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TADPOLE-G

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

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Year of Publication: 2023

Authors: Bouffet E, Hansford JR, Garrè ML, ..., Hargrave DR

Journal: New England Journal of Medicine

Citation: N Engl J Med 2023;389(12):1108-1120

Link: https://doi.org/10.1056/NEJMoa2303815

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2303815

Clinical Question

Does first-line dabrafenib + trametinib outperform carboplatin + vincristine in pediatric BRAF V600-mutant LGG?

Bottom Line

In pediatric patients with treatment-naive BRAF V600-mutant low-grade glioma, first-line dabrafenib plus trametinib produced markedly higher overall response (47% vs 11%), nearly tripled progression-free survival (20.1 vs 7.4 months, HR 0.31), and was far better tolerated than standard carboplatin-vincristine chemotherapy. This establishes BRAF/MEK inhibition as the new first-line standard for this molecularly defined subgroup.

        Major Points
        Phase 2, open-label, multicenter, randomized trial
110 pediatric patients (1-17 years) with newly diagnosed, treatment-naive, unresectable/progressive BRAF V600-mutant LGG randomized 2:1 to dabrafenib + trametinib (73) or carboplatin + vincristine (37)
Dabrafenib 5.25 mg/kg/day divided BID + trametinib 0.032 mg/kg/day once daily until progression or unacceptable toxicity
Primary endpoint: independently assessed overall response (CR+PR) per RANO criteria
Median follow-up 18.9 months at data cutoff
Overall response: 47% (dabrafenib+trametinib) vs 11% (chemotherapy); risk ratio ~4.3
Clinical benefit rate (CR/PR/SD ≥24 weeks): 86% vs 46%
Median progression-free survival: 20.1 months (D+T) vs 7.4 months (chemo); HR 0.31 (95% CI ~0.17-0.58); p<0.001
Grade ≥3 adverse events: 47% (D+T) vs 94% (chemo); significantly lower toxicity burden with targeted therapy
Most common D+T AEs: pyrexia, rash, headache, vomiting, fatigue
Chemotherapy toxicities dominated by cytopenias and peripheral neuropathy
No treatment-related deaths reported
Led to FDA approval of dabrafenib + trametinib for pediatric BRAF V600-mutant LGG (2023)

      

Design

Study Type: Phase 2, multicenter, open-label, randomized, active-controlled trial

Randomization: 1

Blinding: Open-label (independent central review for response)

Enrollment Period: 2019-2022

Follow-up Duration: Median 18.9 months at analysis

Centers: Multicenter international

Sample Size: 110

Analyzed: 110

Analysis: Intention-to-treat

Inclusion Criteria

Age 1-17 years
Newly diagnosed, previously untreated LGG
Confirmed BRAF V600 mutation
Unresectable tumor or progression requiring systemic therapy
Measurable disease per RANO
Adequate organ function

Exclusion Criteria

Prior systemic therapy for LGG
Prior radiotherapy to tumor
High-grade glioma
RAS/NF1 mutation status that would alter treatment decision

Arms

Field	Dabrafenib + Trametinib	Control
N	73	37
Intervention	Dabrafenib 5.25 mg/kg/day divided BID + trametinib 0.032 mg/kg/day once daily	Standard carboplatin + vincristine regimen (weekly induction and maintenance cycles)
Duration	Until progression or unacceptable toxicity	Standard protocol (~1 year)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Independently assessed overall response (complete response + partial response) per RANO criteria	Primary	11% (carboplatin + vincristine)	47% (dabrafenib + trametinib)		p<0.001
Clinical benefit rate (CR + PR + SD ≥24 weeks)	Secondary	46%	86%	Risk ratio ~1.9 favoring D+T	Significant
Progression-free survival (median, months)	Secondary	7.4 months	20.1 months	HR 0.31 (95% CI ~0.17-0.58)	p<0.001
Overall response rate by investigator assessment	Secondary	Similar to central review (~11%)	Similar to central review (~47%)		Consistent with primary
Duration of response	Secondary	Shorter with chemotherapy	Sustained in most D+T responders		Longer with D+T
Any adverse event	Adverse	~100%	~99%		Similar rates
Grade ≥3 adverse event (any)	Adverse	94%	47%		Substantially lower with D+T
Pyrexia	Adverse	~14%	~53%		Much more common with D+T
Rash / dry skin	Adverse	~10%	~40%		More common with D+T
Headache	Adverse	~13%	~36%		More common with D+T
Vomiting	Adverse	~35%	~33%		Similar
Neutropenia (grade ≥3)	Adverse	~54%	~3%		Dramatically higher with chemotherapy
Peripheral neuropathy	Adverse	~14%	~3%		Higher with vincristine (chemo arm)
Alopecia	Adverse	~54%	~2%		Dramatically higher with chemotherapy
Treatment discontinuation due to AEs	Adverse	Higher	Lower		More discontinuation with chemotherapy
Treatment-related deaths	Adverse	None reported	None reported		Not applicable

Subgroup Analysis

Benefit of dabrafenib + trametinib was consistent across prespecified subgroups by age (1-11 vs 12-17), baseline tumor location, and histology (pilocytic astrocytoma vs other LGG histologies with BRAF V600). No subgroup with preferential benefit to chemotherapy identified. Post-discontinuation tumor rebound was described for some patients stopping D+T — an open clinical question about optimal duration.

Criticisms

Open-label design with subjective PFS assessments mitigated by independent central review
Short median follow-up (18.9 months) does not yet address long-term disease control after stopping therapy (rebound reported with BRAF inhibitor discontinuation)
Carboplatin-vincristine (COG) regimen is one of several accepted first-line regimens; other comparators (e.g., weekly vinblastine) were not evaluated
Optimal duration of D+T therapy remains unknown
Does not address patients with BRAF fusion (KIAA1549-BRAF) — a different molecular subgroup

Funding

Novartis (manufacturer of dabrafenib + trametinib)

Based on: TADPOLE-G (New England Journal of Medicine, 2023)

Authors: Bouffet E, Hansford JR, Garrè ML, ..., Hargrave DR

Citation: N Engl J Med 2023;389(12):1108-1120

Content summarized and formatted by NeuroTrials.ai.

TADPOLE-G

(2023)

Objective

Dabrafenib + trametinib vs standard chemotherapy (carboplatin + vincristine) — to evaluate BRAF/MEK inhibition as first-line therapy in pediatric low-grade glioma harboring BRAF V600 mutations.

Study Summary

• Dabrafenib plus trametinib more than quadrupled the overall response rate vs standard carboplatin-vincristine chemotherapy (47% vs 11%; risk ratio 4.3) in pediatric BRAF V600-mutant low-grade glioma.
• Median progression-free survival was almost tripled with dabrafenib+trametinib (20.1 vs 7.4 months; HR 0.31, p<0.001), with clinical benefit in 86% vs 46% and Grade ≥3 AEs far less common (47% vs 94%) than chemotherapy.
• Establishes BRAF/MEK inhibition as the new first-line standard of care for pediatric BRAF V600-mutant low-grade glioma, replacing decades-old carboplatin-vincristine chemotherapy for this molecularly defined subgroup.

Intervention

Dabrafenib 5.25 mg/kg/day (divided BID) plus trametinib 0.032 mg/kg/day once daily vs standard chemotherapy (carboplatin + vincristine) until progression, unacceptable toxicity, or end of planned treatment.

Inclusion Criteria

Pediatric patients 1–17 years with newly diagnosed, treatment-naive, unresectable or progressive low-grade glioma harboring a BRAF V600 mutation.

Study Design

Arms: Dabrafenib + Trametinib vs Carboplatin + Vincristine (2:1)

Patients per Arm: Dabrafenib + Trametinib 73; Carboplatin + Vincristine 37

Outcome

• Primary: Overall response (RANO): 47% (D+T) vs 11% (chemo); risk ratio 4.3
• Progression-free survival: median 20.1 mo (D+T) vs 7.4 mo (chemo); HR 0.31, p<0.001
• Clinical benefit rate (CR+PR+SD≥24 wk): 86% vs 46%
• Grade ≥3 AEs: 47% (D+T) vs 94% (chemo)
• Safety: D+T well-tolerated; most common AEs pyrexia, rash, headache. Chemo AEs hematologic/neuropathic

Clinical Question

Does first-line dabrafenib plus trametinib improve response and progression-free survival compared to standard carboplatin-vincristine chemotherapy in pediatric BRAF V600-mutant low-grade glioma?

Bottom Line

Major Points

Phase 2, open-label, multicenter, randomized trial
110 pediatric patients (1-17 years) with newly diagnosed, treatment-naive, unresectable/progressive BRAF V600-mutant LGG randomized 2:1 to dabrafenib + trametinib (73) or carboplatin + vincristine (37)
Dabrafenib 5.25 mg/kg/day divided BID + trametinib 0.032 mg/kg/day once daily until progression or unacceptable toxicity
Primary endpoint: independently assessed overall response (CR+PR) per RANO criteria
Median follow-up 18.9 months at data cutoff
Overall response: 47% (dabrafenib+trametinib) vs 11% (chemotherapy); risk ratio ~4.3
Clinical benefit rate (CR/PR/SD ≥24 weeks): 86% vs 46%
Median progression-free survival: 20.1 months (D+T) vs 7.4 months (chemo); HR 0.31 (95% CI ~0.17-0.58); p<0.001
Grade ≥3 adverse events: 47% (D+T) vs 94% (chemo); significantly lower toxicity burden with targeted therapy
Most common D+T AEs: pyrexia, rash, headache, vomiting, fatigue
Chemotherapy toxicities dominated by cytopenias and peripheral neuropathy
No treatment-related deaths reported
Led to FDA approval of dabrafenib + trametinib for pediatric BRAF V600-mutant LGG (2023)

Study Design

Study Type: Phase 2, multicenter, open-label, randomized, active-controlled trial
Randomization: Yes
Blinding: Open-label (independent central review for response)
Sample Size: 110
Follow-up: Median 18.9 months at analysis
Centers: Multicenter international

Primary Outcome

Definition: Independently assessed overall response (complete response + partial response) per RANO criteria

Control	Intervention	HR/OR	P-value
11% (carboplatin + vincristine)	47% (dabrafenib + trametinib)	-	p<0.001

Limitations & Criticisms

Open-label design with subjective PFS assessments mitigated by independent central review
Short median follow-up (18.9 months) does not yet address long-term disease control after stopping therapy (rebound reported with BRAF inhibitor discontinuation)
Carboplatin-vincristine (COG) regimen is one of several accepted first-line regimens; other comparators (e.g., weekly vinblastine) were not evaluated
Optimal duration of D+T therapy remains unknown
Does not address patients with BRAF fusion (KIAA1549-BRAF) — a different molecular subgroup

Citation

N Engl J Med 2023;389(12):1108-1120

View Original Publication →

TADPOLE-G

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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