1. Challenges in drug development for Andrés Felipe Cardona, MD MSc PhD.
agresive meningiomas
Andrés Felipe Cardona, MD MSc PhD.
Clinical and Translational Oncology Group
Institute of Oncology, Fundación Santa Fe de Bogotá
Clinical Epidemiology
Universidad El Bosque
Foundation for Clinical and Applied Cancer Research
Cochrane Colombian Branch / LATINREC / ONCOLGroup

2. Background
WHO grade I is the most prevalent (78-81%), followed by the atypical variety (15-20%), and only 1-4% of meningiomas are anaplastic
The majority of WHO grade I meningiomas (50%-60%) have been linked to mutations of the NF2 gene on chromosome 22 (q12.2; Merlin)
Merlin is localized to the cell membrane at regions that regulate cell–cell contact and motility (binding CD44 and β1-integrin)
Merlin regulates YAP levels, which controls cell proliferation and the unintentional entry into the S-phase of the cell cycle
Neuropathol Appl Neurobiol Apr;31(2):141-9.

3. Patterns of cytogenetic alterations and progression of meningiomas (Ketter hypothesis)
Diploid -6
-22
-1p
-10
-14 -X
-18
Tetrapolid -Y
-19
Normal meningeal cell
1q+9q+12q+15q+17q+20
-22
17q
1q-6q-10q-14q
-18q
Complex karyotype
-9p
WHO grade I
WHO grade II
WHO grade III
Neurochirurgie Sep 19. pii: S (14)

4. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations
Slide 14
Nat Genet Mar;45(3):285-9.

5. TERT promoter mutations and risk of recurrence in meningioma
TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively.
TERT promoter mutations were statistically significantly associated with shorter time to progression
JNCI J Natl Cancer Inst. 2016;108(5):djv377.

6. 60% and 90% of grade II and III meningiomas have shown point mutations (mainly deletions) in chromosomes
Merlin losses have been observed in 60% of atypical meningiomas and 70% of anaplastic meningiomas

7. WHO classification and accuracy of meningioma grading
WHO grade
Description
Grade I
Any histologic pattern other than clear cell, choroid, papillary or rhabdoid
Lacks criteria of atypical or anaplastic meningioma
Grade II
Mitoses 4-19 (10 hfp)
Macronuclei, spontaneous necrosis, hyper cellularity, small cell formation, sheeting architecture (any of theses 3 to 5 parameters or possibly more)
Meningioma protrudes into the brain parenchyma
Clear cell or choroid cell types
Grade III
Mitoses +20 hpf
Apparent anaplasia (carcinoma/sarcoma like histology)
Rhabdoid or papillary cell type
Inter OV 23.4%
Intra OV 17.5%
Inter OV 38.4%
Intra OV 24.0%

8. Correlation of the neuropathologic classification according to WHO classification and outcome in atypical and anaplastic meningiomas
WHO 1993
WHO 2007
OS p=0.96
OS p=0.02
N = 62 patients
Int J Radiat Oncol Biol Phys Dec 1;81(5):

9. Correlation of the neuropathologic classification according to WHO classification and outcome in atypical and anaplastic meningiomas
WHO 1993
WHO 2007
OS p=0.44
OS p=0.005
N = 62 patients
Int J Radiat Oncol Biol Phys Dec 1;81(5):

10. Histological, clinical and molecular correlation
Experiment Molecular Pathol. 2015;99:354–359.

11. Prognosis: Age Meningioma 2012
Neuro Oncol Oct;16 Suppl 4:iv1-63.

12. Prognosis: MIB index
World Neurosurg Sep;84(3):

13. Controversy: Adjuvant RT for atypical meningiomas
Outcome of adjuvant radiotherapy after GTR of atypical meningioma
World Neurosurg May;83(5):

14. Controversy: Adjuvant RT for atypical meningiomas
Outcome of adjuvant radiotherapy after GTR of atypical meningioma
Median values of recurrence
World Neurosurg May;83(5):

15. Controversy: Adjuvant RT for atypical meningiomas
Outcome of adjuvant radiotherapy after GTR of atypical meningioma
5 year recurrence
Adjuvant RT after GTR of AMs improves local control but does not affect 5-year overall survival
World Neurosurg May;83(5):

16. ROAM/EORTC-1308 trial: radiation versus observation following surgical resection of atypical meningioma

17. Drugs that (probably) don´t work
Preusser M, et al. ASCO 2015.

18. Drugs that (probably) don´t work
Drugs that may work
Preusser M, et al. ASCO 2015.

19. Angiogenesis and VEGF in meningioma
Slide 5
Acta Neuropathol Nov;126(5):
Clin Neuropathol Sep-Oct;31(5):

20. Positive correlation of VEGF-R2 with PFS
Kaley S, et al. Society of Neuro-Oncol

21. Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma
PFS 22 months C )
DCR 88%
Shih K, et al. J Neurooncol Jun 16. [Epub ahead of print]

22. Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma
PFS 22 months C )
DCR 88%
Shih K, et al. J Neurooncol Jun 16. [Epub ahead of print]

23. Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma
Shih K, et al. J Neurooncol Jun 16. [Epub ahead of print]

24. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma
PFS6 = 44% (95% CI: 27.0–59.7); median PFS = 5.2 mo (95% CI: 2.8–8.3 mo); median OS = 24.6 mo
(95% CI: 16.5–38.4 mo); 1-year OS = 79.2% (95% CI: 61.1–89.7); 2-year OS = 51.7% (95% CI: 29.4–70.4).
Neuro Oncol Jan;17(1): doi: /neuonc/nou148.

25. Combined treatment by octreotide and everolimus

26. Combined treatment by octreotide and everolimus
J Neurooncol Aug;124(1):33-43.

27. Combined treatment by octreotide and everolimus
Cardona AF, et al. SNO 2015.

28. Trabectedin (Yondelis)
Preusser M, et al. ASCO 2015.

29. Slide 11
Cancer Oct 15;118(20):

30. EORTC-1320-BTG: Trabectedin for recurrent grade II or III meningioma: a randomized phase II study of the EORTC Brain Tumor Group

31. Conclusions