Rigor Reviewed

Rigor-Reviewed Manuscript

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

Name: Adcurare Rigor Record — Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.
Item: Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.
Rating: 96
Author: Adcurare

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

Paper source

Read full text (PMC)Journal

Embed this Rigor badge

Adcurare Rigor Review — 4.75★ (Strong), 0 critical, 5 high issues for “Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.”

Links back to this Rigor Record.

Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

4.75 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.6.0Source: full text

Problems surfaced1 type

Data/code availability incomplete

This Adcurare Rigor Review uses AI 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.

The BREAKWATER trial is well-designed and reported, with strong scientific premise, rigorous statistical analysis, and transparent reporting. The primary gap is the absence of a data availability statement. Minor improvements include naming the statistical software and citing a reporting guideline.

Evaluated the full manuscript text. All three independent reviewers substantially agreed; divergence was limited to minor checklist sub-criterion ratings. Coverage: statistics component verified 6 of 6 recomputed tests as consistent; citation component found no retracted or not-found references; reproducibility component confirmed all 8 checked links live; registry audit confirmed prospective registration. Dimensions not applicable (e.g., animal biology, code sharing) were excluded from scoring.

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

Recomputed 6 tests: 6 consistent, 0 inconsistent, 6 via agent-written checks.

Reporting

Eight Dimensions7 pass · 1 warn

The introduction describes the poor prognosis of BRAF V600E-mutant mCRC, the mechanism of BRAF inhibition and EGFR-mediated feedback reactivation, and the prior BEACON trial. The limitations of current SOC are stated. The majority of sub-criteria are adequate.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study establishes a strong scientific foundation by citing prior research on BRAF V600E-mutant mCRC as a distinct subtype with poor prognosis, the rationale for dual BRAF/EGFR inhibition, and the prior BEACON trial results.

Evidence

direct quote[Introduction, paragraphs 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.”

direct quote[Introduction, paragraph 3]

“chemotherapy with or without a biologic agent (e.g., bevacizumab) was the SOC for BRAF V600E-mutant mCRC and was associated with inferior outcomes versus BRAF wild-type mCRC”

direct quote[Introduction, paragraph 3]

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

PASSReviewer 2· 95% conf

The scientific premise is well-established, citing prior work on BRAF V600E-mutant mCRC as a distinct poor-prognosis subtype, the mechanism of EGFR-mediated feedback reactivation, and the rationale for combining BRAF and EGFR inhibition with chemotherapy.

Evidence

direct quote[Introduction, paragraphs 1-2]

“BRAF V600E-mutant mCRC has emerged as a distinct mCRC subtype characterized by poor prognosis versus BRAF wild-type disease and lower responses to chemotherapy.”

direct quote[Introduction, paragraph 2]

“In CRC, BRAF inhibition can cause rapid pathway feedback reactivation through epidermal growth factor receptor (EGFR), attenuating its activity.”

direct quote[Introduction, paragraph 2]

“In the first-line setting, chemotherapy with or without a biologic agent (e.g., bevacizumab) was the SOC for BRAF V600E-mutant mCRC and was associated with inferior outcomes versus BRAF wild-type mCRC (median progression-free survival of 5.8 vs. 9.2 months; median overall survival of 11.1 vs. 23.7 months).”

PASSReviewer 3· 90% conf

The study clearly establishes its scientific premise by citing prior research on BRAF V600E-mutant mCRC, the mechanism of encorafenib, and the rationale for combining BRAF and EGFR inhibition.

Evidence

direct quote[INTRODUCTION, paragraph 1]

“BRAF V600E-mutant mCRC has emerged as a distinct mCRC subtype characterized by poor prognosis versus BRAF wild-type disease and lower responses to chemotherapy.”

direct quote[INTRODUCTION, paragraph 1]

“Encorafenib is a highly selective, ATP-competitive, small molecule BRAF inhibitor with anti-proliferative and apoptotic activity in tumor cells expressing BRAF V600E mutations and has prolonged pharmacodynamic activity compared with other approved BRAF inhibitors. , In CRC, BRAF inhibition can cause rapid pathway feedback reactivation through epidermal growth factor receptor (EGFR), attenuating its activity.”

direct quote[INTRODUCTION, paragraph 2]

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

The study is a phase 3 open-label randomized trial. Randomization was implemented by Interactive Response Technology. Inclusion/exclusion criteria are described. A sample size calculation is provided. The open-label design is stated. Replication of findings is not applicable for a single pivotal trial. Controls: the SOC arm serves as the comparator.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingN/A

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is a well-described phase 3 randomized trial with a pre-specified primary analysis and sample size calculation. Blinding is not possible due to the open-label design, and this is stated. The trial is registered.

Evidence

direct quote[Methods, Trial Design]

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

direct quote[Methods, Statistical Analysis]

“The primary analysis of progression-free survival was preplanned to occur after ≥230 events... 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.”

direct quote[Abstract]

“The open-label, phase 3 BREAKWATER study”

PASSReviewer 2· 90% conf

The study design is rigorous for a phase 3 open-label trial. Randomization, stratification, and a pre-specified power analysis are reported. Blinding is not applicable due to the open-label design, which is stated. Inclusion/exclusion criteria are clearly defined.

Evidence

direct quote[Methods, Trial Design, Patients, and Treatment]

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

direct quote[Methods, Statistical Analysis]

“The primary analysis of progression-free survival was preplanned to occur after ≥230 events for the EC+mFOLFOX6 and SOC arms and ≥12 months after the completion of enrollment of the phase 3 portion of the study; 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.”

direct quote[Methods, Trial Design, Patients, and Treatment]

“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.”

PASSReviewer 3· 90% conf

The study design is robust, detailing randomization, blinding, inclusion/exclusion criteria, and a power analysis for the primary endpoint.

Evidence

direct quote[METHODS, TRIAL DESIGN, PATIENTS, AND TREATMENT, paragraph 2]

“Patients were randomized 1:1:1 to receive EC, EC+mFOLFOX6 or SOC.”

direct quote[METHODS, TRIAL DESIGN, PATIENTS, AND TREATMENT, paragraph 3]

“Randomization stratification factors were Eastern Cooperative Oncology Group performance status (0 vs. 1) (a 5-point scale where higher numbers reflect greater disability) and region (US/Canada vs. Europe vs. Rest of World). Randomization was implemented by Interactive Response Technology (details available in the protocol available at NEJM.org (http://nejm.org) ).”

direct quote[STATISTICAL ANALYSIS, paragraph 1]

“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.”

Table 1 provides a comprehensive breakdown of baseline demographics and disease characteristics, including age (median and range), sex (male/female percentages), race, tumor side, stage, and other clinical features. Age, weight, and health status are captured via ECOG performance status and other baseline labs. Species/strain and housing conditions are not applicable for a human trial. Demographics are adequately reported.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Human subject demographics, including age, sex, race, ECOG status, and disease characteristics, are comprehensively reported in a baseline table.

Evidence

direct quote[Table 1]

“Table 1. Characteristics of Patients at Baseline... Sex — no. (%) Male... Female... Age — yr Median... Race — no. (%) White... Asian...”

PASSReviewer 2· 95% conf

Key biological variables for a human clinical trial are well-reported, including age, sex, race, and disease characteristics. Sex is reported for all arms, and since both sexes are enrolled, a justification for a single sex is not applicable.

Evidence

direct quote[Table 1]

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

direct quote[Table 1]

“Age — yr | | Median | 59.0 | 60.0 | 62.0 | | Range | 26.0–84.0 | 24.0–81.0 | 28.0–84.0”

direct quote[Table 1]

“Side of tumor — no. (%) | | Left | 69 (43.7) | 90 (38.1) | 98 (40.3) | | Right | 89 (56.3) | 146 (61.9) | 145 (59.7)”

PASSReviewer 3· 90% conf

Patient demographics, including age, sex, and race, are comprehensively reported in a baseline characteristics table.

Evidence

direct quote[RESULTS, PATIENTS, paragraph 1]

“Baseline demographics and disease characteristics are reported in .”

direct quote[Table 1]

“Age — yr | | Median | 59.0 | 60.0 | 62.0 | | Range | 26.0–84.0 | 24.0–81.0 | 28.0–84.0 |”

direct quote[Table 1]

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

The paper states that the protocol was approved by the relevant ethics committee/institutional review board at each site, that informed consent was obtained from patients before enrollment, and that the trial was performed in accordance with the Declaration of Helsinki and ICH-GCP guidelines.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study reports ethics committee approval, informed consent, and regulatory compliance, meeting all applicable criteria for a human trial.

Evidence

direct quote[Methods, Trial Oversight]

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

direct quote[Methods, Trial Design]

“Informed consent was obtained from patients before enrollment.”

direct quote[Methods, Trial Oversight]

“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.”

PASSReviewer 2· 90% conf

Ethical approvals are adequately reported. The study states approval by relevant ethics committees/IRBs, informed consent was obtained, and compliance with the Declaration of Helsinki and ICH-GCP is declared.

Evidence

direct quote[Methods, Trial Oversight]

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

direct quote[Methods, Trial Design, Patients, and Treatment]

“Informed consent was obtained from patients before enrollment.”

direct quote[Methods, Trial Oversight]

PASSReviewer 3· 90% conf

The study explicitly states approval by relevant ethics committees/IRBs at each site and that informed consent was obtained from patients.

Evidence

direct quote[METHODS, TRIAL OVERSIGHT, paragraph 1]

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

direct quote[METHODS, TRIAL DESIGN, PATIENTS, AND TREATMENT, paragraph 2]

“Informed consent was obtained from patients before enrollment.”

direct quote[METHODS, TRIAL OVERSIGHT, paragraph 1]

For a drug trial, the investigational product is the key resource. Encorafenib, cetuximab, and the chemotherapy agents (oxaliplatin, leucovorin, 5-FU) are identified with doses, schedules, and routes. No antibodies or cell lines were used for laboratory assays, so those are not applicable. No bespoke software was mentioned.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (encorafenib, cetuximab, chemotherapy agents) are identified by name, manufacturer, dose, and regimen. Software tools are not a major focus, but no bespoke analysis software is described.

Evidence

direct quote[Methods, Trial Design]

“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])”

direct quote[Funding / Trial Oversight]

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

PASSReviewer 2· 85% conf

Key resources for this drug trial are adequately identified. The investigational products (encorafenib, cetuximab, chemotherapies) are named with manufacturers and dosing regimens. Software tools are identified.

Evidence

direct quote[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])”

absence[Methods, Statistical Analysis]

The statistical software is not explicitly named in the main text.

PASSReviewer 3· 90% conf

The investigational products (encorafenib and cetuximab) and chemotherapy components are identified with their dosages and administration routes.

Evidence

direct quote[METHODS, TRIAL DESIGN, PATIENTS, AND TREATMENT, paragraph 2]

“Patients were randomized 1:1:1 to receive EC (encorafenib 300 mg orally once daily; cetuximab 500 mg/m 2 intravenously once every 2 weeks)”

direct quote[METHODS, TRIAL DESIGN, PATIENTS, AND TREATMENT, paragraph 2]

“EC+mFOLFOX6 (encorafenib 300 mg orally once daily; cetuximab 500 mg/m 2 intravenously once every 2 weeks; oxaliplatin 85 mg/m 2 intravenously, leucovorin 400 mg/m 2 intravenously, and 5-FU 400 mg/m 2 intravenous bolus, then 5-FU 2400 mg/m 2 continuous intravenous infusion over 46–48 hours, all once every 2 weeks [mFOLFOX6; 28-day cycle])”

direct quote[ENDPOINTS, paragraph 3]

“Adverse events were coded using Medical Dictionary for Regulatory Activities v27.1, and severity of adverse events was graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.”

The primary analysis uses a stratified Cox proportional hazards model and Kaplan-Meier methodology. The sample size and power calculation are specified. Exact p-values and 95% confidence intervals are reported. The paper describes the hierarchical testing procedure for overall survival. Data presentation includes Kaplan-Meier curves, forest plots, and tables, which is standard for large clinical trials.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The statistical analysis is well-described with named tests, effect sizes, confidence intervals, and exact p-values provided. A pre-planned hierarchical testing procedure controls type I error. Data presentation follows clinical trial conventions.

Evidence

direct quote[Methods, Statistical Analysis]

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

direct quote[Results, Efficacy]

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

direct quote[Methods, Statistical Analysis]

“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.”

PASSReviewer 2· 90% conf

Statistical analysis is rigorous and well-reported. Tests are named, a pre-specified hierarchical testing procedure is described, exact p-values and confidence intervals are reported, and data presentation includes Kaplan-Meier curves and forest plots.

Evidence

direct quote[Methods, Statistical Analysis]

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

direct quote[Results, Efficacy]

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

direct quote[Methods, Statistical Analysis]

“Following a pre-specified hierarchical testing procedure to control the family-wise type I error rate, an interim analysis of the key secondary endpoint of overall survival in all randomized patients could be conducted using a portion of the one-sided alpha of 0.023 if results of the progression-free survival primary analysis were significant”

PASSReviewer 3· 90% conf

The statistical analysis section clearly names tests, specifies alpha levels, and reports exact p-values, hazard ratios, and confidence intervals. Data presentation includes Kaplan-Meier curves and forest plots.

Evidence

direct quote[STATISTICAL ANALYSIS, paragraph 1]

“The primary endpoint of progression-free survival by blinded independent central review was analyzed in all patients randomized using one-sided alpha of 0.023. ... The treatment effect of progression-free survival was evaluated using a Cox proportional hazards model stratified by baseline stratification factors. ... The Kaplan–Meier approach was used to estimate median progression-free survival for each arm; the 95% CIs were calculated using the Brookmeyer–Crowley method.”

direct quote[RESULTS, EFFICACY, paragraph 1]

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

paraphrase[Figure 1, Figure 2]

“Kaplan–Meier estimates of progression-free survival and overall survival are shown in Panel A of Figure 1 and Figure 2, respectively. Forest plots of subgroup analyses are shown in Panel B of Figure 1 and Figure 2.”

For a company-sponsored phase 3 trial, a data availability statement is expected, even if it states that data are not available or are available upon request through a managed-access platform. The paper mentions the protocol is available at NEJM.org but does not include a data availability section. No repository deposit is mentioned. Code sharing is not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

The trial is registered and the protocol is available, but there is no data availability statement or commitment to share individual patient data. The paper does not mention a data-sharing plan or repository.

Evidence

absence[Entire paper]

No data availability statement is present.

direct quote[Abstract]

“ClinicalTrials.gov number, NCT04607421”

WARNReviewer 2· 85% conf

The trial is registered and the protocol is available, but the data availability statement is vague ('available from the corresponding author on reasonable request' is not stated, but no repository or managed access platform is named). Code sharing is not applicable.

Evidence

absence[Entire manuscript]

No data availability statement is present in the main text.

direct quote[Abstract and Methods]

“ClinicalTrials.gov (http://clinicaltrials.gov) number, NCT04607421”

PASSReviewer 3· 90% conf

A data availability statement is present, directing readers to ClinicalTrials.gov with an accession number, and the protocol is available at NEJM.org.

Evidence

direct quote[Abstract, CONCLUSION]

“(Funded by Pfizer, Inc; ClinicalTrials.gov (http://clinicaltrials.gov) number, NCT04607421 (https://clinicaltrials.gov/ct2/show/NCT04607421) .)”

direct quote[METHODS, TRIAL OVERSIGHT, paragraph 1]

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

The methods are detailed enough for replication. The trial is prospectively registered (NCT04607421). Funding sources and conflict-of-interest disclosures are provided. The Discussion mentions the open-label design and the EC arm closure as limitations. No reporting guideline (e.g., CONSORT) is cited in the manuscript. The conclusions are proportional to the evidence presented.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedINADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: methods are detailed, the trial is registered, funding and conflicts are disclosed, and limitations are briefly discussed. Reporting guidelines are not explicitly mentioned.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov number, NCT04607421”

direct quote[Funding and Footnotes]

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

direct quote[Discussion]

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

PASSReviewer 2· 90% conf

Reporting is transparent. Methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional to the evidence, and funding/COI are disclosed.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov (http://clinicaltrials.gov) number, NCT04607421”

direct quote[Discussion]

“EC arm enrollment was closed based on the low likelihood of EC demonstrating superiority versus SOC following the results of the phase 2 ANCHOR study of encorafenib, cetuximab, and binimetinib.”

direct quote[Funding and Footnotes]

“Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

PASSReviewer 3· 90% conf

The methods are sufficiently detailed for replication, the trial is registered, limitations are discussed, and conclusions are proportional to the evidence. Funding and COI are also reported.

Evidence

direct quote[Abstract, CONCLUSION]

“(Funded by Pfizer, Inc; ClinicalTrials.gov (http://clinicaltrials.gov) number, NCT04607421 (https://clinicaltrials.gov/ct2/show/NCT04607421) .)”

paraphrase[DISCUSSION, paragraph 3]

“The discussion explains that EC arm enrollment was closed due to low likelihood of superiority and that progression-free and overall survival data from the EC arm underscore the need for an intensive first-line regimen like EC+mFOLFOX6.”

direct quote[FUNDING, Footnotes]

“FUNDING BREAKWATER was sponsored by Pfizer with support from ONO Pharmaceutical, Merck KGaA, Darmstadt, Germany, and Eli Lilly and Company. It was also supported by the National Institutes of Health/National Cancer Institute Cancer Center Core Grant P30 CA008748. Footnotes Disclosure forms provided by the authors are available with the full text of this article at NEJM.org (http://nejm.org) .”

17 copyedit issues flagged: mostly punctuation, consistency, other.

Checked 22 references: 1 verified — 21 not checked.

Reproducibility

8 data/code links checked; 6 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready to submit after minor edits. The most consequential gap is the missing data availability statement, which should be added before submission to meet standard ICMJE/repository expectations. The copyedit issues (empty parentheticals, typo in Table 1) are quick fixes. Addressing these will raise the manuscript from very good to excellent.

1.
HIGHdata code
Add a data availability statement to the Methods section, specifying a managed-access platform (e.g., Vivli) or a data-access committee with conditions for requesting patient-level data.
This is expected for a pharmaceutical-sponsored phase 3 trial; its absence is the single most likely cause of a reviewer comment.
2.
HIGHcopyedit
Fill all empty parenthetical references in the Results section (e.g., '()', '(, )') with the correct table or figure numbers (Tables S1–S12, Figures 1–2, S1).
Empty references make the manuscript look incomplete and will confuse readers and reviewers.
3.
HIGHcopyedit
Fix the typo in Table 1, C-reactive protein 'Missing' row: change '6(25' to '6 (2.5)' for the EC+mFOLFOX6 arm.
This is a reproducible data presentation error that could undermine trust in the table.
4.
HIGHreporting
Explicitly cite the CONSORT 2010 reporting guideline in the Methods section and consider submitting the completed CONSORT checklist as supplementary material.
Not citing a reporting guideline is a minor transparency gap easily closed; many journals require or expect it.
5.
HIGHstatistics
Name the statistical software package (e.g., SAS version 9.4, R version 4.x) used for the primary and secondary analyses in the Statistical Analysis section.
Reproducibility requires knowing the software; this is a standard expectation in clinical trial reporting.
6.
MEDIUMreporting
Expand the limitations section to include a brief statement on the open-label design and potential sources of bias (e.g., investigator bias in secondary endpoints).
While the open-label design and EC arm closure are mentioned, a more thorough limitations paragraph addresses reviewer expectations.
7.
MEDIUMstatistics
Add a brief statement on how missing data were handled in the primary PFS analysis (e.g., censoring rules) and whether proportional hazards assumptions were verified for the Cox model.
Provides methodological clarity and preempts reviewer questions about standard model diagnostics.
8.
MEDIUMreporting
Include a CONSORT flow diagram showing patient disposition through screening, randomization, treatment, and follow-up.
A flow diagram is a key element of transparent trial reporting and is expected by most journals.
9.
LOWcopyedit
Consider reporting one-sided p-values alongside the reported two-sided p-values, with a justification for the two-sided presentation.
The pre-specified test was one-sided; editors may appreciate consistency or a brief rationale.
10.
LOWreporting
Add a statement about the availability of the full protocol and statistical analysis plan (SAP), ideally with a direct link or reference beyond the protocol at NEJM.org.
Provides greater transparency and facilitates independent review of the planned analyses.

Full text (39,207 chars)Analyzed: Jul 7, 2026

Read alongside

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

Read full text (PMC)

Journal

DOI

10.1056/NEJMoa2501912

Share this Rigor Review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://adcurare.com/verify/2c254bad-036b-4872-aa90-af5791c72a43" target="_blank" rel="noopener">
  <img src="https://adcurare.com/verify/2c254bad-036b-4872-aa90-af5791c72a43/badge" alt="Adcurare Rigor Review — 4.75★ (Strong), 0 critical, 5 high issues for “Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Rigor Record.

Record fingerprint

e0ad42539f1c884be8130de37479e34648b9835cbddddf61eab2cf06bd36dec2

Verify via API

Issued Jul 7, 2026Engine 7.6.0

Adcurare assesses methodological rigor, not the importance of the findings. See how we evaluate →