Letter: Role of Tyrosine Kinase Inhibitors in Recurrent Meningiomas: Controversies and Promises

Letter: Role of Tyrosine Kinase Inhibitors in Recurrent Meningiomas: Controversies and Promises To the Editor: Meningiomas are primary tumors of the central nervous system (CNS) that constitute more than 20% of adult brain tumors.1 The best chance of cure is complete surgical resection, but unfortunately it is not safely possible for all tumors.2 The risk of recurrence depends upon the histological grading with benign meningiomas (WHO grade 1) having a recurrence risk of 7% to 20% after gross total resection3-5 and atypical meningiomas (grade 2) having a 40% recurrence rate despite resection.5 Malignant meningiomas (grade 3) represent 1% to 3% of meningiomas but recur in 50% to 80% of patients.3,4 Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment. Treatment of these surgery- and radiation-refractory recurrent meningiomas requires systemic therapy, but unfortunately currently there is no effective systemic therapy that stands out as the standard of care despite a number of agents like chemotherapy, hormonal and biological therapies that have been investigated.6-17 Recently, there has been increasing use of targeted therapies directed at recognized mutations of meningioma oncogenesis, such as receptor tyrosine kinases (RTK). The RTKs believed to be most relevant for meningioma growth and proliferation are Epidermal Growth Factor Receptor (EGFR), Platelet Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF) and recently Fibroblast Growth Factor Receptor (FGFR).18-21 We would like to critically evaluate the findings of available prospective trials and infer its significance in terms of present role of RTK inhibitors in recurrent meningiomas, summarized in Table 1. All these trials used 6-mo progression-free survival (PFS) as their primary endpoint for evaluating outcomes with secondary outcome being overall survival and radiological response. However, there is paucity of data regarding the natural history of untreated recurrent meningiomas making it hard to interpret the results of these trials. TABLE 1. Summary of the Prospective Trials Evaluating Receptor Tyrosine Kinases for Recurrent Meningiomas Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity View Large TABLE 1. Summary of the Prospective Trials Evaluating Receptor Tyrosine Kinases for Recurrent Meningiomas Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity View Large Trials involving imatinib22 and erlotinib/geftinib23 failed to demonstrate effectiveness given the low 6-mo PFS and lack of radiological response. However, there were limitations of these studies (summarized in Table 1) that could have contributed to the outcome. Along with the lack of receptor status evaluation for all patients, the low number of subjects recruited in both of these trials make it difficult to draw statistically robust conclusions. Although PDGFR is expressed in the majority of meningiomas24-29 and EGFR in more than 60% of meningiomas,30-33 subjects chosen may have had a different phenotype. In addition, the subjects were heterogeneous with regard to pretreatment. The 6-mo PFS in the imatinib trial in Grade 2/3 meningiomas was 0%, whereas it was 29% in the geftinib/erlotinib trial. This could be because in the imatinib trial the subjects were heavily pretreated as there was no limitation in the number of prior therapies, which could already signify a more advanced disease resulting in poorer outcome, whereas in the geftinib/erlotinib trial patients having greater than 2 recurrences were excluded resulting in less heavily pretreated cohort selection. Another possible explanation could be the inhibition of PDGFR or EGFR alone is insufficient to prevent growth of meningiomas and that other tyrosine kinases such as VEGF/IGF/FGF, may play a greater role in maintaining the transformed phenotype. Kaley et al34 evaluated sunitinib in recurrent meningiomas and it is the first prospective trial that demonstrated efficacy of a medical treatment for patients with aggressive meningioma. Primary efficacy endpoint was reached, with 6-mo PFS of 42% in the primary study cohort of atypical and anaplastic meningioma. Although subject were heterogeneous with regard to earlier trials with other tyrosine kinase inhibitors, sunitinib being a multityrosine kinase inhibitor35 (PDGFRa, PDGFRb, VEGFR2, and KIT) might therefore have been more effective by blocking multiple pathways. However, considerable toxicity to sunitinib was observed with 30 patients (60%) experiencing grade 3 or higher toxicity, but overall toxicity was rather similar to the prior literature on sunitinib with the exception of the CNS hemorrhages. Correlation of receptor status with PFS and overall survival (OS) was also done. In 28 patients of meningiomas (3 grade 1 and 25 grade 2/3), VEGF2 negative patients had a predicted median PFS of 1.4 mo versus 6.4 mo in VEGFR2 positive patients (P = .005). Similarly, predicted median OS was 9.1 mo in VEGFR2-negative patients versus 24.6 mo in VEGFR2-positive patients (P = .002). Tumors were variably positive with a wide range for PDGFRa and PDGFRb, but no significant correlation was noted of PDGFRa or PDGFRb expression with outcome measures in meningioma. However, it cannot be concluded that VEGF2 positivity is a good prognostic marker, as patients who did not receive sunitinib were not evaluated. Another recent trial with PTK787 (Vatalanib)36 also shows antitumor activity of this molecule in recurrent meningiomas with acceptable toxicity profile. Wen et al22 suggested that a positive trial for recurrent Grade 2 and 3 meningiomas would demonstrate a PFS-6 greater or equal to 30%. The PFS-6 for Grade 2/3 patients combined was 54.4% suggesting PTK787 is an active agent for high-grade meningiomas but this trial could not be concluded as positive because prespecified statistical analysis was powered for Grade 1 meningiomas based on the assumption that the most of the patients enrolled would be Grade 1 but 22 out of 25 patients enrolled were Grade 2/3. There have been only a handful of studies that met their predetermined statistical criteria in evaluating this promising targeted therapy, although 1 is currently enrolling and utilizing bevacizumab (NCT01125046) and would be completed by this year. Another recent study evaluating Sorafenib and Regorafenib in meningiomas has shown antitumor activity both in Vitro and in Vivo by targeting PDGFR and p44/42 ERK signaling and warrants human trial.37 However, it is difficult to draw any meaningful conclusion regarding the role of tyrosine kinase inhibitors in recurrent meningiomas as there are no randomized trials, the few trials available have small sample size, lack appropriate control group, and have significant heterogeneity among them with regard to the tumor grade and the specific tyrosine kinase inhibitor evaluated. Also, there is absence of any objective response evaluation criteria for chemotherapy in recurrent meningiomas. Also, response assessment is challenging in this recurrent group of meningioma patients due to unknown natural history of this disease subset. Macdonald criteria38 were used in all these trials in which the largest cross-sectional area of the tumor was assessed but due to irregularity of tumor shapes, this measurement may be inaccurate. Improved response assessment criteria specifically for meningioma are needed for more standardized trial designs in the future. Sunitinib and Valatanib have shown efficacy against high-grade meningiomas and warrant further investigation in randomized setting. Though, long-term durable antitumor activity was not present as all patients finally progressed highlighting that there may be the activation of alternate pathways, incomplete target suppression, or the target not being the sole driver of meningioma growth and proliferation. Recently, AKT and SMO mutations have also been shown in meningiomas39,40 so the need of the hour is to either come up with a targeted therapy that blocks at multiple levels the growth of tumor or try combination therapy in a randomized setting like combining PI3K inhibitor with an mTOR inhibitor or an AKT inhibitor with an antiangiogenic agent to more effectively block alternate pathway activation and to improve the already grim prognosis in this subgroup of patients. Though the various tyrosine kinase inhibitors show great promise in the treatment of these refractory meningiomas, the specifics of their use is surrounded by several controversies. There is need to develop standardized objective response assessment parameters and evaluate the different drugs using them in randomized controlled trials to pull off this shroud of controversies. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. 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Goodwin JW , Crowley J , Eyre HJ , Stafford B , Jaeckle KA , Townsend JJ . A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study . J Neurooncol . 1993 ; 15 ( 1 ): 75 - 77 . Google Scholar CrossRef Search ADS PubMed 16. Chamberlain MC , Glantz MJ , Fadul CE . Recurrent meningioma: salvage therapy with long-acting somatostatin analogue . Neurology . 2007 ; 69 ( 10 ): 969 - 973 . Google Scholar CrossRef Search ADS PubMed 17. Norden AD , Ligon KL , Hammond SN et al. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma . Neurology . 2015 ; 84 ( 3 ): 280 - 286 . Google Scholar CrossRef Search ADS PubMed 18. Johnson M , Toms S . Mitogenic signal transduction pathways in meningiomas: novel targets for meningioma chemotherapy? J Neuropathol Exp Neurol . 2005 ; 64 ( 12 ): 1029 - 1036 . Google Scholar CrossRef Search ADS PubMed 19. Ragel BT , Jensen RL . Aberrant signaling pathways in meningiomas . 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J Neurooncol . 2010 ; 96 ( 2 ): 211 - 217 . Google Scholar CrossRef Search ADS PubMed 24. Black PM , Carroll R , Glowacka D , Riley K , Dashner K . Platelet-derived growth factor expression and stimulation in human meningiomas . J Neurosurg . 1994 ; 81 ( 3 ): 388 - 393 . Google Scholar CrossRef Search ADS PubMed 25. Johnson MD , Woodard A , Kim P , Frexes-Steed M . Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells . J Neurosurg . 2001 ; 94 ( 2 ): 293 - 300 . Google Scholar CrossRef Search ADS PubMed 26. Maxwell M , Galanopoulos T , Tessa Hedley-Whyte E , Black PM , Antoniades HN . Human meningiomas co-express platelet-derived growth factor (pdgf) and pdgf-receptor genes and their protein products . Int J Cancer . 1990 ; 46 ( 1 ): 16 - 21 . Google Scholar CrossRef Search ADS PubMed 27. Todo T , Adams EF , Fahlbusch R , Dingermann T , Werner H . 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Expression and activation of epidermal growth factor receptors in meningiomas . J Neurosurg . 1997 ; 87 ( 2 ): 315 - 323 . Google Scholar CrossRef Search ADS PubMed 32. Jones NR , Rossi ML , Gregoriou M , Hughes JT . Epidermal growth factor receptor expression in 72 meningiomas . Cancer . 1990 ; 66 ( 1 ): 152 - 155 . Google Scholar CrossRef Search ADS PubMed 33. Sanfilippo JS , Rao CV , Guarnaschelli JJ et al. Detection of epidermal growth factor and transforming growth factor alpha protein in meningiomas and other tumors of the central nervous system in human beings . Surg Gynecol Obstet . 1993 ; 177 ( 5 ): 488 - 496 . Google Scholar PubMed 34. Kaley TJ , Wen P , Schiff D et al. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma . Neuro Oncol . 2015 ; 17 ( 1 ): 116 - 121 . Google Scholar CrossRef Search ADS PubMed 35. Mendel DB , Laird AD , Xin X et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship . Clin Cancer Res . 2003 ; 9 ( 1 ): 327 - 337 . Google Scholar PubMed 36. Raizer JJ , Grimm SA , Rademaker A et al. A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas . J Neurooncol . 2014 ; 117 ( 1 ): 93 - 101 . Google Scholar CrossRef Search ADS PubMed 37. Tuchen M , Wilisch-Neumann A , Daniel EA et al. Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits growth and invasion of meningioma cells . Eur J Cancer . 2017 ; 73 : 9 - 21 . Google Scholar CrossRef Search ADS PubMed 38. Macdonald DR , Cascino TL , Schold SC , Cairncross JG . Response criteria for phase II studies of supratentorial malignant glioma . J Clin Oncol . 1990 ; 8 ( 7 ): 1277 - 1280 . Google Scholar CrossRef Search ADS PubMed 39. Clark VE , Erson-Omay EZ , Serin A et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO . Science . 2013 ; 339 ( 6123 ): 1077 - 1080 . Google Scholar CrossRef Search ADS PubMed 40. Brastianos PK , Horowitz PM , Santagata S et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations . Nat Genet . 2013 ; 45 ( 3 ): 285 - 289 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Letter: Role of Tyrosine Kinase Inhibitors in Recurrent Meningiomas: Controversies and Promises

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Abstract

To the Editor: Meningiomas are primary tumors of the central nervous system (CNS) that constitute more than 20% of adult brain tumors.1 The best chance of cure is complete surgical resection, but unfortunately it is not safely possible for all tumors.2 The risk of recurrence depends upon the histological grading with benign meningiomas (WHO grade 1) having a recurrence risk of 7% to 20% after gross total resection3-5 and atypical meningiomas (grade 2) having a 40% recurrence rate despite resection.5 Malignant meningiomas (grade 3) represent 1% to 3% of meningiomas but recur in 50% to 80% of patients.3,4 Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment. Treatment of these surgery- and radiation-refractory recurrent meningiomas requires systemic therapy, but unfortunately currently there is no effective systemic therapy that stands out as the standard of care despite a number of agents like chemotherapy, hormonal and biological therapies that have been investigated.6-17 Recently, there has been increasing use of targeted therapies directed at recognized mutations of meningioma oncogenesis, such as receptor tyrosine kinases (RTK). The RTKs believed to be most relevant for meningioma growth and proliferation are Epidermal Growth Factor Receptor (EGFR), Platelet Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF) and recently Fibroblast Growth Factor Receptor (FGFR).18-21 We would like to critically evaluate the findings of available prospective trials and infer its significance in terms of present role of RTK inhibitors in recurrent meningiomas, summarized in Table 1. All these trials used 6-mo progression-free survival (PFS) as their primary endpoint for evaluating outcomes with secondary outcome being overall survival and radiological response. However, there is paucity of data regarding the natural history of untreated recurrent meningiomas making it hard to interpret the results of these trials. TABLE 1. Summary of the Prospective Trials Evaluating Receptor Tyrosine Kinases for Recurrent Meningiomas Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity View Large TABLE 1. Summary of the Prospective Trials Evaluating Receptor Tyrosine Kinases for Recurrent Meningiomas Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity Study Subjects Drug and dose Efficacy Comments Wen et al (2009) 22 n = 23 Imatinib mesylate (600 mg/day to 800 mg/day with 4 wk cycle) 1. 6M-PFS—29.4%. 1. Inadequate sample size Benign—13 45% for benign, 0% for atypical and malignant. 2. Selection bias. Atypical—5 3. Tumor receptor status available for only 5 patients. Malignant—5 Norden et al (2010) 23 n = 25 Gefitinib (500 mg/day) or Erlotinib (150 mg/day) with 4 wk cycle. 1. 6M PFS—25% for benign, 29% for atypical and malignant. 1. Meningioma management was not primary objective Benign—8 2. 6M OS—63% for benign, 71% for atypical and malignant. 2. Small sample size and heterogeneity. Atypical—9 Malignant—8 3. Comparison between geftinib and erlotinib 3. Difference in OS in Geftinib vs Erlotinib- likelihood of false positive due to small sample size Geftinib—16 (64%) PFS—NS Erlotinib—9 (36%) OS—S (Geftinib better than Erlotinib) Raizer et al (2014) 36 n = 24 PTK787/ZK 222 584 (Vatalanib) (500 mg twice a day with 4 wks cycle) 1. 6M PFS—54.4% for atypical and malignant 1.Prespecified statistical analysis was powered for Grade I meningiomas while Benign—2 Atypical—14 2. Vatalanib is active in grade 2/3 meningiomas. Malignant—8 Kaley et al (2015) 34 n = 36 Sunitinib (50 mg/day with 4 wk cycle) 1. 6M PFS—42% 1. First positive trial Atypical—30 Anaplastic—6 2. Considerable toxicity View Large Trials involving imatinib22 and erlotinib/geftinib23 failed to demonstrate effectiveness given the low 6-mo PFS and lack of radiological response. However, there were limitations of these studies (summarized in Table 1) that could have contributed to the outcome. Along with the lack of receptor status evaluation for all patients, the low number of subjects recruited in both of these trials make it difficult to draw statistically robust conclusions. Although PDGFR is expressed in the majority of meningiomas24-29 and EGFR in more than 60% of meningiomas,30-33 subjects chosen may have had a different phenotype. In addition, the subjects were heterogeneous with regard to pretreatment. The 6-mo PFS in the imatinib trial in Grade 2/3 meningiomas was 0%, whereas it was 29% in the geftinib/erlotinib trial. This could be because in the imatinib trial the subjects were heavily pretreated as there was no limitation in the number of prior therapies, which could already signify a more advanced disease resulting in poorer outcome, whereas in the geftinib/erlotinib trial patients having greater than 2 recurrences were excluded resulting in less heavily pretreated cohort selection. Another possible explanation could be the inhibition of PDGFR or EGFR alone is insufficient to prevent growth of meningiomas and that other tyrosine kinases such as VEGF/IGF/FGF, may play a greater role in maintaining the transformed phenotype. Kaley et al34 evaluated sunitinib in recurrent meningiomas and it is the first prospective trial that demonstrated efficacy of a medical treatment for patients with aggressive meningioma. Primary efficacy endpoint was reached, with 6-mo PFS of 42% in the primary study cohort of atypical and anaplastic meningioma. Although subject were heterogeneous with regard to earlier trials with other tyrosine kinase inhibitors, sunitinib being a multityrosine kinase inhibitor35 (PDGFRa, PDGFRb, VEGFR2, and KIT) might therefore have been more effective by blocking multiple pathways. However, considerable toxicity to sunitinib was observed with 30 patients (60%) experiencing grade 3 or higher toxicity, but overall toxicity was rather similar to the prior literature on sunitinib with the exception of the CNS hemorrhages. Correlation of receptor status with PFS and overall survival (OS) was also done. In 28 patients of meningiomas (3 grade 1 and 25 grade 2/3), VEGF2 negative patients had a predicted median PFS of 1.4 mo versus 6.4 mo in VEGFR2 positive patients (P = .005). Similarly, predicted median OS was 9.1 mo in VEGFR2-negative patients versus 24.6 mo in VEGFR2-positive patients (P = .002). Tumors were variably positive with a wide range for PDGFRa and PDGFRb, but no significant correlation was noted of PDGFRa or PDGFRb expression with outcome measures in meningioma. However, it cannot be concluded that VEGF2 positivity is a good prognostic marker, as patients who did not receive sunitinib were not evaluated. Another recent trial with PTK787 (Vatalanib)36 also shows antitumor activity of this molecule in recurrent meningiomas with acceptable toxicity profile. Wen et al22 suggested that a positive trial for recurrent Grade 2 and 3 meningiomas would demonstrate a PFS-6 greater or equal to 30%. The PFS-6 for Grade 2/3 patients combined was 54.4% suggesting PTK787 is an active agent for high-grade meningiomas but this trial could not be concluded as positive because prespecified statistical analysis was powered for Grade 1 meningiomas based on the assumption that the most of the patients enrolled would be Grade 1 but 22 out of 25 patients enrolled were Grade 2/3. There have been only a handful of studies that met their predetermined statistical criteria in evaluating this promising targeted therapy, although 1 is currently enrolling and utilizing bevacizumab (NCT01125046) and would be completed by this year. Another recent study evaluating Sorafenib and Regorafenib in meningiomas has shown antitumor activity both in Vitro and in Vivo by targeting PDGFR and p44/42 ERK signaling and warrants human trial.37 However, it is difficult to draw any meaningful conclusion regarding the role of tyrosine kinase inhibitors in recurrent meningiomas as there are no randomized trials, the few trials available have small sample size, lack appropriate control group, and have significant heterogeneity among them with regard to the tumor grade and the specific tyrosine kinase inhibitor evaluated. Also, there is absence of any objective response evaluation criteria for chemotherapy in recurrent meningiomas. Also, response assessment is challenging in this recurrent group of meningioma patients due to unknown natural history of this disease subset. Macdonald criteria38 were used in all these trials in which the largest cross-sectional area of the tumor was assessed but due to irregularity of tumor shapes, this measurement may be inaccurate. Improved response assessment criteria specifically for meningioma are needed for more standardized trial designs in the future. Sunitinib and Valatanib have shown efficacy against high-grade meningiomas and warrant further investigation in randomized setting. Though, long-term durable antitumor activity was not present as all patients finally progressed highlighting that there may be the activation of alternate pathways, incomplete target suppression, or the target not being the sole driver of meningioma growth and proliferation. Recently, AKT and SMO mutations have also been shown in meningiomas39,40 so the need of the hour is to either come up with a targeted therapy that blocks at multiple levels the growth of tumor or try combination therapy in a randomized setting like combining PI3K inhibitor with an mTOR inhibitor or an AKT inhibitor with an antiangiogenic agent to more effectively block alternate pathway activation and to improve the already grim prognosis in this subgroup of patients. Though the various tyrosine kinase inhibitors show great promise in the treatment of these refractory meningiomas, the specifics of their use is surrounded by several controversies. There is need to develop standardized objective response assessment parameters and evaluate the different drugs using them in randomized controlled trials to pull off this shroud of controversies. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. 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NeurosurgeryOxford University Press

Published: May 8, 2018

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