Roger Stupp

Bio: Roger Stupp is an academic researcher from Northwestern University. The author has contributed to research in topics: Temozolomide & Glioma. The author has an hindex of 93, co-authored 430 publications receiving 63025 citations. Previous affiliations of Roger Stupp include Merck & Co. & University of St. Gallen.

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Abstract: Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

Elevated levels of MIC‐1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome

Abstract: For patients with brain tumors identification of diagnostic and prognostic markers in easy accessible biological material, such as plasma or cerebrospinal fluid (CSF), would greatly facilitate patient management. MIC-1/GDF15 (growth differentiation factor 15) is a secreted protein of the TGF-beta superfamily and emerged as a candidate marker exhibiting increasing mRNA expression during malignant progression of glioma. Determination of MIC-1/GDF15 protein levels by ELISA in the CSF of a cohort of 94 patients with intracranial tumors including gliomas, meningioma and metastasis revealed significantly increased concentrations in glioblastoma patients (median, 229 pg/ml) when compared with control cohort of patients treated for non-neoplastic diseases (median below limit of detection of 156 pg/ml, p < 0.0001, Mann-Whitney test). However, plasma MIC-1/GDF15 levels were not elevated in the matching plasma samples from these patients. Most interestingly, patients with glioblastoma and increased CSF MIC-1/GDF15 had a shorter survival (p = 0.007, log-rank test). In conclusion, MIC-1/GDF15 protein measured in the CSF may have diagnostic and prognostic value in patients with intracranial tumors.

Lb-05phase iii trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of a glioblastoma: the eortc 26101 trial

Abstract: LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Abstract: methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

Abstract: The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Abstract: BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.