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

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. 2005 Apr;31(2):141-9.

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. 2014 Sep 19. pii: S0028-3770(14)00113-1.

Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations Slide 14 Nat Genet. 2013 Mar;45(3):285-9.

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.

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

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%

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. 2011 Dec 1;81(5):1415-21.

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. 2011 Dec 1;81(5):1415-21.

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

Prognosis: Age Meningioma 2012 Neuro Oncol. 2014 Oct;16 Suppl 4:iv1-63.

Prognosis: MIB index World Neurosurg. 2015 Sep;84(3):839-45.

Controversy: Adjuvant RT for atypical meningiomas Outcome of adjuvant radiotherapy after GTR of atypical meningioma World Neurosurg. 2015 May;83(5):808-15.

Controversy: Adjuvant RT for atypical meningiomas Outcome of adjuvant radiotherapy after GTR of atypical meningioma Median values of recurrence World Neurosurg. 2015 May;83(5):808-15.

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. 2015 May;83(5):808-15.

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

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

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

Angiogenesis and VEGF in meningioma Slide 5 Acta Neuropathol. 2013 Nov;126(5):757-62. Clin Neuropathol. 2012 Sep-Oct;31(5):352-60.

Positive correlation of VEGF-R2 with PFS Kaley S, et al. Society of Neuro-Oncol. 2015.

Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma PFS 22 months C4.5-26.8) DCR 88% Shih K, et al. J Neurooncol. 2016 Jun 16. [Epub ahead of print]

Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma PFS 22 months C4.5-26.8) DCR 88% Shih K, et al. J Neurooncol. 2016 Jun 16. [Epub ahead of print]

Phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma Shih K, et al. J Neurooncol. 2016 Jun 16. [Epub ahead of print]

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. 2015 Jan;17(1):116-21. doi: 10.1093/neuonc/nou148.

Combined treatment by octreotide and everolimus

Combined treatment by octreotide and everolimus J Neurooncol. 2015 Aug;124(1):33-43.

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

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

Slide 11 Cancer. 2012 Oct 15;118(20):5038-49.

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

Conclusions