Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy
Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy
Aims: 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 (C meanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods: Individual exposures (C meanIND ) 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. Results: 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 C meanIND (hazard ratio = 1.74 and 0.394 at 5 th and 95 th percentile compared to median C meanIND ) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions: 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.
monoclonal antibodies, oncology, pharmacokinetic-pharmacodynamic, pharmacokinetics, population analysis
1495-1506
Jamois, Candice
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Gibiansky, Ekaterina
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Gibiansky, Leonid
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Buchheit, Vincent
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Sahin, Denis
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Cartron, Guillaume
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Marcus, Robert
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Hiddemann, Wolfgang
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Seymour, John F.
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Strefford, Jonathan C.
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Hargreaves, Chantal E.
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Meneses-Lorente, Georgina
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Frey, Nicolas
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Fingerle-Rowson, Günter
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1 July 2019
Jamois, Candice
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Gibiansky, Ekaterina
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Gibiansky, Leonid
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Buchheit, Vincent
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Sahin, Denis
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Cartron, Guillaume
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Marcus, Robert
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Hiddemann, Wolfgang
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Seymour, John F.
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Strefford, Jonathan C.
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Hargreaves, Chantal E.
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Meneses-Lorente, Georgina
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Frey, Nicolas
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Fingerle-Rowson, Günter
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Jamois, Candice, Gibiansky, Ekaterina, Gibiansky, Leonid, Buchheit, Vincent, Sahin, Denis, Cartron, Guillaume, Marcus, Robert, Hiddemann, Wolfgang, Seymour, John F., Strefford, Jonathan C., Hargreaves, Chantal E., Meneses-Lorente, Georgina, Frey, Nicolas and Fingerle-Rowson, Günter
(2019)
Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy.
British Journal of Clinical Pharmacology, 85 (7), .
(doi:10.1111/bcp.13920).
Abstract
Aims: 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 (C meanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods: Individual exposures (C meanIND ) 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. Results: 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 C meanIND (hazard ratio = 1.74 and 0.394 at 5 th and 95 th percentile compared to median C meanIND ) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions: 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.
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bcp.13920
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Accepted/In Press date: 10 March 2019
e-pub ahead of print date: 13 March 2019
Published date: 1 July 2019
Keywords:
monoclonal antibodies, oncology, pharmacokinetic-pharmacodynamic, pharmacokinetics, population analysis
Identifiers
Local EPrints ID: 432056
URI: http://eprints.soton.ac.uk/id/eprint/432056
ISSN: 0306-5251
PURE UUID: 287f14ab-4603-4ebf-9d74-721559592e71
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Date deposited: 28 Jun 2019 16:30
Last modified: 16 Mar 2024 03:40
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Contributors
Author:
Candice Jamois
Author:
Ekaterina Gibiansky
Author:
Leonid Gibiansky
Author:
Vincent Buchheit
Author:
Denis Sahin
Author:
Guillaume Cartron
Author:
Robert Marcus
Author:
Wolfgang Hiddemann
Author:
John F. Seymour
Author:
Chantal E. Hargreaves
Author:
Georgina Meneses-Lorente
Author:
Nicolas Frey
Author:
Günter Fingerle-Rowson
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