Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.
Herrera AF, LeBlanc M, Castellino SM, Li H, Rutherford SC, Evens AM, Davison K, Punnett A, Parsons SK, Ahmed S, Casulo C, Bartlett NL, Tuscano JM, Mei MG, Hess BT, Jacobs R, Saeed H, Torka P, Hu B, Moskowitz C, Kaur S, Goyal G, Forlenza C, Doan A, Lamble A, Kumar P, Chowdhury S, Brinker B, Sharma N, Singh A, Blum KA, Perry AM, Kovach AE, Hodgson D, Constine LS, Shields LK, Prica A, Dillon H, Little RF, Shipp MA, Crump M, Kahl B, Leonard JP, Smith SM, Song JY, Kelly KM, Friedberg JW
- DOI
- 10.1056/NEJMoa2405888
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-22
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/4a8eb289-53c9-45b9-9989-f15cedd8447b is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- StatisticsStatistic did not reproduce−0.5★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingData & code availability partially met−0.25★
- 01Reported statistic does not recompute
Check p-value for HR 0.48 with 99% CI 0.27-0.87
“HR 0.48, 99%CI, 0.27–0.87, p<0.001”
- 02Printed percentage does not match its own count
0.01% does not match the reported count 0/483
“hypothyroidism, 0.01%”
ResultsFind in source
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 randomized phase 3 trial with strong scientific premise, rigorous design, and transparent reporting. The main weaknesses are the lack of a clear data availability statement and a p-value inconsistency in the primary analysis that warrants verification.
Both reviewers agreed on study type (interventional). The statistics verification component recomputed only a subset of reported tests; the p-value discrepancy is a specific finding. Other dimensions were assessed based on full-text review.
Numerical inconsistencies
3 findings · worst highValues 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.
- Reported statistics do not recomputeRecomputed
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 1 consistent, 1 inconsistent; 2 via agent-written checks. 1 printed percentage that does not match its own count.
- PERCENT0.01% does not match the reported count 0/483
“hypothyroidism, 0.01%”
ResultsFind in source
- INCONSISTENTreported p < .001 · recomputed p = .014Reviewers 1, 2Check p-value for HR 0.48 with 99% CI 0.27-0.87
“HR 0.48, 99%CI, 0.27–0.87, p<0.001”
Taken as given: The HR is a ratio (log scale).; The CI is two-sided at 99%.Method: Compute p from HR and CI using normal approximation.How we recomputed it: pCI(0.48, 0.27, 0.87, 1) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Check p-value for HR 0.45 with 95% CI 0.3-0.65
“HR 0.45, 95%CI, 0.3–0.65”
Taken as given: The HR is a ratio (log scale).; The CI is two-sided at 95%.Method: Compute p from HR and CI using normal approximation.How we recomputed it: pCI(0.45, 0.3, 0.65, 1)
- lowinternal contradictionThe abstract reports a p<0.001 for the interim analysis, but the methods state the boundary was one-sided p<.005. This is not a contradiction as two-sided p is reported.
two-sided p<0.001 (Abstract) vs. one-sided p-value <.005 (Methods)
Abstractreviewer’s wording
Overstated conclusions
None foundConclusions 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.
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Nivolumab improved efficacy and was better tolerated compared to BV when combined with AVD in adolescent and adult stage III-IV cHL.The claim is supported by the primary endpoint results and safety data.Evidence: Primary endpoint PFS HR 0.45 (95% CI 0.3-0.65) and lower rates of treatment discontinuation and peripheral neuropathy.
“Nivolumab improved efficacy and was better tolerated compared to BV when combined with AVD in adolescent and adult stage III-IV cHL.”
ConclusionFind in source - supportedReviewers 1, 2N-AVD significantly improved progression-free survival compared with BV-AVD.The primary endpoint was met with a statistically significant HR.Evidence: HR 0.48 (99% CI 0.27-0.87, p<0.001) at interim analysis and HR 0.45 (95% CI 0.3-0.65) at longer follow-up.
“The S1826 study demonstrated that N-AVD significantly improved progression-free survival compared with BV-AVD in adolescent and adult patients with advanced stage cHL.”
Discussion ¶1Find in source - supportedReviewers 1, 2N-AVD was better tolerated than BV-AVD.Safety data show fewer early discontinuations and lower rates of peripheral neuropathy.Evidence: 37 (7.6%) vs 58 (12.0%) early discontinuations; peripheral neuropathy 29% vs 56%.
“N-AVD was better tolerated than BV-AVD – fewer patients stopped treatment early, fewer deaths occurred on treatment, and a low rate of immune-related toxicity observed.”
Discussion ¶1Find in source - supportedReviewer 1Very few patients (<1%) received end of therapy radiotherapy, a dramatic reduction in the use of radiation in adolescent patients.The reported rate of radiation use is 0.7% overall.Evidence: Radiation therapy was administered in 7 (0.7%) patients.
“Very few patients (< 1%) received end of therapy radiotherapy, a dramatic reduction in the use of radiation in adolescent patients compared to contemporary regimens.”
Discussion ¶1Find in source - supportedReviewers 1, 2N-AVD should be a strong candidate for primary treatment for adolescent and adult patients with stage III-IV cHL.The conclusion is supported by the efficacy and safety results, though longer follow-up is needed.Evidence: Improved PFS, better tolerability, and low radiation use.
“N-AVD should be a strong candidate for primary treatment for adolescent and adult patients with stage III-IV cHL.”
DiscussionFind in source - supportedReviewer 2The use of end of therapy consolidative radiation was much lower in S1826 (<1% vs 14% with BrECADD).The paper reports that only 7 patients (0.7%) received radiation in S1826, and cites the HD21 study for the 14% figure.Evidence: Results section states radiation therapy was administered in 7 (0.7%) patients.
“The use of end of therapy consolidative radiation was much lower in S1826 (< 1% vs 14% with BrECADD)”
Discussion ¶9Find in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is progression-free survival (PFS), a hard clinical outcome, not a surrogate. The efficacy claim is based on a statistically significant improvement in PFS with N-AVD compared to BV-AVD.
“The primary endpoint was progression-free survival, defined as the date of randomization to the first observation of progressive disease or death due to any cause.”
- ADEQUATEEffect sizeThe effect size is clinically meaningful: 2-year PFS improved from 83% to 92% (HR 0.45, 95% CI 0.3–0.65), and the authors explicitly state the improvement was 'clinically meaningful' and 'substantial'.
“The progression-free survival advantage observed with N-AVD was substantial and consistent across age, stage, and IPS score subgroups.”
Data authenticity concerns
1 finding · worst lowAn 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).
- lowotherThe paper reports a 2-year PFS of 92% for N-AVD and 83% for BV-AVD, but the HR is 0.45. This seems plausible but the absolute difference is 9% while the HR is 0.45, which may be considered large but is not impossible.
“2-year progression-free survival was 92% (95% CI, 89%−94%) after N-AVD and 83% (95%CI, 79%−86%) after BV-AVD (, HR 0.45, 95%CI, 0.3–0.65).”
ResultsFind in source
Reporting gaps
1 finding · worst mediumRequired 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
The introduction cites multiple prior studies showing improved outcomes with BV-AVD and the efficacy of PD-1 blockade in cHL, and acknowledges limitations such as toxicity and relapse. The rationale for comparing N-AVD to BV-AVD is clearly stated, and the study addresses gaps by including a broader age range and diverse population.
“The incorporation of the CD30-directed antibody drug conjugate, brentuximab vedotin (BV), into treatment of advanced stage cHL has led to improved outcomes.”
“SWOG Cancer Research Network collaborated with the pediatric and adult groups of the National Clinical Trials Network to conduct S1826, a randomized, phase 3 trial to evaluate nivolumab combined with AVD (N-AVD) versus BV-AVD in adolescent and adult patients with newly diagnosed stage III or IV cHL.”
“Nevertheless, relapses after treatment of advanced stage cHL remain problematic, BV use necessitates more growth factor support than prior regimens, BV-AVD is more toxic than ABVD in adults, and 53% of pediatric patients still received radiotherapy with BV-based therapy.”
“The incorporation of the CD30-directed antibody drug conjugate, brentuximab vedotin (BV), into treatment of advanced stage cHL has led to improved outcomes.”
“SWOG Cancer Research Network collaborated with the pediatric and adult groups of the National Clinical Trials Network to conduct S1826, a randomized, phase 3 trial to evaluate nivolumab combined with AVD (N-AVD) versus BV-AVD in adolescent and adult patients with newly diagnosed stage III or IV cHL.”
“BV-AVD is more toxic than ABVD in adults, and 53% of pediatric patients still received radiotherapy with BV-based therapy.”
The study is a randomized phase 3 trial with 1:1 randomization and dynamic balancing by three stratification factors. The randomization method is not explicitly described (e.g., random number generator), but the trial is monitored by a data and safety monitoring committee. Power analysis is provided with a target of 86% power. Inclusion/exclusion criteria are detailed. Blinding is not applicable as it is an open-label trial, which is stated. Outlier handling is addressed through modified ITT analysis and pre-specified analysis populations.
“Patients were randomized 1:1 and dynamically balanced by three stratification factors.”
“Based on simulation, the trial was anticipated to have 86% power to detect a difference of 6% in progression-free survival between the control and experimental arms (2-year progression-free survival of 90%).”
“This was an international, open-label, randomized phase 3 trial”
“Patients were randomized 1:1 and dynamically balanced by three stratification factors.”
“Based on simulation, the trial was anticipated to have 86% power to detect a difference of 6% in progression-free survival between the control and experimental arms (2-year progression-free survival of 90%).”
“This was an international, open-label, randomized phase 3 trial”
The study reports age, sex, race, ethnicity, and disease stage in Table 1. Age is reported as median and range, and age groups are provided. Sex is reported as female percentage. Health status is implied by eligibility criteria. Species/strain and housing are not applicable as this is a human trial.
“Age, median (range) | 27.6 (12.0–83.7) | 26.8 (12.0–81.7)”
“Female Sex | 216 (44%) | 210 (43%)”
“Female Sex | 216 (44%) | 210 (43%)”
“Age, median (range) | 27.6 (12.0–83.7) | 26.8 (12.0–81.7)”
“White | 372 (76%) | 361 (75%)”
The study states that it was approved by the Central Institutional Review Board and conducted in accordance with the Declaration of Helsinki. All patients provided informed consent. Regulatory compliance is stated.
“The study was approved by the Central Institutional Review Board and conducted in accordance with the principles of the Declaration of Helsinki.”
“All patients provided informed consent for participation in the clinical trial.”
“The study was approved by the Central Institutional Review Board and conducted in accordance with the principles of the Declaration of Helsinki.”
“All patients provided informed consent for participation in the clinical trial.”
Nivolumab and BV are named with manufacturers (Bristol-Myers Squibb, Seagen) and dosing regimens. The statistical software is identified as SWOG Statistical Center, though version is not specified. Other bench resources are not applicable.
“Patients were randomized to receive N-AVD (240mg nivolumab in adults/3mg per kilogram nivolumab in children < 18 years capped at 240mg, doxorubicin 25mg/m 2 of body-surface area, vinblastine 6mg/m 2 , dacarbazine 375mg/m 2 ) or BV-AVD (BV 1.2mg/kg of body weight capped at 100kg with AVD as above)”
“Nivolumab was supplied by Bristol-Myers Squibb to the NCI under a Cooperative Research and Development Agreement and Seagen supplied BV to patients enrolled in Canada.”
“All the data were maintained by the SWOG Statistical Center”
The primary analysis uses a stratified log-rank test, and hazard ratios with confidence intervals are reported. Exact p-values are given (e.g., p<0.001). Effect sizes are reported with confidence intervals. Statistical software is not explicitly identified, but the SWOG Statistical Center is mentioned. Data presentation includes Kaplan-Meier curves and tables with per-group n.
“The power calculations assumed uniform patient entry and a one-sided stratified log-rank test at 2.5% significance level”
“N-AVD significantly improved progression-free survival compared to BV-AVD (HR 0.48, 99%CI, 0.27–0.87, p<0.001).”
“2-year progression-free survival was 92% (95% CI, 89%−94%) after N-AVD and 83% (95%CI, 79%−86%) after BV-AVD (, HR 0.45, 95%CI, 0.3–0.65).”
“The power calculations assumed uniform patient entry and a one-sided stratified log-rank test at 2.5% significance level”
“N-AVD significantly improved progression-free survival compared to BV-AVD (HR 0.48, 99%CI, 0.27–0.87, p<0.001).”
“2-year progression-free survival was 92% (95% CI, 89%−94%) after N-AVD and 83% (95%CI, 79%−86%) after BV-AVD (, HR 0.45, 95%CI, 0.3–0.65).”
The paper mentions that the study protocol is available at nejm.org, but does not provide a clear data availability statement for the clinical data. No repository deposit or accession numbers are provided. Since this is a clinical trial, patient-level data may be subject to controlled access, but the mechanism is not stated.
“Dose reductions and modifications are listed in the study protocol, available at nejm.org (http://www.nejm.org/) .”
“Dose reductions and modifications are listed in the study protocol, available at nejm.org (http://www.nejm.org/)”
The trial is registered (NCT03907488). Methods are detailed enough for replication. Limitations are discussed (short follow-up, subgroup analyses underpowered). Conclusions are proportional to the evidence. Funding and conflicts of interest are disclosed. Reporting guideline is not explicitly mentioned but the paper follows CONSORT-like structure.
“ClinicalTrials.gov (http://www.clinicaltrials.gov/) : NCT03907488”
“Limitations to the current S1826 study analysis include the short follow-up time.”
“Funding provided by the National Cancer Institute of the National Institutes of Health U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955 and funding and drug provided by Bristol-Myers Squibb, drug provided by SeaGen for patients enrolled in Canada.”
“ClinicalTrials.gov (http://www.clinicaltrials.gov/) : NCT03907488”
“Limitations to the current S1826 study analysis include the short follow-up time.”
“Funding provided by the National Cancer Institute of the National Institutes of Health U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955 and funding and drug provided by Bristol-Myers Squibb, drug provided by SeaGen for patients enrolled in Canada.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences 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 38 references by DOI: 37 verified — 1 no DOI (shown, not verified).
- NO DOITolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized studyNo 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.
- datahttp://www.nejm.org/UNVERIFIEDHTTP 403Liveness indeterminate — content not checked.
- datahttp://www.clinicaltrials.gov/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT03907488LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly consistency, grammar, clarity.
- MINORconsistencyAbstract, Results“HR 0.45; 95%CI 0.3–0.65”→ Use consistent decimal places: 0.30–0.65Inconsistent decimal places in CI.
- MINORgrammarDiscussion, paragraph 6“S1826 was a collaborative lymphoma study between the between the Children’s Oncology Group (COG) and the adult groups.”→ Remove duplicate 'between the'.Duplicate phrase.
- MINORclarityMethods, Statistical Design“see the section in the”→ Provide a specific reference to the supplementary section.Incomplete reference.
- MINORconsistencyAbstract, Results“HR 0.48, 99%CI 0.27–0.87, two-sided p<0.001”→ Ensure consistent use of spaces around CI and p values.Minor formatting inconsistency.
- MINORgrammarDiscussion, paragraph 7“S1826 was a collaborative lymphoma study between the between the Children’s Oncology Group (COG) and the adult groups.”→ Remove duplicate 'between the'.Typographical error.
- MINORclarityMethods, Statistical Design“see the section in the”→ Complete the cross-reference to the supplementary appendix.Incomplete sentence.
The published work is largely robust, but the p-value inconsistency and lack of data availability statement are notable concerns. An informed reader should weigh these when interpreting the results; a correction or clarification from the authors would strengthen confidence.
- 1.HIGHstatisticsVerify and correct the p-value reported for the primary analysis (HR 0.48, 99% CI 0.27-0.87) in the Abstract and Results; the recomputed p-value is 0.014, not <0.001.A demonstrable inconsistency between reported and recomputed p-value undermines the statistical integrity of the headline result.
- 2.HIGHdata codeAdd a clear data availability statement in the Methods or a dedicated section, specifying how to access de-identified patient-level data (e.g., via a controlled-access repository like Vivli) with conditions and timeframe.The current statement only mentions the protocol, not the data, which is a reporting gap for a data-driven clinical trial.
- 3.HIGHreportingExplicitly mention adherence to CONSORT reporting guidelines in the Methods or a separate section.Reviewer 2 noted the reporting guideline is not explicitly mentioned, which is a transparency gap.
- 4.MEDIUMreportingClarify the randomization implementation (e.g., central web-based system, block size) in the Methods section.Reviewer 1 noted the randomization method is not fully described, which is a minor design reporting gap.
- 5.MEDIUMreportingSpecify the statistical software and version used for analysis (e.g., SAS 9.4, R 4.3.1) in the Methods section.Reviewer 1 noted software is not explicitly identified, which is a reproducibility concern.
- 6.MEDIUMcopyeditFix the duplicate phrase 'between the between the' in Discussion, paragraph 6 (and paragraph 7 if present).Copyedit flagged a grammatical error that should be corrected.
- 7.MEDIUMcopyeditComplete the cross-reference 'see the section in the' in Methods, Statistical Design to point to the specific supplementary section.Copyedit flagged an incomplete reference that reduces clarity.
- 8.LOWcopyeditStandardize decimal places in confidence intervals (e.g., 0.30–0.65 instead of 0.3–0.65) in the Abstract and Results.Copyedit flagged inconsistent decimal places that could be polished.
- 9.LOWcopyeditEnsure consistent spacing around CI and p values (e.g., '95% CI' vs '95%CI') throughout the manuscript.Copyedit flagged minor formatting inconsistencies.
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.”
- 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.
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.