A071401 Abemaciclib for Meningioma
Abemaciclib in meningiomas with somatic NF2 or CDK pathway alterations: the phase 2 Alliance A071401 trial
Clinical Question
Can abemaciclib improve outcomes in patients with progressive high-grade meningiomas harboring NF2 or CDK pathway alterations?
Bottom Line
In patients with recurrent or progressive grade 2 or 3 meningiomas harboring NF2 or CDK pathway alterations, abemaciclib met the primary endpoint with a PFS6 rate of 58%, median PFS of 10.1 months, and was well tolerated, warranting further investigation in this genomically defined population.
Major Points
- First genomically driven national trial for recurrent/progressive meningiomas evaluating targeted therapy based on specific genetic alterations.
- PFS6 rate of 58% (14/24 patients) met the prespecified primary endpoint success threshold of ≥8/24 patients.
- No objective responses were observed; best response was stable disease in 67% of patients, which is clinically meaningful in heavily pretreated patients.
- Patients with NF2 alterations had significantly better outcomes (median PFS 12.1 months, PFS6 62.5%) compared to those with CDK pathway alterations alone (median PFS 2.4 months, PFS6 25%).
- Treatment was well tolerated with grade 3/4 toxicities in 31% of patients, consistent with abemaciclib's known safety profile.
- Higher p16 expression by IHC was associated with clinical benefit (mean 1.8 vs 0.78, P=0.04).
- Results compare favorably to historical controls showing 0-29% PFS6 in grade 2/3 meningiomas treated with systemic therapy.
Design
Study Type: Phase 2, single-arm, open-label
Randomization:
Blinding: Open-label
Allocation: Non-randomized, genomically driven assignment
Enrollment Period: September 15, 2021 to October 3, 2022
Follow-up Duration: Median 21 months
Centers: 21
Countries: United States
Sample Size: 36
Analyzed: 24
Analysis: First 24 eligible patients who began treatment were evaluable for primary endpoint per prespecified design. Intention-to-treat analysis for efficacy; all treated patients for safety.
Power Calculation: 24 evaluable patients provided ≥85% power to detect true PFS6 rate ≥41.5% vs null hypothesis of 15% (α=0.02); and ≥89% power to detect true RR ≥20% vs null hypothesis of 2.5% (α=0.021). Bonferroni correction applied for two co-primary endpoints.
Registration: NCT02523014
Inclusion Criteria
- Intracranial grade 2 or 3 meningioma documented by central pathology review
- Bidimensionally measurable enhancing lesions with minimum diameter of 10 mm
- Presence of NF2 or CDK pathway alteration confirmed by central genetic testing
- Progressive or residual disease defined by: (1) residual measurable disease immediately after surgery, (2) progressive measurable disease (≥25% increase in ≤25 months), or (3) progressive disease after radiation
- Stable steroid dosing for at least 4 days
- ECOG performance status ≤2
- Hemoglobin ≥8 g/dL
- Recovered to CTCAE grade ≤1 toxicity (except residual alopecia or grade 2 neuropathy)
- No chemotherapy, cancer-directed hormonal therapy, or investigational agents within 28 days
- No craniotomy within 28 days before or after registration
- Not pregnant and not nursing
Exclusion Criteria
- Extracranial meningiomas
- Active bacterial, fungal, or detectable viral infection
- Personal history of syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin, or sudden cardiac arrest
- Grade 1 meningioma
Arms
| Field | Abemaciclib |
|---|---|
| N | 36 |
| Intervention | Abemaciclib 200 mg orally twice daily for 28-day cycles until disease progression, excessive toxicity, symptomatic neurological deterioration, or consent withdrawal |
| Duration | Mean 9 cycles (SD 9.9), median follow-up 21 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Progression-free survival at 6 months (PFS6) | Primary | 58% (14/24 patients) | Met prespecified success threshold of ≥8/24 patients | ||
| Response rate | Secondary | 0% (0/24 complete or partial responses) | Did not meet success threshold of ≥3/24 responses | ||
| Stable disease rate | Secondary | 67% (16/24) | |||
| Median progression-free survival | Secondary | 10.1 months | |||
| Median overall survival | Secondary | 29.1 months | |||
| PFS6 by central review (Macdonald criteria) | Secondary | 57% (12/21 with available scans) | |||
| PFS6 by central review (volumetric) | Secondary | 57% (12/21) | |||
| Median PFS in patients with stable disease | Secondary | 11.1 months | |||
| Grade 3 adverse events possibly related to treatment | Safety | 25% (9/36) | |||
| Grade 4 adverse events possibly related to treatment | Safety | 6% (2/36) | |||
| Treatment discontinuation due to AEs | Safety | 19% (7/36) | |||
| Treatment delay in at least one cycle | Safety | 33% (12/36) | |||
| Grade 4 ALT elevation | Safety | 3% (1/36) | |||
| Grade 4 AST elevation | Safety | 3% (1/36) | |||
| Grade 4 vomiting | Safety | 3% (1/36) | |||
| Grade 3+ events possibly related to treatment | Adverse | 31% (11/36 patients) | |||
| Most common grade 3 events | Adverse | AST/ALT elevation, fatigue, diarrhea, nausea | |||
| Grade 4 events | Adverse | AST elevation (n=1), ALT elevation (n=1), vomiting (n=1) | |||
Subgroup Analysis
Patients with NF2 alterations alone had better outcomes: PFS6 62.5% (15/24, 95% CI 41-81%) vs CDK pathway alone 25% (1/4, 95% CI 1-81%) vs both alterations 29% (2/7, 95% CI 4-71%) (Fisher's exact P=0.205). Median PFS significantly longer in NF2 group: 12.1 months (95% CI 7.6-20.6) vs CDK pathway 2.4 months (95% CI 1.6-NE) vs both 2.0 months (95% CI 1.5-NE) (log-rank P=0.0094). Higher p16 expression associated with clinical benefit (mean 1.8 vs 0.78, P=0.04).
Criticisms
- Lack of control arm limits ability to definitively attribute outcomes to drug effect, though lack of standard-of-care options justifies single-arm design
- Small sample size (n=24 evaluable) limits power for subgroup analyses
- No objective responses (complete or partial) observed; all benefits were stable disease
- Lack of central radiology review of pretreatment scans 12-24 months before study entry to systematically assess pretreatment growth rates
- Optimal predictive biomarkers for response to CDK4/6 inhibition in meningioma remain unclear
- Poor outcomes in patients with CDK pathway alterations suggest these may not be the optimal biomarker for patient selection
- Quality of life and neurocognitive outcomes not systematically collected
- Primary endpoint (PFS6) based on historical controls from 2015; more recent RANO pooled analysis (published 2025) suggests PFS6 of 38% in grade 2/3 meningiomas, though current study still compares favorably
- Heterogeneous patient population regarding prior treatments (38% had prior medical therapy)
- Limited generalizability to grade 1 meningiomas
Funding
National Cancer Institute and Alliance for Clinical Trials in Oncology
Based on: A071401 Abemaciclib for Meningioma (Nature Medicine, 2026)
Authors: Brastianos PK, Dooley K, Geyer S, ..., Galanis E
Citation: Brastianos PK, et al. Abemaciclib in meningiomas with somatic NF2 or CDK pathway alterations: the phase 2 Alliance A071401 trial. Nat Med. 2026;32:717-724.
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