Targeted therapies plus radiotherapy for diffuse intrinsic pontine glioma: the randomized phase 2 BIOMEDE trial.
Debily MA, Le Teuff G, Kergrohen T, Varlet P, Castel D, Leblond P, Hargrave D, Nysom K, Blomgren K, McCowage GB, Bautista F, van Vuurden D, Jones C, Mackay A, Izquierdo E, Ziegler DS, Moussa A, Barret E, Puget S, Beccaria K, Aquilina K, Riffaud L, Bolle S, Abbou S, Bertozzi AI, De Carli E, Boddaert N, Dangouloff-Ros V, Calmon R, Blanc P, Vassal G, Le Deley MC, Grill J
- DOI
- 10.1038/s41591-026-04354-1
- 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/fa641dcb-2c36-4303-bc65-4354347a1199 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingEthical approvals partially met−0.25★
- 01Treatment effect not shown to be clinically meaningful
The primary efficacy claim is that the trial was negative for OS, with no significant difference between treatment arms and historical control. However, the paper highlights a subgroup analysis showing that patients with PI3K/AKT/MTOR alterations treated with everolimus had a median OS of 14 months versus 9 months for dasatinib. This effect size is presented without an explicit anchor to a minimal clinically important difference or a clear biological meaningfulness threshold, and it is based on a post-hoc exploratory analysis.
“Patients harboring PIK3/AKT/MTOR pathway mutations, an mTOR activation gene expression signature or 1q gain derived greater benefit from everolimus than from dasatinib, with median OS of 14 months versus 9 months, respectively.”
- 02Printed percentage does not match its own count
49% does not match the reported count 110/233
“110 of 233 patients (49%)”
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 2 trial with rigorous design, clear reporting of methods, and appropriate statistical analysis. The main weakness is the lack of an explicit ethics approval statement naming the committee and approval number, and minor reporting gaps such as not explicitly stating the open-label design and not mentioning a reporting guideline.
Both reviewers classified the study as interventional; no divergence. The evaluation covered the full text, with N/A for animal-related and cell-line criteria. The statistics verification recomputed only a subset of tests (3 tests, 2 consistent, 1 inconsistent but unspecified), so the statistical analysis is not fully verified.
Numerical inconsistencies
2 findings · worst mediumValues 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. 1 printed percentage that does not match its own count.
- PERCENT49% does not match the reported count 110/233
“110 of 233 patients (49%)”
- CONSISTENTreported p = .590 · recomputed p = .597Reviewers 1, 2HR for erlotinib vs dasatinib from CI
“The hazard ratio (HR) stratified by PTEN status was HR (erlotinib/dasatinib) = 0.87 (95% CI: 0.52−1.46), P = 0.59.”
Taken as given: The HR is a ratio (log scale).; The CI is a 95% confidence interval.Method: Two-tailed p-value derived from the HR and its 95% CI using the normal approximation.How we recomputed it: pCI(0.87, 0.52, 1.46, 1) - CONSISTENTreported p = .420 · recomputed p = .438Reviewers 1, 2HR for everolimus vs dasatinib from CI
“The HR stratified by EGFR status was HR (everolimus/dasatinib) = 0.89 (95% CI: 0.66−1.19), P = 0.42.”
Taken as given: The HR is a ratio (log scale).; The CI is a 95% confidence interval.Method: Two-tailed p-value derived from the HR and its 95% CI using the normal approximation.How we recomputed it: pCI(0.89, 0.66, 1.19, 1)
- lowinternal contradictionThe abstract states '36 received erlotinib, 102 received dasatinib and 95 received everolimus' but the results section says 'Ninety-five patients were randomized to receive everolimus, 102 to receive dasatinib and 36 to receive erlotinib.' This is consistent, but the order differs.
“36 received erlotinib, 102 received dasatinib and 95 received everolimus.”
AbstractFind in source
Overstated conclusions
2 findings · worst highConclusions 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.
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
7 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus.The evidence shows associations but with borderline significance and exploratory nature.Evidence: Forest plots and interaction tests with P < 0.1.
“Similarly, mutations in PI3K/AKT/MTOR pathway correlated with better PFS ( P = 0.02) and OS ( P = 0.08) in everolimus-treated patients (Fig. ).”
ResultsFind in source - supportedReviewers 1, 2The trial did not show a significant OS difference between treatment arms and historical control.The presented OS data and statistical comparisons support this claim.Evidence: Median OS values and HRs with CIs are reported for each arm and the control.
No difference was observed for any of the treatment arms compared to the historical control, with median OS of 9.7 months (95% CI: 7.8−14.6), 9.9 months (95% CI: 8.8−11.2) and 11.9 months (95% CI: 10.7−14.2) for patients treated with erlotinib, dasatinib and everolimus, respectively.
Resultsreviewer’s wording - supportedReviewer 1Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity.The safety data presented support this claim.Evidence: Adverse event frequencies and p-values are reported.
“Severe (grade 3 or higher) skin adverse events were significantly more frequent with erlotinib ( P < 0.0001), and severe renal ( P = 0.0054) and gastrointestinal ( P = 0.038) adverse events were significantly more frequent with dasatinib.”
ResultsFind in source - supportedReviewers 1, 2TP53 mutations were the strongest predictor for poor survival in multivariate analysis.The multivariate analysis supports this claim.Evidence: HR = 2.84 (95% CI: 1.92−4.20), P < 0.0001.
“TP53 mutation was the main prognostic factor for OS and remained significant in multivariable analysis (hazard ratio = 2.84 (95% CI: 1.92−4.20), P < 0.0001)”
ResultsFind in source - supportedReviewer 1Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis.The case descriptions support this claim.Evidence: Detailed descriptions of four patients.
“Four patients were alive at last follow-up, 6 years or more after diagnosis, without meaningful sequelae.”
ResultsFind in source - supportedReviewer 2Everolimus showed fewer side effects and treatment discontinuations.The paper reports significantly fewer ocular, renal, skin and gastrointestinal side effects and lower discontinuation rates for everolimus.Evidence: Safety analysis with p-values for adverse events and treatment discontinuation.
“Treatment was stopped because of toxicity in 20%, 3% and 14% for erlotinib, everolimus and dasatinib, respectively (Fisherʼs exact test, P = 0.004).”
ResultsFind in source - supportedReviewer 2Four long-term survivors were treated with mTOR inhibitors.The paper describes four patients alive >6 years, all treated with mTOR inhibitors.Evidence: Case descriptions in Results.
“All patients had been off treatment for at least 1 year and were treated with an mTOR inhibitor: two received everolimus and two received sirolimus due to toxicity or initial progression.”
ResultsFind in source
Premise concern: effect size not shown to be clinically meaningful.
- ADEQUATESurrogate endpointThe primary endpoint is overall survival (OS), a hard clinical outcome. Although the trial was negative for the primary endpoint, the efficacy claim is based on OS, not a surrogate. The paper also reports exploratory biomarker analyses (e.g., PI3K/AKT/MTOR pathway alterations) associated with improved response to everolimus, but these are not the primary basis for the efficacy claim.
“OS was the primary outcome measure.”
- INADEQUATEEffect sizeThe primary efficacy claim is that the trial was negative for OS, with no significant difference between treatment arms and historical control. However, the paper highlights a subgroup analysis showing that patients with PI3K/AKT/MTOR alterations treated with everolimus had a median OS of 14 months versus 9 months for dasatinib. This effect size is presented without an explicit anchor to a minimal clinically important difference or a clear biological meaningfulness threshold, and it is based on a post-hoc exploratory analysis.
“Patients harboring PIK3/AKT/MTOR pathway mutations, an mTOR activation gene expression signature or 1q gain derived greater benefit from everolimus than from dasatinib, with median OS of 14 months versus 9 months, respectively.”
Data authenticity concerns
None foundAn 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
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.
- Ethics/consent reporting incompleteAssessed
The introduction cites prior work on DIPG molecular characterization, actionable targets (EGFR, mTOR, PDGFRA), and preclinical/clinical evidence for the three drugs. It acknowledges the lack of effective chemotherapy and the need for targeted approaches. The rationale for the trial design is clearly linked to the premise, and limitations of prior single-arm trials are implicitly addressed by the randomized design.
“In the past two decades, the reintroduction of stereotactic biopsies and increased autopsy studies – have helped identifiy actionable targets, such as PDGFRA – , EGFR , and mTOR .”
“This included biomarker-driven randomization among three drugs previously tested in phase 1 in patients with DIPG targeting the most frequent druggable alterations known at that time: EGFR tyrosine kinase inhibitor erlotinib, mTOR inhibitor everolimus and multitarget receptor tyrosine kinase inhibitor dasatinib.”
“The large cohort enabled exploration of disease heterogeneity within a single trial.”
“In the past two decades, the reintroduction of stereotactic biopsies and increased autopsy studies – have helped identifiy actionable targets, such as PDGFRA – , EGFR , and mTOR .”
“This included biomarker-driven randomization among three drugs previously tested in phase 1 in patients with DIPG targeting the most frequent druggable alterations known at that time: EGFR tyrosine kinase inhibitor erlotinib, mTOR inhibitor everolimus and multitarget receptor tyrosine kinase inhibitor dasatinib.”
Randomization method is described (biomarker-driven subtrials), and the unit is the patient. Power analysis is provided for the smallest pairwise comparison. Inclusion/exclusion criteria are pre-specified. Blinding is not reported, but the trial is open-label; this is acceptable for a phase 2 oncology trial. Outlier handling is addressed via ITT analysis and missing data handling.
“Considering the smallest pairwise comparison (erlotinib versus everolimus), 79 events and 90 patients were required to achieve 80% power to compare OS curves using a two-sided log-rank test ( α = 20%), if the hazard ratio of death was 0.62, equivalent to a 10.6% increase in the 2-year OS (5% versus 15.6%) assuming an exponential survival distribution, proportional hazards and an expected accrual of 22.5 patients per year (East software; Cytel).”
“After diagnosis confirmation (DMG H3K27-altered with an epicenter in the pons) by central pathology reviewer, enrollment in the treatment randomization based on biomarkers was offered in case of age over 6 months, absence of active intratumoral hemorrhage, ability to undergo radiotherapy, Lansky Play Scale >50% and life expectancy longer than 3 months.”
“Considering the smallest pairwise comparison (erlotinib versus everolimus), 79 events and 90 patients were required to achieve 80% power to compare OS curves using a two-sided log-rank test ( α = 20%), if the hazard ratio of death was 0.62, equivalent to a 10.6% increase in the 2-year OS (5% versus 15.6%) assuming an exponential survival distribution, proportional hazards and an expected accrual of 22.5 patients per year (East software; Cytel).”
“To confirm the impact of theranostic biomarkers on the response to everolimus, we compiled an independent cohort of 31 patients with DIPG with available sequencing data who were treated at Gustave Roussy with sirolimus or everolimus either before trial initiation or after randomization was stopped.”
Sex is reported in Table 1 (balanced). Age is reported with median and ranges. Demographics include country of treatment. Health status is implied by inclusion criteria (Lansky score) but not explicitly detailed. Species/strain and housing are not applicable for a human trial.
“Male | 19 | 52.8 | 43 | 45.3 | 52 | 51.0 | 114 | 48.9”
“Median age was 8.1 years (range, 1.8−30.3).”
“France | 23 | 63.9 | 70 | 73.7 | 75 | 73.5 | 168 | 72.1”
“Median | 9.5 | 7.8 | 8.1 | 8.1”
The paper states that the trial was conducted in accordance with ethical principles but does not name the IRB/ethics committee that approved the study. Informed consent is implied by the mention of 'consented to biopsy' but not explicitly described. Regulatory compliance is mentioned (Declaration of Helsinki) but not detailed.
“Patients with radiologically suspected DIPG first consented to biopsy.”
“A radiotherapy-only control arm was deemed unethical; as parent associations considered the poor outcome with radiotherapy alone, they supported adjuvant treatment for all patients, consistent with registry data suggesting improved outcomes with any adjuvant therapy .”
“ClinicalTrials.gov: NCT02233049 (https://clinicaltrials.gov/study/NCT02233049) .”
“Patients with radiologically suspected DIPG first consented to biopsy.”
The three drugs (erlotinib, everolimus, dasatinib) are identified with doses and regimen. Statistical software (East, Cytel) is named. No antibodies, cell lines, or mycoplasma testing are applicable. Organisms are not applicable.
“Three drugs were compared: everolimus 5 mg m −2 per dose once daily, erlotinib 125 mg m −2 per dose once daily or dasatinib 85 mg m −2 per dose twice daily.”
“East software; Cytel”
“The authors declare that three drugs (everolimus, erlotinib and dasatinib) were supplied free of charge by the pharmaceutical companies (Novartis, F. Hoffman-La Roche and Bristol Myers Squibb, respectively).”
“Three drugs were compared: everolimus 5 mg m −2 per dose once daily, erlotinib 125 mg m −2 per dose once daily or dasatinib 85 mg m −2 per dose twice daily.”
“East software; Cytel”
The paper names tests (log-rank, Fisher's exact, chi-square, Wilcoxon) and reports HRs with 95% CIs. Exact p-values are given for many analyses. Assumptions are not explicitly verified but standard methods are used. Data presentation includes KM curves and forest plots. Mathematical plausibility is not applicable for large-N survival data.
“The hazard ratio (HR) stratified by PTEN status was HR (erlotinib/dasatinib) = 0.87 (95% CI: 0.52−1.46), P = 0.59.”
“The HR stratified by EGFR status was HR (everolimus/dasatinib) = 0.89 (95% CI: 0.66−1.19), P = 0.42.”
“East software; Cytel”
“eye ( P < 0.0001), skin ( P = 0.004) and infectious ( P = 0.042) adverse events were more frequent with erlotinib”
“median OS = 10.8 months (95% confidence interval (CI): 9.5−13.0)”
Genomic data are deposited in EGA with an accession number. Clinical data are available upon reasonable request through a data transfer agreement, which is a legitimate managed-access route. Radiologic data are being uploaded to a repository. Code sharing is not mentioned, but no bespoke code is described.
“Genomic data are available through the European Genome-phenome Archive ( EGAS50000001164 (https://ega-archive.org/studies/EGAS50000001164) ).”
“Clinical data (sex, age, OS and PFS) will be available upon reasonable request through the signature of a data transfer agreement because these data are sensitive and belong to the sponsor of the study.”
“Genomic data are available through the European Genome-phenome Archive ( EGAS50000001164 (https://ega-archive.org/studies/EGAS50000001164) ).”
“Clinical data (sex, age, OS and PFS) will be available upon reasonable request through the signature of a data transfer agreement because these data are sensitive and belong to the sponsor of the study.”
The trial is registered (NCT02233049). Methods are detailed enough for replication. Limitations are discussed (e.g., lack of radiotherapy-only control, confounding by reirradiation). Conclusions are proportional to the evidence. Funding and COI are declared. A reporting guideline (CONSORT) is not explicitly mentioned, but the paper includes a CONSORT diagram.
“ClinicalTrials.gov: NCT02233049 (https://clinicaltrials.gov/study/NCT02233049) .”
“A radiotherapy-only control arm was deemed unethical; as parent associations considered the poor outcome with radiotherapy alone, they supported adjuvant treatment for all patients, consistent with registry data suggesting improved outcomes with any adjuvant therapy .”
“The authors declare that three drugs (everolimus, erlotinib and dasatinib) were supplied free of charge by the pharmaceutical companies (Novartis, F. Hoffman-La Roche and Bristol Myers Squibb, respectively).”
“ClinicalTrials.gov: NCT02233049 (https://clinicaltrials.gov/study/NCT02233049) .”
“The authors declare that three drugs (everolimus, erlotinib and dasatinib) were supplied free of charge by the pharmaceutical companies (Novartis, F. Hoffman-La Roche and Bristol Myers Squibb, respectively).”
“A radiotherapy-only control arm was deemed unethical; as parent associations considered the poor outcome with radiotherapy alone, they supported adjuvant treatment for all patients, consistent with registry data suggesting improved outcomes with any adjuvant therapy .”
Registered (2 IDs: ClinicalTrials.gov, EudraCT). Reporting guideline cited: CONSORT.
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 81 references by DOI: 79 verified — 2 no DOI (shown, not verified).
- NO DOI[Infiltrating glioblastoma of the brain stem in an 8-year-old child; normalization of the pneumoencephalogram after radiotherapy]No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem gliomaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- dataEGALIVEHTTP 200https://ega-archive.org/studies/EGAS50000001164Resolves to EGA (data repository).
- datahttps://clinicaltrials.gov/study/NCT02233049LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoIntroduction, paragraph 3“identifiy”→ identifyTypographical error.
- MINORconsistencyResults, Survival analysis“median OS = 10.8 months (95% confidence interval (CI): 9.5−13.0)”→ Ensure consistent use of 'median OS' vs 'median overall survival'.Abbreviation used inconsistently.
- MINORclarityMethods, Trial design and endpoints“Patients with biomarker-negative tumors received dasatinib without randomization and were excluded from the final analysis.”→ Clarify whether these patients were included in any analysis or safety population.Potential ambiguity.
- MINORconsistencyResults, Survival analysis“median OS = 10.8 months (95% CI: 9.5−13.0) in any of the three arms (median OS = 9.7 months (95% CI: 7.8−14.6) for erlotinib; 9.9 months (95% CI: 8.8−11.2) for dasatinib; and 11.9 months (95% CI: 10.7−14.2) for everolimus).”→ Ensure consistent use of 'median OS' and '95% CI' formatting.Minor formatting inconsistency.
The published work is robust overall, but readers should weigh the missing explicit ethics approval statement and the minor reporting gaps. An erratum or clarification adding the ethics committee name and approval number, and explicitly stating the open-label design, would strengthen the record.
- 1.HIGHethicsAdd the name of the ethics committee/IRB and the approval number to the Methods section.The paper currently lacks an explicit ethics approval statement, which is a standard requirement for clinical trials.
- 2.HIGHethicsExplicitly describe the informed consent process (written, oral, or waiver) in the Methods.Informed consent is only implied by 'consented to biopsy' and should be clearly documented.
- 3.MEDIUMreportingMention adherence to a reporting guideline such as CONSORT in the Methods or cover letter.The paper includes a CONSORT diagram but does not explicitly reference the guideline, which is a common expectation.
- 4.MEDIUMdata codeProvide a data availability statement for code, or state that no custom code was used.Code sharing is not mentioned, and clarifying this would enhance reproducibility.
- 5.MEDIUMreportingClarify the open-label design and rationale for lack of blinding in the Methods.Blinding is not reported, and explicitly stating the open-label design would remove ambiguity.
- 6.MEDIUMstatisticsDescribe how outliers were handled in the statistical analysis, if applicable.Outlier handling is not explicitly described, and adding this would improve methodological transparency.
- 7.MEDIUMreportingInclude a statement on health status of participants beyond inclusion criteria, if available.Health status is implied by inclusion criteria but not explicitly detailed.
- 8.LOWcopyeditFix the typo 'identifiy' to 'identify' in the Introduction, paragraph 3.Typographical errors should be corrected for professionalism.
- 9.LOWcopyeditEnsure consistent use of 'median OS' vs 'median overall survival' and consistent formatting of '95% CI' throughout the Results.Inconsistent abbreviation usage can confuse readers.
- 10.LOWcopyeditClarify whether patients with biomarker-negative tumors who received dasatinib without randomization were included in any analysis or safety population.The current text is ambiguous about the inclusion of these patients.
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.