- Email: [email protected]
6 inhibitor in aggressive meningioma patients
abstracts options: Novartis Pharmaceuticals Corp.; Full / Part-time employment: Novartis Pharmaceuticals Corp. P. Cazorla Arratia: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corporation; Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Song: Shareholder / Stockholder / Stock options, Restricted Stock Unit: Novartis Pharmaceutical Corporation; Full / Part-time employment: Novartis Pharmaceutical Corporation. F. Branle: Shareholder / Stockholder / Stock options: Novartis AG; Full / Part-time employment: Novartis AG. M. Shi: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis Pharmaceuticals Corporation. L.Q. Chow: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc., Alkermes, Amgen, Sanofi-Genzyme, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc. and Alkermes,Incyte, VentiRx and Lily/Imclone. All other authors have declared no conflicts of interest.
Prognostic role of the EANO ESMO classification of leptomeningeal metastases
E. Le Rhun1, P. Devos2, J. Weller3, K. Seystahl4, F. Mo5, A. Compter6, A.S. Berghoff7, J. Jongen8, F. Wolpert4, R. Ruda5, D. Brandsma6, M. Preusser9, M.J. van den Bent10, U. Herrlinger11, M. Weller12 1 Neuro-oncology, Neurosurgery Department, Roger Salengro Hospital, Lille, France, 2 Biostatistic Unit, Lille University Hospital, Lille, France, 3Neurology, University Hospital of Bonn, Bonn, Germany, 4Neurology, University Hospital and University of Zurich, Zurich, Switzerland, 5Neurology, City of Health and Science and University of Turin, Turin, Italy, 6Neurology, Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, Netherlands, 7Department of Medicine 1, Medizinische Universitaet Wien (Medical University of Vienna), Vienna, Austria, 8Neurology, Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, Netherlands, 9Department of Medicine I, Vienna General Hospital (AKH) - Medizinische Universit€ at Wien, Vienna, Austria, 10 Neurology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands, 11 Department of Neurology and Center for Integrated Oncology, Universit€ atsklinikum atsspital Zu¨rich, Zurich, Switzerland Bonn, Bonn, Germany, 12Neurology, Universit€ Background: The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear þ nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the correlation between EANO ESMO subtypes of LM and outcome to assess their clinical utility. Methods: We collected data from 254 patients with newly diagnosed LM from different primary solid tumors. Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. Results: Median age at LM diagnosis was 56.5 years (range 20-82 years). The main primary tumors were breast cancer (n ¼ 98, 45%), lung cancer (n ¼ 65, 25.5%) and melanoma (n ¼ 51, 13.5%). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n ¼ 33, 13%), C (n ¼ 54, 21%) and D (n ¼ 50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Assignment to EANO ESMO classes was as follows: type IA 86 (34%), IB 19 (7.5%), IC 39 (15.5%), ID 45 (17.5%), IIA 28 (11%), IIB 13 (5%), IIC 16 (6.5%), IID 8 (3%). LM was confirmed in 189 (74.5%), probable in 51 (20%) and possible in 14 (5.5%) patients. The median overall survival (OS) was 2.75 months (range 0.09-220 months). OS was inferior in type I compared with type II LM patients (p ¼ 0.0024). EANO ESMO subtype IIA patients had the longest survival (p ¼ 0.0103). Patients with MRI patterns A and D pooled had poorer survival than B and C patients pooled in the presence of tumor cells in the CSF (type I) (p ¼ 0.0402), but longer survival in the absence of tumor cells in the CSF (type II) (p ¼ 0.0273). Conclusions: The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are prognostic and should be considered in the design of clinical trials. Legal entity responsible for the study: University Hospital of Zurich. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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A phase 0/II clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients
N. Sanai1, A.-C. Tien1, J. Li2, X. Bao2, A. DeRogatis1, Y. Fujita1, C. Pennington-Krygier1, S. Kim3, S. Mehta1 1 Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ, USA, 2 Pharmacology Core, Karmanos Cancer Institute, Detroit, MI, USA, 3Oncology, Karmanos Cancer Institute, Detroit, MI, USA Background: New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor
v144 | CNS Tumours
pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. Methods: Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04 mM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory phase 2 cohort. Results: The median CSF concentration of ribociclib was 0.25 mM. In tumor tissue, the median unbound ribociclib concentration was 1.36 mM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. Conclusions: Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted. Clinical trial identification: NCT02933736. Legal entity responsible for the study: The authors. Funding: The Ben and Catherine Ivy Foundation. Disclosure: All authors have declared no conflicts of interest.
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Is immuno-oncology therapy effective in hypermutator glioblastomas with somatic or germline mutations?
C. Kamiya-Matsuoka1, N. Metrus1, S-P. Weathers1, J. Ross2, K. Shaw3, M. Penas-Prado4, M. Loghin1, K. Alfaro-Munoz1, B. O’Brien1, R. Harrison1, Z. Sadighi5, N. Majd1, W. Yung1, F. Meric-Bernstam6, D. Hambardzumyan2, J. de Groot1 1 Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Pediatrics, Emory University School of Medicine, Atlanta, GA, USA, 3Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 4Neuro-Oncology, National Institute of Health, Bethesda, MD, USA, 5 Pediatrics, MD Anderson Cancer Center, Houston, TX, USA, 6Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO. Methods: Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes. Results: 30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N ¼ 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months. Conclusions: IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population. Legal entity responsible for the study: The authors. Funding: This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center. Disclosure: All authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz243.002/5577609 by guest on 25 October 2019
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Annals of Oncology
Prognostic role of the EANO ESMO classification of leptomeningeal metastases
E. Le Rhun1, P. Devos2, J. Weller3, K. Seystahl4, F. Mo5, A. Compter6, A.S. Berghoff7, J. Jongen8, F. Wolpert4, R. Ruda5, D. Brandsma6, M. Preusser9, M.J. van den Bent10, U. Herrlinger11, M. Weller12 1 Neuro-oncology, Neurosurgery Department, Roger Salengro Hospital, Lille, France, 2 Biostatistic Unit, Lille University Hospital, Lille, France, 3Neurology, University Hospital of Bonn, Bonn, Germany, 4Neurology, University Hospital and University of Zurich, Zurich, Switzerland, 5Neurology, City of Health and Science and University of Turin, Turin, Italy, 6Neurology, Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, Netherlands, 7Department of Medicine 1, Medizinische Universitaet Wien (Medical University of Vienna), Vienna, Austria, 8Neurology, Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, Netherlands, 9Department of Medicine I, Vienna General Hospital (AKH) - Medizinische Universit€ at Wien, Vienna, Austria, 10 Neurology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands, 11 Department of Neurology and Center for Integrated Oncology, Universit€ atsklinikum atsspital Zu¨rich, Zurich, Switzerland Bonn, Bonn, Germany, 12Neurology, Universit€ Background: The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear þ nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the correlation between EANO ESMO subtypes of LM and outcome to assess their clinical utility. Methods: We collected data from 254 patients with newly diagnosed LM from different primary solid tumors. Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. Results: Median age at LM diagnosis was 56.5 years (range 20-82 years). The main primary tumors were breast cancer (n ¼ 98, 45%), lung cancer (n ¼ 65, 25.5%) and melanoma (n ¼ 51, 13.5%). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n ¼ 33, 13%), C (n ¼ 54, 21%) and D (n ¼ 50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Assignment to EANO ESMO classes was as follows: type IA 86 (34%), IB 19 (7.5%), IC 39 (15.5%), ID 45 (17.5%), IIA 28 (11%), IIB 13 (5%), IIC 16 (6.5%), IID 8 (3%). LM was confirmed in 189 (74.5%), probable in 51 (20%) and possible in 14 (5.5%) patients. The median overall survival (OS) was 2.75 months (range 0.09-220 months). OS was inferior in type I compared with type II LM patients (p ¼ 0.0024). EANO ESMO subtype IIA patients had the longest survival (p ¼ 0.0103). Patients with MRI patterns A and D pooled had poorer survival than B and C patients pooled in the presence of tumor cells in the CSF (type I) (p ¼ 0.0402), but longer survival in the absence of tumor cells in the CSF (type II) (p ¼ 0.0273). Conclusions: The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are prognostic and should be considered in the design of clinical trials. Legal entity responsible for the study: University Hospital of Zurich. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
392O
A phase 0/II clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients
N. Sanai1, A.-C. Tien1, J. Li2, X. Bao2, A. DeRogatis1, Y. Fujita1, C. Pennington-Krygier1, S. Kim3, S. Mehta1 1 Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ, USA, 2 Pharmacology Core, Karmanos Cancer Institute, Detroit, MI, USA, 3Oncology, Karmanos Cancer Institute, Detroit, MI, USA Background: New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor
v144 | CNS Tumours
pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. Methods: Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04 mM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory phase 2 cohort. Results: The median CSF concentration of ribociclib was 0.25 mM. In tumor tissue, the median unbound ribociclib concentration was 1.36 mM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. Conclusions: Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted. Clinical trial identification: NCT02933736. Legal entity responsible for the study: The authors. Funding: The Ben and Catherine Ivy Foundation. Disclosure: All authors have declared no conflicts of interest.
393O
Is immuno-oncology therapy effective in hypermutator glioblastomas with somatic or germline mutations?
C. Kamiya-Matsuoka1, N. Metrus1, S-P. Weathers1, J. Ross2, K. Shaw3, M. Penas-Prado4, M. Loghin1, K. Alfaro-Munoz1, B. O’Brien1, R. Harrison1, Z. Sadighi5, N. Majd1, W. Yung1, F. Meric-Bernstam6, D. Hambardzumyan2, J. de Groot1 1 Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2 Pediatrics, Emory University School of Medicine, Atlanta, GA, USA, 3Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 4Neuro-Oncology, National Institute of Health, Bethesda, MD, USA, 5 Pediatrics, MD Anderson Cancer Center, Houston, TX, USA, 6Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO. Methods: Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes. Results: 30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N ¼ 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months. Conclusions: IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population. Legal entity responsible for the study: The authors. Funding: This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center. Disclosure: All authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz243.002/5577609 by guest on 25 October 2019
391O
Annals of Oncology