concept has been provided by the SWOG S1801 study in patients with resectable melanoma, which demonstrated improved disease-free survival (DFS) by moving 3 of 18 doses of pembrolizumab to the preoperative window.”

paraphrase[Introduction, paragraph 4]

“Dual blockade of both immune checkpoints synergistically enhanced T cell function and antitumor activity in preclinical models.”

“Although this approach resulted in impressive histopathological response rates and improved event-free survival, combined chemoimmunotherapy may obscure the contribution of the ICI component at the single patient level.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The study builds on a well-established rationale for neoadjuvant immunotherapy and dual PD-1/LAG-3 blockade, citing prior clinical and preclinical evidence.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Based on their distinct and potentially synergistic mode of action, combined targeting of the immune checkpoints LAG-3 and PD-1 is a rational choice to overcome immune resistance in NSCLC.”

Introduction ¶4Find in source

Introduction ¶3Find in source

Randomization was performed via an interactive web response system (1:1) without stratification or blinding, which is appropriate for an open-label feasibility trial. The primary endpoint (surgery within 43 days) is clearly defined, and a sample size rationale is provided (up to 30 evaluable patients per arm). Inclusion/exclusion criteria are detailed. Blinding is not applicable as it is an open-label design, and the paper states this. Power analysis is not a formal statistical power calculation but a feasibility-based sample size, which is acceptable for a phase 2 trial.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The trial is a randomized, open-label phase 2 study with a clear primary endpoint and predefined feasibility criteria; randomization method and inclusion/exclusion criteria are described.

Evidence

“Patients were randomly assigned (1:1) via an interactive web response system provided by Alcedis GmbH”

MethodsFind in source

paraphrase[Methods, Study design and treatment]

“NEOpredict-Lung is an open-label, randomized phase 2 trial”

“Based on published results of a study with preoperative nivolumab each study arm included up to 30 evaluable patients with the expectation that at least 26 of 30 patients treated in each study arm will undergo curatively intended surgery within 6 weeks of initiation of study treatment.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The trial design is appropriate for a phase 2 feasibility study, with clear randomization, inclusion/exclusion criteria, and a pre-specified primary endpoint, though blinding is absent (open-label) and no formal power calculation is reported.

Evidence

“Patients were randomly assigned (1:1) via an interactive web response system provided by Alcedis GmbH ( https://www.alcedis.de/en ); there was no stratification or blinding.”

MethodsFind in source

paraphrase[Methods, Clinical study]

“Additional inclusion criteria (see for full study protocol) are women and men ≥18 years of age, Eastern Cooperative Oncology Group performance score ≤1, exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3), exclusion of distant metastases...”

Statistical analysisFind in source

Table 1 reports sex (female/male counts), age (median and range), ECOG performance status, histology, clinical stage, PD-L1 status, and smoking status. Both sexes are enrolled, so sex_justified is not applicable. Age and health status (ECOG PS) are reported. Demographics are adequate for a clinical 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

Patient demographics including sex, age, and clinical characteristics are reported in Table 1; sex distribution is balanced and no single-sex justification is needed.

Evidence

“n (female, male) | 30 (15, 15) | 30 (13, 17) | | Age in years, median (range) | 64 (43–77) | 67 (43–81)”

Table 1Find in source

“ECOG PS (0, 1) | 28, 2 | 28, 2”

Table 1Find in source

PASSReviewer 2· 90% conf

Patient demographics, including sex, age, and clinical characteristics, are reported in Table 1; sex is balanced across arms, so no single-sex justification is needed.

Evidence

“n (female, male) | 30 (15, 15) | 30 (13, 17) | | Age in years, median (range) | 64 (43–77) | 67 (43–81)”

Table 1Find in source

“Histology | | Adenocarcinoma | 13 | 15 | | Squamous cell carcinoma | 10 | 9 | | Adenosquamous carcinoma | 2 | 2 | | Other | 5 | 4”

Table 1Find in source

The paper names the Ethics Committee of the Medical Faculty of the University Duisburg-Essen (approval 19-8828-AF) and other ethics committees for each site, with protocol numbers. It states that all patients provided written informed consent. Regulatory compliance with the Declaration of Helsinki and ICH-GCP is explicitly mentioned.

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 trial has explicit ethics committee approvals from named bodies, informed consent is documented, and compliance with the Declaration of Helsinki and ICH-GCP is stated.

Evidence

“the Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Essen, Germany, granted primary approval on 10 September 2019 (19-8828-AF).”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval from named committees and regulatory authorities is documented, and written informed consent is reported.

Evidence

“The Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Essen, Germany, granted primary approval on 10 September 2019 (19-8828-AF).”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

The drugs are named with manufacturer (Bristol Myers Squibb) and dosing (240 mg and 80 mg). Software tools for analysis are identified with versions (e.g., EdgeR v.3.40.0, Snakemake workflows) and code repositories are provided. Antibodies and reagents used in exploratory assays are identified with catalog numbers (e.g., PD-L1 clone 22C3, DAKO/Agilent M3653).

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational drugs (nivolumab and relatlimab) are identified with doses and schedule; software tools are identified with versions and repositories.

Evidence

“two doses of nivolumab (240 mg every 14 days per intravenous infusion, arm A) or nivolumab and relatlimab (240 and 80 mg, respectively, every 14 days per intravenous infusion, arm B)”

MethodsFind in source

“Further data analysis was performed using our open-source Snakemake workflow dna-seq-varlociraptor (v.3.24, https://github.com/snakemake-workflows/dna-seq-varlociraptor )”

MethodsFind in source

“PD-L1 expression by tumor cells was assessed locally using the primary antibody clone 22C3 (DAKO/Agilent M3653)”

MethodsFind in source

PASSReviewer 2· 85% conf

The investigational drugs (nivolumab and relatlimab) are identified with doses and schedule, and software tools are named with versions and repositories.

Evidence

“This manuscript reports results from arms A and B of the study, which treated patients with two doses of nivolumab (240 mg every 14 days per intravenous infusion, arm A) or nivolumab and relatlimab (240 and 80 mg, respectively, every 14 days per intravenous infusion, arm B).”

MethodsFind in source

“Further data analysis was performed using our open-source Snakemake workflow dna-seq-varlociraptor (v.3.24, https://github.com/snakemake-workflows/dna-seq-varlociraptor )”

MethodsFind in source

The paper names tests (e.g., Wilcoxon matched pairs signed-rank test, log-rank test, EdgeR quasi-likelihood F-test). Exact p-values are reported for exploratory analyses (e.g., P = 0.04, P = 0.068). Effect sizes are presented as rates and survival percentages with confidence intervals implied in Kaplan-Meier curves. Statistical software is identified (EdgeR, etc.). Data presentation includes individual patient dots in figures and per-group n. Mathematical plausibility is not applicable for large-N continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical tests are named, p-values are reported exactly in exploratory analyses, effect sizes are presented with confidence intervals where applicable, and software is identified.

Evidence

“Wilcoxon matched pairs signed-rank test was applied for statistical comparison.”

Figure 3Find in source

“Comparable effects were observed in responders treated with nivolumab monotherapy ( n = 13, P = 0.04) and nivolumab plus relatlimab ( n = 13, P = 0.068)”

ResultsFind in source

“differential expression analysis was performed using the quasi-likelihood F -test approach of EdgeR (two-sided, v.3.40.0)”

MethodsFind in source

PASSReviewer 2· 80% conf

Statistical tests are named, effect sizes with CIs are reported for survival endpoints, and the analysis is largely descriptive as appropriate for a phase 2 trial; however, some p-values are reported as thresholds and exact p-values are not consistently provided.

Evidence

“Wilcoxon matched pairs signed-rank test was applied for statistical comparison.”

Figure 3Find in source

paraphrase[Results, Secondary outcomes]

“With a median duration of follow-up of 12 months, rates of DFS and overall survival (OS) at 12 months were 89% and 93% with nivolumab monotherapy, and 93% and 100% with nivolumab plus relatlimab.”

“Comparable effects were observed in responders treated with nivolumab monotherapy ( n = 13, P = 0.04) and nivolumab plus relatlimab ( n = 13, P = 0.068)”

ResultsFind in source

The data availability statement describes a managed-access process via the sponsor's Data Access Committee with a response timeframe. De-identified raw sequencing data are deposited in EGA with accession EGAS00001007753. Code is available in Zenodo with DOIs. For patient-level clinical data, managed access is appropriate and adequately described.

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability statement is concrete with a managed-access route, sequencing data are deposited in EGA with accession, and code is shared in Zenodo repositories.

Evidence

“Requests should be submitted to the Office of Data Governance of the study sponsor, University Hospital Essen ( https://www.uk-essen.de/ ), which also serves as Data Access Committee (DAC). Responses can be expected within 4 weeks.”

Data availabilityFind in source

“De-identified raw data from gene expression profiling and whole-exome sequencing have been deposited in the European Genome-Phenome Archive (EGA) with accession number EGAS00001007753”

Data availabilityFind in source

“The Snakemake workflows for whole-exome sequencing analysis and NanoString nCounter gene expression analysis can be found at https://zenodo.org/records/10838511”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability statement is present with a concrete access route (EGA accession and data access committee), and code is shared in public repositories.

Evidence

“De-identified raw data from gene expression profiling and whole-exome sequencing have been deposited in the European Genome-Phenome Archive (EGA) with accession number EGAS00001007753 (https://ega-archive.org/studies/EGAS00001007753) . Requests should be submitted to the Office of Data Governance of the study sponsor, University Hospital Essen ( https://www.uk-essen.de/ ), which also serves as Data Access Committee (DAC). Responses can be expected within 4 weeks.”

Data availabilityFind in source

“The Snakemake workflows for whole-exome sequencing analysis and NanoString nCounter gene expression analysis can be found at https://zenodo.org/records/10838511 (ref. ) and https://zenodo.org/doi/10.5281/zenodo.10838907 (ref. ).”

Data availabilityFind in source

The trial is registered with ClinicalTrials.gov identifier NCT04205552. Methods are comprehensive. Limitations are explicitly discussed, including sample size, lack of formal statistical comparison, and potential bias from PD-L1 imbalance. Conclusions are appropriately cautious. Funding sources and competing interests are disclosed.

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· 90% conf

The trial is registered (NCT04205552), methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov Indentifier: NCT04205552”

AbstractFind in source

“First, the moderate sample size and study design preclude formal assessment of clinical efficacy, and appreciation of an additional contribution of relatlimab to pathological and radiographic response rates and survival endpoints.”

Discussion ¶3Find in source

“M.S., K.C., B.H., J.K., F.M., A.P., B.M., H.R., P.B., A.S. and C.A. received institutional funding, paid to the University Hospital Essen, from Bristol Myers Squibb to support the study NEOpredict-Lung.”

Competing interestsFind in source

PASSReviewer 2· 85% conf

The trial is registered (NCT04205552), methods are detailed, limitations are discussed, and funding/COI are disclosed; however, no reporting guideline (e.g., CONSORT) is explicitly mentioned.

Evidence

“ClinicalTrials.gov Indentifier: NCT04205552 (https://clinicaltrials.gov/ct2/show/NCT04205552)”

AbstractFind in source

Discussion ¶3Find in source

Competing interestsFind in source

Registered (2 IDs: ClinicalTrials.gov, EudraCT). 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 52 references by DOI: 50 verified — 2 no DOI (shown, not verified).

6 data/code links checked; 6 live.

Copyediting

5 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported, with minor reporting gaps that do not undermine its conclusions. An informed reader should weigh the lack of a formal power calculation and the absence of an explicit reporting guideline, but these are not validity threats. The copyedit issues are minor and do not warrant a correction.

1.
HIGHreporting
Add an explicit statement of adherence to a reporting guideline (e.g., CONSORT) in the Methods or Reporting Summary, and include a completed checklist as supplementary material.
The paper does not explicitly mention a reporting guideline, which is a standard expectation for clinical trials and would strengthen transparency.
2.
HIGHstatistics
Add a formal power analysis or sample size justification with effect size, alpha, and power in the Statistical analyses section.
The current sample size rationale is feasibility-based; a formal power calculation would clarify the study's ability to detect clinically meaningful differences.
3.
MEDIUMstatistics
Provide exact p-values for all statistical comparisons, especially in figures, rather than only thresholds like 'P < 0.05'.
Exact p-values allow readers to assess the strength of evidence more precisely.
4.
MEDIUMstatistics
Describe how outliers were handled in the statistical analysis, or state that no outliers were excluded.
The paper does not explicitly describe outlier handling, which is a common reviewer request for transparency.
5.
MEDIUMstatistics
Include a statement on verification of statistical assumptions (e.g., normality, proportional hazards) for the tests used.
Verification of assumptions is important for the validity of the statistical tests employed.
6.
MEDIUMreporting
Clarify the blinding status: since the trial is open-label, state explicitly that blinding was not feasible and why.
Explicitly stating the lack of blinding and its rationale addresses a potential reviewer concern.
7.
MEDIUMdata code
In the Data Availability section, specify the conditions for data access more concretely (e.g., proposal requirements, approval criteria).
More concrete access conditions would improve the reproducibility of the data sharing process.
8.
MEDIUMreporting
Add a section on patient and public involvement if applicable, or state that it was not done.
Patient and public involvement is increasingly expected in clinical research reporting.
9.
MEDIUMreporting
Consider reporting the study according to the CONSORT extension for pilot/feasibility trials.
This extension is specifically designed for feasibility studies and would improve reporting completeness.
10.
MEDIUMreporting
In the Discussion, explicitly address the lack of formal statistical comparison between arms as a limitation and suggest future confirmatory trials.
This would strengthen the interpretation of the results and set expectations for future work.
11.
LOWcopyedit
Fix the typo 'Indentifier' to 'Identifier' in the Abstract.
Correcting the typo improves professionalism and readability.
12.
LOWcopyedit
Clarify the ambiguous 'respectively' in the Results section regarding pathological responses (60% and 72%) to specify which arm each percentage refers to.
Ambiguous phrasing can lead to misinterpretation of the results.
13.
LOWcopyedit
Clarify the sentence about DFS and OS rates to explicitly state that 89% and 93% refer to DFS and OS respectively for arm A, and similarly for arm B.
This prevents potential misreading of the survival outcomes.
14.
LOWcopyedit
Specify which secondary parameters were evaluated with which summary statistics (means, medians, ranges, SD, CI) in the Statistical analyses section.
The current description is vague and could be more precise.

Full text (76,739 chars · analyzed ~98%, head + tail)Analyzed: Aug 16, 2026

Start the discussion on JRNLClub

Community discussion on jrnlclub.com

Read alongside

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Read full text (PMC)

DOI

10.1038/s41591-024-02965-0

Share this Kaimen Rigor review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://alpha1science.com/verify/7150f091-4ade-4080-8cf4-4cb9575e4d7b" target="_blank" rel="noopener">
  <img src="https://alpha1science.com/verify/7150f091-4ade-4080-8cf4-4cb9575e4d7b/badge" alt="Kaimen Rigor review — 2.75★ (Weak), 0 critical, 2 high issues for “Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Kaimen Rigor review.

Record fingerprint

2324fb14eb08b15ae5365fdc449c114248a2b8baefa1727c582f0d23470e475c

Verify via API

Issued Aug 16, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

2.75 / 5

Weak — serious problems found

Interventional 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★
StatisticsPrinted percentage does not match its own count (capped) ×2−0.25★

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 pathological response (major pathological response, MPR) and radiographic response rates, which are surrogate endpoints. The study does not demonstrate target engagement at the tested dose (no PK/PD data) and does not cite validated evidence linking MPR to long-term clinical outcomes in this setting. The paper itself acknowledges limitations in assessing clinical efficacy.
“The rates of major pathological responses (MPR, ≤10% viable tumor cells) were 27% and 30% ... With a median duration of follow-up of 12 months, rates of DFS and overall survival (OS) at 12 months were 89% and 93% with nivolumab monotherapy, and 93% and 100%…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect sizes (e.g., MPR rates of 27% and 30%) are presented without anchoring to a minimal clinically important difference or to the normal/reference value. The study is not powered for efficacy and the authors state it was not designed for formal statistical comparison. The clinical meaningfulness of these response rates is not established.
“The study was not designed for formal statistical comparison of both treatment arms. ... the moderate sample size and study design preclude formal assessment of clinical efficacy.”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
30% does not match the reported count 9/29
“and 30%”
Results
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
89% does not match the reported count 27/30
“rates of DFS and overall survival (OS) at 12 months were 89% and 93% with nivolumab monotherapy”
ResultsFind in source

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit5 minor suggestions

Numerical inconsistencies

2 findings · worst medium

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

2 printed percentages that do not match their own count.

Overstated conclusions

2 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

6 major claims checked against the paper's own evidence: all 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 study builds on a well-established rationale for neoadjuvant immunotherapy and dual PD-1/LAG-3 blockade, citing prior clinical and preclinical evidence.

Evidence

paraphrase[Introduction, paragraphs 2-4]

paraphrase[Introduction, paragraph 4]

“Dual blockade of both immune checkpoints synergistically enhanced T cell function and antitumor activity in preclinical models.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The study builds on a well-established rationale for neoadjuvant immunotherapy and dual PD-1/LAG-3 blockade, citing prior clinical and preclinical evidence.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Based on their distinct and potentially synergistic mode of action, combined targeting of the immune checkpoints LAG-3 and PD-1 is a rational choice to overcome immune resistance in NSCLC.”

Introduction ¶4Find in source

Introduction ¶3Find in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The trial is a randomized, open-label phase 2 study with a clear primary endpoint and predefined feasibility criteria; randomization method and inclusion/exclusion criteria are described.

Evidence

“Patients were randomly assigned (1:1) via an interactive web response system provided by Alcedis GmbH”

MethodsFind in source

paraphrase[Methods, Study design and treatment]

“NEOpredict-Lung is an open-label, randomized phase 2 trial”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

Evidence

“Patients were randomly assigned (1:1) via an interactive web response system provided by Alcedis GmbH ( https://www.alcedis.de/en ); there was no stratification or blinding.”

MethodsFind in source

paraphrase[Methods, Clinical study]

Statistical analysisFind in source

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

Patient demographics including sex, age, and clinical characteristics are reported in Table 1; sex distribution is balanced and no single-sex justification is needed.

Evidence

“n (female, male) | 30 (15, 15) | 30 (13, 17) | | Age in years, median (range) | 64 (43–77) | 67 (43–81)”

Table 1Find in source

“ECOG PS (0, 1) | 28, 2 | 28, 2”

Table 1Find in source

PASSReviewer 2· 90% conf

Patient demographics, including sex, age, and clinical characteristics, are reported in Table 1; sex is balanced across arms, so no single-sex justification is needed.

Evidence

“n (female, male) | 30 (15, 15) | 30 (13, 17) | | Age in years, median (range) | 64 (43–77) | 67 (43–81)”

Table 1Find in source

“Histology | | Adenocarcinoma | 13 | 15 | | Squamous cell carcinoma | 10 | 9 | | Adenosquamous carcinoma | 2 | 2 | | Other | 5 | 4”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial has explicit ethics committee approvals from named bodies, informed consent is documented, and compliance with the Declaration of Helsinki and ICH-GCP is stated.

Evidence

“the Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Essen, Germany, granted primary approval on 10 September 2019 (19-8828-AF).”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval from named committees and regulatory authorities is documented, and written informed consent is reported.

Evidence

“The Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Essen, Germany, granted primary approval on 10 September 2019 (19-8828-AF).”

MethodsFind in source

“All patients provided written informed consent before enrollment.”

MethodsFind in source

“The study was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational drugs (nivolumab and relatlimab) are identified with doses and schedule; software tools are identified with versions and repositories.

Evidence

“two doses of nivolumab (240 mg every 14 days per intravenous infusion, arm A) or nivolumab and relatlimab (240 and 80 mg, respectively, every 14 days per intravenous infusion, arm B)”

MethodsFind in source

“Further data analysis was performed using our open-source Snakemake workflow dna-seq-varlociraptor (v.3.24, https://github.com/snakemake-workflows/dna-seq-varlociraptor )”

MethodsFind in source

“PD-L1 expression by tumor cells was assessed locally using the primary antibody clone 22C3 (DAKO/Agilent M3653)”

MethodsFind in source

PASSReviewer 2· 85% conf

The investigational drugs (nivolumab and relatlimab) are identified with doses and schedule, and software tools are named with versions and repositories.

Evidence

MethodsFind in source

“Further data analysis was performed using our open-source Snakemake workflow dna-seq-varlociraptor (v.3.24, https://github.com/snakemake-workflows/dna-seq-varlociraptor )”

MethodsFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Statistical tests are named, p-values are reported exactly in exploratory analyses, effect sizes are presented with confidence intervals where applicable, and software is identified.

Evidence

“Wilcoxon matched pairs signed-rank test was applied for statistical comparison.”

Figure 3Find in source

“Comparable effects were observed in responders treated with nivolumab monotherapy ( n = 13, P = 0.04) and nivolumab plus relatlimab ( n = 13, P = 0.068)”

ResultsFind in source

“differential expression analysis was performed using the quasi-likelihood F -test approach of EdgeR (two-sided, v.3.40.0)”

MethodsFind in source

PASSReviewer 2· 80% conf

Evidence

“Wilcoxon matched pairs signed-rank test was applied for statistical comparison.”

Figure 3Find in source

paraphrase[Results, Secondary outcomes]

“Comparable effects were observed in responders treated with nivolumab monotherapy ( n = 13, P = 0.04) and nivolumab plus relatlimab ( n = 13, P = 0.068)”

ResultsFind in source

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability statement is concrete with a managed-access route, sequencing data are deposited in EGA with accession, and code is shared in Zenodo repositories.

Evidence

Data availabilityFind in source

“De-identified raw data from gene expression profiling and whole-exome sequencing have been deposited in the European Genome-Phenome Archive (EGA) with accession number EGAS00001007753”

Data availabilityFind in source

“The Snakemake workflows for whole-exome sequencing analysis and NanoString nCounter gene expression analysis can be found at https://zenodo.org/records/10838511”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability statement is present with a concrete access route (EGA accession and data access committee), and code is shared in public repositories.

Evidence

Data availabilityFind in source

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· 90% conf

The trial is registered (NCT04205552), methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov Indentifier: NCT04205552”

AbstractFind in source

Discussion ¶3Find in source

Competing interestsFind in source

PASSReviewer 2· 85% conf

The trial is registered (NCT04205552), methods are detailed, limitations are discussed, and funding/COI are disclosed; however, no reporting guideline (e.g., CONSORT) is explicitly mentioned.

Evidence

“ClinicalTrials.gov Indentifier: NCT04205552 (https://clinicaltrials.gov/ct2/show/NCT04205552)”

AbstractFind in source

Discussion ¶3Find in source

Competing interestsFind in source

Registered (2 IDs: ClinicalTrials.gov, EudraCT). 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 52 references by DOI: 50 verified — 2 no DOI (shown, not verified).

6 data/code links checked; 6 live.

Copyediting

5 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
Add an explicit statement of adherence to a reporting guideline (e.g., CONSORT) in the Methods or Reporting Summary, and include a completed checklist as supplementary material.
The paper does not explicitly mention a reporting guideline, which is a standard expectation for clinical trials and would strengthen transparency.
2.
HIGHstatistics
Add a formal power analysis or sample size justification with effect size, alpha, and power in the Statistical analyses section.
The current sample size rationale is feasibility-based; a formal power calculation would clarify the study's ability to detect clinically meaningful differences.
3.
MEDIUMstatistics
Provide exact p-values for all statistical comparisons, especially in figures, rather than only thresholds like 'P < 0.05'.
Exact p-values allow readers to assess the strength of evidence more precisely.
4.
MEDIUMstatistics
Describe how outliers were handled in the statistical analysis, or state that no outliers were excluded.
The paper does not explicitly describe outlier handling, which is a common reviewer request for transparency.
5.
MEDIUMstatistics
Include a statement on verification of statistical assumptions (e.g., normality, proportional hazards) for the tests used.
Verification of assumptions is important for the validity of the statistical tests employed.
6.
MEDIUMreporting
Clarify the blinding status: since the trial is open-label, state explicitly that blinding was not feasible and why.
Explicitly stating the lack of blinding and its rationale addresses a potential reviewer concern.
7.
MEDIUMdata code
In the Data Availability section, specify the conditions for data access more concretely (e.g., proposal requirements, approval criteria).
More concrete access conditions would improve the reproducibility of the data sharing process.
8.
MEDIUMreporting
Add a section on patient and public involvement if applicable, or state that it was not done.
Patient and public involvement is increasingly expected in clinical research reporting.
9.
MEDIUMreporting
Consider reporting the study according to the CONSORT extension for pilot/feasibility trials.
This extension is specifically designed for feasibility studies and would improve reporting completeness.
10.
MEDIUMreporting
In the Discussion, explicitly address the lack of formal statistical comparison between arms as a limitation and suggest future confirmatory trials.
This would strengthen the interpretation of the results and set expectations for future work.
11.
LOWcopyedit
Fix the typo 'Indentifier' to 'Identifier' in the Abstract.
Correcting the typo improves professionalism and readability.
12.
LOWcopyedit
Clarify the ambiguous 'respectively' in the Results section regarding pathological responses (60% and 72%) to specify which arm each percentage refers to.
Ambiguous phrasing can lead to misinterpretation of the results.
13.
LOWcopyedit
Clarify the sentence about DFS and OS rates to explicitly state that 89% and 93% refer to DFS and OS respectively for arm A, and similarly for arm B.
This prevents potential misreading of the survival outcomes.
14.
LOWcopyedit
Specify which secondary parameters were evaluated with which summary statistics (means, medians, ranges, SD, CI) in the Statistical analyses section.
The current description is vague and could be more precise.

Full text (76,739 chars · analyzed ~98%, head + tail)Analyzed: Aug 16, 2026