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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
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
0306-5251
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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Jamois, Candice
f4e808bc-fbc5-4778-9933-20498e1e653b
Gibiansky, Ekaterina
2bba64b9-239f-4d3d-96d3-3ad45914e586
Gibiansky, Leonid
b8b89d73-9df4-4625-bc89-e76aa93d96fe
Buchheit, Vincent
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Sahin, Denis
a66da7bf-c761-4830-a7c2-a58142213e74
Cartron, Guillaume
72759c0d-d4f5-4ab5-a117-335bb3216e4d
Marcus, Robert
a16601ff-650d-473e-a0ff-81558e16cef5
Hiddemann, Wolfgang
0710f0bd-14f1-4840-9abd-2349f69e8677
Seymour, John F.
1f4d9aba-841a-40ec-a758-80d6f81dc376
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Hargreaves, Chantal E.
19adb5c3-4559-4ebc-8c28-4c28767d225e
Meneses-Lorente, Georgina
276a043c-7e77-47c2-9145-d8b123fa3448
Frey, Nicolas
870bf0c1-5c1f-439d-94e4-12dc1b01bd3b
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), 1495-1506. (doi:10.1111/bcp.13920).

Record type: Article

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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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
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 28 Jun 2019 16:30
Last modified: 07 Oct 2020 01:50

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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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