Alpha¹ by KaimenConfidential

Kaimen Rigor review

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.

Elez E, Yoshino T, Shen L, Lonardi S, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Morris VK, Wu C, Usari T, Laliberte R, Dychter SS, Zhang X, Tabernero J, Kopetz S, BREAKWATER Trial Investigators

DOI: 10.1056/NEJMoa2501912
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-20

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/3a922189-b074-48e5-9a3f-ba565e44b7c8 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
StatisticsPrinted percentage does not match its own count (capped) ×3−0.25★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 4 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
60.9% is unattainable for n=236 (nearest: 60.6, 61%)
“confirmed objective response rate 60.9% (95% CI 59.4, 71.4)”
EC+mFOLFOX6 arm, confirmed ORRFind in source
02Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
52% is unattainable for n=243 (nearest: 51.9, 52.3%)
“overall survival probability 52.0% vs. 29.0% at 24 months”
SOC arm, OS at 12 monthsFind in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
29% is unattainable for n=243 (nearest: 28.8, 29.2%)
“overall survival probability 29.0% at 24 months”
SOC arm, OS at 24 monthsFind in source

Findings by category

201ArithmeticNumerical inconsistencies 02OverreachNone found 103AuthenticityData authenticity concerns 104DisclosureReporting gaps 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 phase 3 randomized trial with rigorous design, clear reporting of demographics, ethics, and statistical methods. The main weaknesses are the lack of a formal data availability statement and the omission of statistical software identification, both of which are minor reporting gaps. The copyedit pass identified a few minor typographical and grammatical issues that do not affect the scientific integrity.

Both reviewers classified the study as interventional, and this was adopted. The evaluation covered the full text, with all eight dimensions scored. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification component checked only a subset of reported tests; the three 'inconsistent' results were not detailed and may reflect rounding or unverifiable threshold-only p-values, so they were not treated as 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

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks. 3 printed percentages that do not match their own count.

Numeric forensics— values impossible for the reported sample size

PERCENT
60.9% is unattainable for n=236 (nearest: 60.6, 61%)
“confirmed objective response rate 60.9% (95% CI 59.4, 71.4)”
EC+mFOLFOX6 arm, confirmed ORRFind in source
PERCENT
52% is unattainable for n=243 (nearest: 51.9, 52.3%)
“overall survival probability 52.0% vs. 29.0% at 24 months”
SOC arm, OS at 12 monthsFind in source
PERCENT
29% is unattainable for n=243 (nearest: 28.8, 29.2%)
“overall survival probability 29.0% at 24 months”
SOC arm, OS at 24 monthsFind in source

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
PFS HR 0.53 with 95% CI 0.407-0.677
“HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001)”
Find in source
Taken as given: The HR is the point estimate.; The CI is a 95% confidence interval.; The CI is for the hazard ratio (log scale).
Method: Two-sided p-value derived from the reported HR and 95% CI using the normal approximation for the log hazard ratio.
How we recomputed it: pCI(0.53, 0.407, 0.677, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
OS HR 0.49 with 95% CI 0.375-0.632
“HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001)”
Find in source
Taken as given: The HR is the point estimate.; The CI is a 95% confidence interval.; The CI is for the hazard ratio (log scale).
Method: Two-sided p-value derived from the reported HR and 95% CI using the normal approximation for the log hazard ratio.
How we recomputed it: pCI(0.49, 0.375, 0.632, 1)

lowinternal contradiction
In Table 1, the C-reactive protein row for EC+mFOLFOX6 shows '6(25' which appears to be a typo for '6 (2.5)'.
6(25
Table 1reviewer’s wording

Overstated conclusions

None found

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Checked — nothing surfaced.

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

supportedReviewer 1
EC+mFOLFOX6 significantly improves progression-free survival compared to SOC in BRAF V600E-mutant mCRC.
The reported HR 0.53 with 95% CI excluding 1 and P<0.0001 supports the claim.
Evidence: HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001); median PFS 12.8 vs 7.1 months.
“BREAKWATER met its other dual primary endpoint, demonstrating significant progression-free survival improvement with EC+mFOLFOX6 vs. SOC: hazard ratio (HR) 0.53 (95% confidence interval [CI] 0.407, 0.677; two-sided P<0.0001); median progression-free survival 12.8 vs. 7.1 months.”
AbstractFind in source
supportedReviewers 1, 2
EC+mFOLFOX6 significantly improves overall survival compared to SOC.
The reported HR 0.49 with 95% CI excluding 1 and P<0.0001 supports the claim.
Evidence: HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001); median OS 30.3 vs 15.1 months.
“Interim analysis of overall survival demonstrated significant improvement vs. SOC: HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001); median overall survival 30.3 vs. 15.1 months.”
AbstractFind in source
supportedReviewers 1, 2
EC+mFOLFOX6 is the first front-line activation pathway-targeted treatment indicated in BRAF V600E-mutant mCRC.
The paper states this based on FDA accelerated approval, which is a regulatory fact.
Evidence: Statement of FDA accelerated approval.
“EC+mFOLFOX6 is the first front-line activation pathway-targeted treatment indicated in BRAF V600E-mutant mCRC.”
IntroductionFind in source
supportedReviewers 1, 2
The safety profile of EC+mFOLFOX6 is consistent with known profiles of each agent.
The paper reports adverse event rates and states consistency with known profiles.
Evidence: Safety data reported in Results and Tables.
“The safety profile was consistent with that known for each agent and no substantial increase in chemotherapy dose reduction or discontinuation was needed.”
ResultsFind in source
supportedReviewer 2
EC+mFOLFOX6 significantly improves progression-free survival compared to SOC.
The reported HR and p-value directly support this claim.
Evidence: HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001)
“HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001)”
AbstractFind in source

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

ADEQUATESurrogate endpoint
The primary efficacy endpoints are progression-free survival and overall survival, which are hard clinical outcomes. The trial also reports objective response rate, but the main claims are based on survival endpoints.
“BREAKWATER met its other dual primary endpoint, demonstrating significant progression-free survival improvement with EC+mFOLFOX6 vs. SOC: hazard ratio (HR) 0.53 (95% confidence interval [CI] 0.407, 0.677; two-sided P<0.0001); median progression-free survival 12.8 vs. 7.1 months. Interim analysis of overall survival demonstrated significant improvement vs. SOC: HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001); median overall survival 30.3 vs. 15.1 months.”
Find in source
ADEQUATEEffect size
The effect sizes are large and clinically meaningful: median PFS nearly doubled (12.8 vs 7.1 months) and median OS doubled (30.3 vs 15.1 months), with hazard ratios of 0.53 and 0.49, respectively. These are anchored to clinical outcomes and are statistically significant.
“median progression-free survival 12.8 vs. 7.1 months ... median overall survival 30.3 vs. 15.1 months”
Find in source

Data authenticity concerns

1 finding · worst low

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.

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

lowother
The paper reports a median OS of 30.3 months in the EC+mFOLFOX6 arm, which is notably high for BRAF-mutant mCRC, but this is plausible given the significant HR.
“The median overall survival (95% CI) was 30.3 months (21.7, not estimable) and 15.1 months (13.7, 17.7) in the EC+mFOLFOX6 and SOC arms, respectively; HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001)”
ResultsFind in source

Reporting gaps

1 finding · worst medium

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

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior studies (BEACON, ANCHOR) and explains the biological rationale for targeting BRAF and EGFR. It acknowledges the poor prognosis of BRAF-mutant mCRC and the need for better first-line treatment. The limitations of prior work are implicitly addressed by the design of a phase 3 trial with dual primary endpoints.

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 strong scientific premise by citing prior research on BRAF V600E-mutant mCRC, the rationale for combining BRAF and EGFR inhibition, and the need for improved first-line therapy.

Evidence

paraphrase[Introduction, paragraph 1-3]

“Based on results from BEACON, encorafenib plus cetuximab, an anti-EGFR monoclonal antibody, was established as standard of care (SOC) for previously treated BRAF V600E-mutant mCRC.”

“A first-line activation pathway-targeted treatment that can demonstrate improved efficacy in BRAF V600E-mutant mCRC is needed.”

Introduction ¶3Find in source

“Results from the safety lead-in portion of BREAKWATER showed encouraging response rates and progression-free survival of EC+mFOLFOX6 or EC plus irinotecan, leucovorin, and 5-FU (FOLFIRI).”

Introduction ¶4Find in source

PASSReviewer 2· 90% conf

Evidence

paraphrase[Introduction, paragraph 1-3]

“Based on results from BEACON, encorafenib plus cetuximab, an anti-EGFR monoclonal antibody, was established as standard of care (SOC) for previously treated BRAF V600E-mutant mCRC.”

“A first-line activation pathway-targeted treatment that can demonstrate improved efficacy in BRAF V600E-mutant mCRC is needed.”

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 4]

“The study evaluates EC+mFOLFOX6 vs SOC in first-line, building on prior safety lead-in results.”

Randomization was 1:1:1 (later 1:1 after EC arm closure) using Interactive Response Technology, with stratification factors specified. Blinding was applied to the independent central review for response and progression endpoints, though the trial was open-label. A power analysis was provided for the PFS primary endpoint. Inclusion/exclusion criteria were detailed. The analysis population (all randomized) and hierarchical testing procedure were pre-specified.

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· 90% conf

The trial design is rigorous with clear randomization, stratification, and pre-specified endpoints, though blinding is not applicable due to the open-label design.

Evidence

paraphrase[Methods, Trial Design, Patients, and Treatment]

“Randomization was implemented by Interactive Response Technology (details available in the protocol available at NEJM.org).”

“The sample size (235 patients per arm) was determined based on the assumption of an HR of 0.67 under the exponential model assumptions with median progression-free survival of 7 and 10.4 months in the SOC and EC+mFOLFOX6 arms.”

Statistical analysisFind in source

“Exclusion criteria included prior systemic treatment for metastatic disease, prior BRAF or EGFR inhibitor, symptomatic brain metastases, microsatellite instability-high/mismatch repair deficient tumors (MSI-H/dMMR) (unless ineligible to receive immune checkpoint inhibitors), or a RAS mutation.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, stratification, blinding of central review, pre-specified endpoints, and a power analysis.

Evidence

paraphrase[Methods, Trial Design, Patients, and Treatment]

“Randomization was implemented by Interactive Response Technology (details available in the protocol available at NEJM.org).”

paraphrase[Methods, Endpoints]

“The dual primary endpoints are objective response rate ... and progression-free survival both by blinded independent central review”

“this number of events was required to have at least 85% power to detect an HR of 0.67 using a one-sided stratified log-rank test at a significance level of 0.023.”

Statistical analysisFind in source

Sex is reported for all arms. Age is reported as median and range. Demographics include race, tumor side, stage, and other characteristics. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Patient demographics and baseline characteristics are thoroughly reported, including sex, age, race, and disease characteristics.

Evidence

paraphrase[Table 1]

“Sex — no. (%) | Male | 79 (50.0) | 123 (52.1) | 119 (49.0) | | Female | 79 (50.0) | 113 (47.9) | 124 (51.0)”

paraphrase[Table 1]

“Race — no. (%) | White | 88 (55.7) | 141 (59.7) | 144 (59.3)”

PASSReviewer 2· 90% conf

Patient demographics and key clinical characteristics are reported in detail, including sex, age, race, and disease characteristics.

Evidence

paraphrase[Table 1]

“Male 79 (50.0) | 123 (52.1) | 119 (49.0)”

paraphrase[Table 1]

“Median 59.0 | 60.0 | 62.0”

paraphrase[Table 1]

“Liver metastases — no. (%) Yes 94 (59.5) | 147 (62.3) | 160 (65.8)”

The protocol was approved by the relevant ethics committee/institutional review board at each site. Informed consent was obtained from patients. Regulatory compliance is stated with the Declaration of Helsinki and ICH-GCP. The ethics statement is adequate.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethical approvals and informed consent are adequately reported, with a named ethics committee approval and compliance with the Declaration of Helsinki.

Evidence

“The protocol, including amendments, is available at NEJM.org and was approved by the relevant ethics committee/institutional review board at each site.”

MethodsFind in source

“Informed consent was obtained from patients before enrollment.”

MethodsFind in source

“BREAKWATER was performed in accordance with consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and CIOMS International Ethical Guidelines, applicable International Conference on Harmonization Good Clinical Practice guidelines, and applicable laws and regulations, including applicable privacy laws.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethical approval and informed consent are adequately documented.

Evidence

“The protocol, including amendments, is available at NEJM.org and was approved by the relevant ethics committee/institutional review board at each site.”

MethodsFind in source

“Informed consent was obtained from patients before enrollment.”

MethodsFind in source

The drugs are named with manufacturers (Pfizer, etc.) and dosing regimens are provided. The statistical software is not explicitly named, but the analysis methods are described. Since this is a drug trial, the bench criteria (antibodies, cell lines, mycoplasma, organisms) are not applicable. Reagents are the investigational products, which are adequately identified.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (encorafenib, cetuximab, and chemotherapies) are adequately identified with dosing details, and statistical software is identified.

Evidence

paraphrase[Methods, Trial Design, Patients, and Treatment]

“Patients were randomized 1:1:1 to receive EC (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks), EC+mFOLFOX6 (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks; oxaliplatin 85 mg/m2 intravenously, leucovorin 400 mg/m2 intravenously, and 5-FU 400 mg/m2 intravenous bolus, then 5-FU 2400 mg/m2 continuous intravenous infusion over 46–48 hours, all once every 2 weeks [mFOLFOX6; 28-day cycle]), or investigator’s choice SOC (mFOLFOX6 with or without bevacizumab; FOLFOXIRI with or without bevacizumab; CAPOX with or without bevacizumab; dosing reported previously).”

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 85% conf

The investigational drugs and key reagents are identified with dosing details, and statistical software is not specified but the trial is a drug trial.

Evidence

paraphrase[Methods, Trial Design, Patients, and Treatment]

“EC (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks)”

paraphrase[Methods, Trial Design, Patients, and Treatment]

“oxaliplatin 85 mg/m2 intravenously, leucovorin 400 mg/m2 intravenously, and 5-FU 400 mg/m2 intravenous bolus, then 5-FU 2400 mg/m2 continuous intravenous infusion over 46–48 hours”

Tests are named (Cox proportional hazards, Kaplan-Meier, log-rank). Assumptions are handled by design (stratified Cox model). Exact p-values are reported (e.g., P<0.0001). Effect sizes are reported with 95% CIs. Statistical software is not identified, but this is a minor omission. Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility is not applicable for large-N continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are rigorous with named tests, exact p-values, effect sizes with CIs, and appropriate data presentation for a clinical trial.

Evidence

“The treatment effect of progression-free survival was evaluated using a Cox proportional hazards model stratified by baseline stratification factors.”

Statistical analysisFind in source

“HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001)”

ResultsFind in source

“HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001)”

ResultsFind in source

PASSReviewer 2· 90% conf

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

Evidence

“The treatment effect of progression-free survival was evaluated using a Cox proportional hazards model stratified by baseline stratification factors.”

Statistical analysisFind in source

“HR 0.53 (95% CI 0.407, 0.677; two-sided P<0.0001)”

ResultsFind in source

“HR 0.49 (95% CI 0.375, 0.632; two-sided P<0.0001)”

ResultsFind in source

The paper does not include a dedicated data availability statement. The protocol is available at NEJM.org, but individual patient data are not deposited in a repository. Since this is a clinical trial with identifiable patient data, repository deposit and accession numbers are not applicable. Code sharing is not applicable as no bespoke code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

The data availability statement is vague, stating data are available from the corresponding author on reasonable request, but no repository or managed-access mechanism is specified.

Evidence

absence[Entire paper]

No explicit data availability statement is present.

“The protocol, including amendments, is available at NEJM.org”

MethodsFind in source

WARNReviewer 2· 80% conf

The data availability statement is vague, and no data repository or code sharing is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

Methods are detailed enough for replication. Trial registration number is provided (NCT04607421). A reporting guideline (CONSORT) is not explicitly mentioned, but the paper follows clinical trial reporting standards. All pre-specified outcomes are reported. Limitations are discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent with detailed methods, trial registration, and discussion of limitations, though a reporting guideline is not explicitly mentioned.

Evidence

paraphrase[Abstract and Introduction]

“ClinicalTrials.gov number, NCT04607421”

“BREAKWATER was sponsored by Pfizer with support from ONO Pharmaceutical, Merck KGaA, Darmstadt, Germany, and Eli Lilly and Company.”

FundingFind in source

“The safety data continued to show that EC+mFOLFOX6 caused grade 3 or higher adverse events in more than half that patients but the adverse events were largely reversible.”

DiscussionFind in source

PASSReviewer 2· 90% conf

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

Evidence

paraphrase[Abstract and Introduction]

“ClinicalTrials.gov number, NCT04607421”

“EC arm enrollment was closed based on the low likelihood of EC demonstrating superiority versus SOC”

DiscussionFind in source

“BREAKWATER was sponsored by Pfizer with support from ONO Pharmaceutical, Merck KGaA, Darmstadt, Germany, and Eli Lilly and Company.”

FundingFind in source

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

ClinicalTrials.gov

NCT04607421

ClinicalTrials.gov

NCT05217446

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 22 references by DOI: 17 verified — 5 no DOI (shown, not verified).

NO DOI
Abstract 3790: Preclinical profile of LGX818: a potent and selective RAF kinase inhibitor
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
515MO Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): updated results from the BREAKWATER safety lead-in (SLI)
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC)
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Welcome to the ICH MedDRA website
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

2 of 3 data/code links checked; 2 live; 1 not probed.

datahttps://clinicaltrials.gov/ct2/show/NCT04607421LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://clinicaltrials.gov/ct2/show/NCT05217446LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://www.nejm.org/doi/full/10.1056/NEJMoa2501912UNVERIFIEDHTTP 403
Liveness indeterminate — content not checked.

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.

MINORtypoTable 1, C-reactive protein row
“6(25”
→ 6 (2.5)
Missing closing parenthesis and space.
MINORconsistencyDiscussion
“more than half that patients”
→ more than half of patients
Grammatical error.
MINORclarityResults, Safety
“grade 5 (fatal) adverse events in 2.6%, 4.3%, and 4.4%, only one patient in the SOC arm experienced a grade 5 treatment-related adverse event”
→ Consider rephrasing for clarity.
Run-on sentence.
MINORconsistencyResults, Safety
“more than half that patients”
→ more than half of the patients
Grammatical error.
MINORclarityDiscussion
“The safety data continued to show that EC+mFOLFOX6 caused grade 3 or higher adverse events in more than half that patients but the adverse events were largely reversible.”
→ The safety data continued to show that EC+mFOLFOX6 caused grade 3 or higher adverse events in more than half of the patients, but the adverse events were largely reversible.
Clarify wording.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and the findings are credible, but an informed reader should weigh the absence of a formal data availability statement and the lack of statistical software identification as minor transparency gaps. The copyedit issues are trivial and do not warrant a correction, but the authors should consider issuing a data availability clarification or a minor erratum for the typographical errors.

1.
HIGHdata code
Add a formal data availability statement in the Methods or a dedicated section, specifying that de-identified patient data may be requested from the sponsor through a data access committee, with conditions and a timeframe.
The absence of a data availability statement is a reporting gap that limits transparency and reproducibility for a data-driven clinical trial.
2.
HIGHstatistics
Identify the statistical software (e.g., SAS version) used for analyses in the Statistical Analysis section.
Naming the software is a standard reporting expectation that aids reproducibility and was flagged by both reviewers.
3.
MEDIUMreporting
Mention adherence to CONSORT reporting guidelines in the Methods or as a supplementary file.
Explicitly referencing CONSORT would strengthen the transparency of the trial reporting.
4.
MEDIUMcopyedit
Fix the typo in Table 1, C-reactive protein row: change '6(25' to '6 (2.5)'.
The current text is missing a closing parenthesis and space, which could be misread as an impossible value.
5.
MEDIUMcopyedit
Correct the grammatical error in the Discussion: change 'more than half that patients' to 'more than half of the patients'.
The phrase is grammatically incorrect and appears twice in the manuscript.
6.
LOWcopyedit
Rephrase the run-on sentence in Results, Safety regarding grade 5 adverse events for clarity.
The sentence is difficult to parse and could be misinterpreted.

Full text (32,559 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.

DOI

10.1056/NEJMoa2501912

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-20