Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first line immunochemotherapy.
Br J Clin Pharmacol. 2019 Mar 13;:
Authors: Jamois C, Gibiansky E, Gibiansky L, Buchheit V, Sahin D, Cartron G, Marcus R, Hiddemann W, Seymour JF, Strefford JC, Hargreaves CE, Meneses-Lorente G, Frey N, Fingerle-Rowson G
AIMS: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated follicular lymphoma (1L FL). We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in 1L FL 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, 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 T232T 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 non-responder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with more than one dose level of G could help resolve this uncertainty.
PMID: 30866056 [PubMed – as supplied by publisher]