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Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy.

Authors
  • Jamois, Candice1
  • Gibiansky, Ekaterina2
  • Gibiansky, Leonid2
  • Buchheit, Vincent1
  • Sahin, Denis3
  • Cartron, Guillaume4
  • Marcus, Robert5
  • Hiddemann, Wolfgang6
  • Seymour, John F7
  • Strefford, Jonathan C8
  • Hargreaves, Chantal E8
  • Meneses-Lorente, Georgina3
  • Frey, Nicolas1
  • Fingerle-Rowson, Günter9
  • 1 Department of Clinical Pharmacology, F. Hoffmann-La Roche, Roche Innovation Center Basel, Switzerland. , (Switzerland)
  • 2 QuantPharm LLC, North Potomac, MD, USA.
  • 3 Roche Innovation Center, Welwyn, UK.
  • 4 Department of Hematology, CHU Montpellier, Montpellier, France. , (France)
  • 5 Kings College Hospital, London, UK.
  • 6 Department of Medicine III, University Hospital, LMU Munich, Germany. , (Germany)
  • 7 Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia. , (Australia)
  • 8 Cancer Genomics, Cancer Sciences, Faculty of Medicine, Group University of Southampton, Southampton, UK.
  • 9 Pharma Development Oncology, F. Hoffmann-La Roche, Basel, Switzerland. , (Switzerland)
Type
Published Article
Journal
British Journal of Clinical Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jul 01, 2019
Volume
85
Issue
7
Pages
1495–1506
Identifiers
DOI: 10.1111/bcp.13920
PMID: 30866056
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Individual exposures (CmeanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan-Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing CmeanIND (hazard ratio = 1.74 and 0.394 at 5th and 95th percentile compared to median CmeanIND ) and was inferior in patients with high baseline tumour size and B symptoms. It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty. © 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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