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

Br J Clin Pharmacol. 2019 Jul;85(7):1495-1506. doi: 10.1111/bcp.13920. Epub 2019 May 17.

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 (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.

Keywords: monoclonal antibodies; oncology; pharmacokinetic-pharmacodynamic; pharmacokinetics; population analysis.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Bendamustine Hydrochloride / administration & dosage
  • Body Weight
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Lymphoma, Follicular / drug therapy*
  • Lymphoma, Follicular / pathology
  • Male
  • Models, Biological*
  • Prednisone / administration & dosage
  • Progression-Free Survival
  • Sex Factors
  • Treatment Outcome
  • Vincristine / administration & dosage

Substances

  • Antibodies, Monoclonal, Humanized
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Bendamustine Hydrochloride
  • obinutuzumab
  • Prednisone

Supplementary concepts

  • CHOP protocol
  • COP protocol 2