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

• Published in: British journal of clinical pharmacology Vol. 85; no. 7; pp. 1495 - 1506
• Main Authors: 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, Fingerle‐Rowson, Günter
• Format: Journal Article
• Language: English
• Published: England Wiley 01.07.2019; John Wiley and Sons Inc
• Subjects: Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Bendamustine Hydrochloride - administration & dosage; Body Weight; Cancer; Cyclophosphamide - administration & dosage; Doxorubicin - administration & dosage; Drug Resistance, Neoplasm; Female; Humans; Life Sciences; Lymphoma, Follicular - drug therapy; Lymphoma, Follicular - pathology; Male; Models, Biological; monoclonal antibodies; oncology; Original; Pharmaceutical sciences; pharmacokinetics; pharmacokinetic‐pharmacodynamic; population analysis; Prednisone - administration & dosage; Progression-Free Survival; Sex Factors; Treatment Outcome; Vincristine - administration & dosage; pharmacokinetics; pharmacokinetic-pharmacodynamic; population analysis; oncology; monoclonal antibodies; Pharmacokinetic-pharmacodynamic; Monoclonal antibodies; Population analysis; Oncology; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13920

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 (CmeanIND) in front‐line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods 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. 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 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. 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.