BIOMEDE
(2026)Objective
Test whether adding biomarker-matched targeted therapy (erlotinib, everolimus or dasatinib) to standard radiotherapy improves overall survival in newly diagnosed, biopsy-proven diffuse intrinsic pontine glioma (DIPG).
Study Summary
• Pairwise comparisons all non-significant: everolimus vs dasatinib HR 0.89 (95% CI 0.66–1.19, P=0.42); erlotinib vs dasatinib HR 0.87 (0.52–1.46, P=0.59); erlotinib vs everolimus HR 0.94 (0.54–1.65, P=0.84).
• TP53 mutation was the strongest poor-prognosis marker (multivariate HR 2.84, 95% CI 1.92–4.20, P<0.0001).
• Everolimus had significantly better tolerability: treatment discontinuation for toxicity 3% vs 14% (dasatinib) vs 20% (erlotinib), P=0.004; fewer eye, skin and infectious AEs than erlotinib.
• Exploratory: in patients with PI3K/AKT/MTOR pathway mutations, mTOR activation signature or 1q gain, everolimus outperformed dasatinib (median OS 14 vs 9 mo); 4 long-term survivors (>6 yr) all received an mTOR inhibitor.
Intervention
Erlotinib 125 mg/m² once daily, everolimus 5 mg/m² once daily, or dasatinib 85 mg/m² twice daily, given during and after normofractionated radiotherapy at 54 Gy.
Inclusion Criteria
Biopsy-proven DIPG (diffuse midline glioma, H3K27-altered, pontine epicenter); age >6 months and <30 years; no prior chemotherapy or cerebral radiotherapy; Lansky Play Scale >50%; life expectancy >3 months; biomarker assessment available (EGFR by IHC and PTEN status).
Study Design
Arms: Three biomarker-matched targeted therapy arms added to radiotherapy: (1) Erlotinib (EGFR inhibitor), (2) Everolimus (mTOR inhibitor), (3) Dasatinib (multi-kinase inhibitor). Randomization scheme R1/R2/R3 depended on EGFR overexpression and/or PTEN loss. Compared against 66 historical controls who received radiotherapy + temozolomide.
Patients per Arm: Erlotinib 36, Dasatinib 102, Everolimus 95 (total 233 randomized; 66 historical controls)
Outcome
• PFS comparable across arms (log-rank P=0.89); median PFS everolimus 6.4 mo vs dasatinib 7.1 mo.
• 2-year OS: 62% died <1 yr, 30% 1–2 yr, 8% >2 yr; similar across arms.
• Safety: 78% grade 3–4 AE; no treatment-related deaths. Treatment discontinuation for toxicity 20% erlotinib, 14% dasatinib, 3% everolimus (P=0.004).
• Prognostic: TP53 mutation HR 2.84 (1.92–4.20), P<0.0001; H3.1K27M favorable, H3.3K27M worse (driven by TP53 co-occurrence).
• Theranostic: PI3K/AKT/MTOR alterations or 1q gain → everolimus median OS 14 vs 9 mo (dasatinib).
Clinical Question
In children, adolescents and young adults with newly diagnosed, biopsy-proven DIPG, does adding biomarker-matched targeted therapy (erlotinib, everolimus or dasatinib) to standard radiotherapy improve overall survival compared with radiotherapy plus historical controls?
Bottom Line
Adding biomarker-matched erlotinib, everolimus or dasatinib to radiotherapy did NOT improve overall survival in DIPG (median OS ~10–12 months across arms, no different from historical controls), but everolimus showed the best tolerability and signals of benefit in patients with PI3K/AKT/mTOR pathway alterations or 1q gain, supporting it as the standard arm for the next-generation adaptive BIOMEDE trial.
Major Points
- Largest biology-driven randomized phase 2 trial in DIPG: 233 biopsy-proven patients across 8 countries, randomized to erlotinib, everolimus or dasatinib + radiotherapy based on EGFR overexpression and PTEN-loss biomarkers.
- Trial stopped for futility on primary endpoint (overall survival): median OS from biopsy 11.1 months overall vs 10.8 months in historical controls; no pairwise comparison reached significance.
- Median OS by arm — erlotinib 9.7 mo (95% CI 7.8–14.6), dasatinib 9.9 mo (8.8–11.2), everolimus 11.9 mo (10.7–14.2).
- Everolimus had significantly better safety: treatment discontinuation for toxicity 3% vs 14% (dasatinib) vs 20% (erlotinib), P=0.004; significantly fewer eye, skin and infectious adverse events than erlotinib.
- TP53 mutation prospectively validated as the strongest adverse prognostic biomarker (multivariate HR 2.84, 95% CI 1.92–4.20, P<0.0001); H3.1K27M favorable, H3.3K27M worse (driven by TP53 co-occurrence).
- Theranostic signal: patients with PI3K/AKT/MTOR pathway mutations, mTOR activation gene-expression signature, or 1q chromosomal gain derived greater benefit from everolimus than dasatinib (median OS 14 vs 9 months).
- Four very-long-term survivors (>6 years from diagnosis) were all treated with an mTOR inhibitor.
- These results support everolimus as the standard arm for the next BIOMEDE adaptive trial, which will compare everolimus to ONC201.
Study Design
- Study Type
- Randomized, biomarker-driven, open-label phase 2 trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 233
- Follow-up
- Median 5.3 years
- Centers
- Multicenter international (Gustave Roussy coordinating)
- Countries
- France, United Kingdom, Denmark, Sweden, Spain, Australia, The Netherlands, New Zealand
Primary Outcome
Definition: Overall survival (OS) from biopsy, with pairwise comparisons among treatment arms and vs historical control
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Trial designed >10 years ago when DIPG biology was less understood; biomarker selection (EGFR IHC, PTEN IHC) reflects 2014 knowledge.
- First-generation kinase inhibitors used; newer-generation EGFR and mTOR inhibitors with better CNS penetration may yield different results.
- No radiotherapy-only randomized control arm (deemed unethical by parent associations); historical-control comparison only.
- Open-label design, with possible treatment crossover at progression (some patients switched drugs, 25% received reirradiation).
- Smallest pairwise comparison (erlotinib vs everolimus) included only 59 patients — limited power for that arm.
- Single coordinating center (Gustave Roussy) for historical controls; 72% of trial patients enrolled in France — generalizability outside Europe may be limited.
- Theranostic mTOR benefit is exploratory and hypothesis-generating; requires prospective validation (planned in next-generation BIOMEDE adaptive trial vs ONC201).
Citation
Nat Med 2026;32(6):2201-2215