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6 Head-To-Head Comparison Of Obinutuzumab (GA101) Plus Chlorambucil (Clb) Versus Rituximab Plus Clb In Patients With Chronic Lymphocytic Leukemia (CLL) and Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: Plenary Session
Sunday, December 8, 2013: 4:15 PM
Hall F (Ernest N. Morial Convention Center)

Valentin Goede, MD1*, Kirsten Fischer, MD1*, Raymonde Busch, PhD2*, Anja Engelke3*, Barbara Eichhorst, MD3, Clemens M Wendtner, MD1,4, Tatiana Chagorova, MD5*, Javier De la Serna, MD, PhD6, Marie-Sarah Dilhuydy, MD7*, Stephen Opat, MD8, Carolyn J. Owen, MD, FRCPC9, Olga Samoylova, MD10*, Karl-Anton Kreuzer, MD3*, Anton W Langerak, PhD11*, Matthias Ritgen, MD12*, Stephan Stilgenbauer, MD13, Hartmut Döhner, MD13, Elina Asikanius14*, Kathryn Humphrey15*, Michael K Wenger, MD16 and Michael Hallek, MD3

1German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany
2Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany
3Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany
4Klinikum Schwabing, Munich, Germany
5Penza Regional Oncology Dispensary, Penza, Russia
6Servicio De Hematologia, Hospital Univ 12 De Octubre, Madrid, Spain
7Hopital Haut Leveque, Bordeaux, Pessac, France
8Department of Haematology, Monash Medical Centre, Clayton, Australia
9University of Calgary, Calgary, AB, Canada
10Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod, Russia
11Department of Immunology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands
12Medical Department II, University of Schleswig Holstein, City Hospital Kiel, Kiel, Germany
13Department of Internal Medicine III, University, Hospital of Ulm, Ulm, Germany
14F. Hoffmann-La Roche Ltd, Basel, Switzerland
15F. Hoffmann-La Roche Ltd, Welwyn, England
16Genentech, Inc., South San Francisco, CA

Introduction:

CLL11 is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities, i.e. patients typically treated in daily practice. Here, we present:

(i) The final stage 2 analysis with efficacy and safety results of the head-to-head comparison between GA101 plus Clb (GClb) and rituximab plus Clb (RClb); at the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board.

(ii) An update on the stage I analysis (GClb vs. Clb and RClb vs. Clb comparisons) with longer observation time; the final stage 1 analysis recently showed that GClb or RClb has superior efficacy to chemotherapy with Clb alone.

Methods:

Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score >6 and/or an estimated creatinine clearance (CrCl) <70 mL/min were eligible. Patients received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progression-free survival (PFS). Response rates, minimal residual disease (MRD), and overall survival (OS) were key secondary efficacy endpoints.

Results:

Final results of the stage 2 analysis: Median observation time was 19 months. The GClb and RClb treatment arms were well balanced for baseline characteristics. Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 63 mL/min respectively. Key efficacy and safety results are shown in the table.

The PFS benefit of GClb over RClb was supported by all pre-planned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with MRD negative blood samples at end-of-treatment was more than 10-fold higher with GClb compared with RClb (63/214 [29.4%] vs. 6/243 [2.5%]). Grade 3-4 infusion-related reactions with GClb occurred at first infusion only.

Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p<.0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p<.0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached.

Conclusions:

GA101, a novel, glycoengineered, type II CD20 antibody, in combination with Clb (GClb regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with RClb in previously untreated CLL patients with comorbidities. Infusion-related reactions and neutropenia were more common with GClb without an increase in infections. Furthermore, GClb vs. Clb alone demonstrated a prolongation of OS. Overall, GClb is superior to RClb and a highly active treatment in this typical CLL patient population.

Disclosures: Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Fischer: Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Engelke: F. Hoffmann-La Roche: Travel grants Other. Eichhorst: Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Wendtner: F. Hoffmann-La Roche: Consultancy, Research Funding. Dilhuydy: F. Hoffmann-La Roche: Consultancy. Opat: F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Owen: F. Hoffmann-La Roche: Honoraria. Kreuzer: F. Hoffmann-La Roche: Consultancy, Honoraria. Langerak: F. Hoffmann-La Roche: Research Funding. Ritgen: F. Hoffmann-La Roche: Research Funding. Stilgenbauer: F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Asikanius: F. Hoffmann-La Roche: Employment. Humphrey: F. Hoffmann-La Roche: Employment. Wenger: F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Hallek: F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

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