PGx7642: Meta-analysis of data from FCGR PGx evaluations of ofatumumab CLL studies OMB110911, OMB114242, OMB115991 and OMB110913

Trial description: At the time this study was initiated, GlaxoSmithKline (GSK) was developing ofatumumab (GSK1841157), an anti-CD20 monoclonal antibody (mAb), for the treatment of multiple oncology indications, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and diffuse large B-cell lymphoma (DLBCL), as well as non-oncology indications including multiple sclerosis and pemphigus vulgaris. Ofatumumab was approved by the Food and Drug Administration (FDA) in 2009 for the treatment of CLL subjects refractory to both alemtuzumab and fludarabine. In 2014, the FDA approved ofatumumab in combination with chlorambucil for the treatment of previously untreated patients with CLL, for whom fludarabine-based therapy is considered inappropriate. Ofatumumab recognizes an epitope of the CD20 molecule distinct from the epitope recognized by other CD20 mAbs, including the rituximab binding site, and induces cell lysis primarily through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). ADCC is regulated by activating and inhibiting Fc-gamma receptors (FCGRs). A significant body of research has been conducted and published regarding the association of functional variants in the activating FCGRs, FCGR3A and FCGR2A, with the efficacy of mAbs including rituximab. The association differs by indication and treatment regimen (Mellor et al 2013), and the role of FCGR genetic variation on efficacy of ofatumumab is not known. The evaluation summarized in this document is intended to contribute towards understanding the role of FCGR genetic variation in ofatumumab efficacy. The objective of this study is to evaluate the association between FCGR3A rs396991 (V158F) or FCGR2A rs1801274 (H131R) and efficacy endpoints as measured by overall response rate (ORR) and progression-free survival (PFS) in ofatumumab-treated subjects with CLL in studies OMB110911, OMB110913, OMB114242 and OMB115991.Within each study (OMB110911, OMB110913, OMB114242, OMB115991), an additive genetic model will be applied based on the number of alleles (i.e. either FCGR3A 158V or FCGR2A 131H) to generate per-allele odds and hazard ratios, with 95% confidence intervals for subjects treated with ofatumumab. A logistic regression model will be used to assess the association of genotype with ORR while a Cox proportional hazards model will be used to assess the association of genotype with PFS.Fixed effects meta-analysis will be used to assess the association between FCGR3A V158F and FCGR2A H131R and efficacy endpoints across clinical studies. One-tailed tests will be used to evaluate the hypotheses that FCGR3A 158V or FCGR2A 131H are associated with increased efficacy. Significance thresholds are set at p<0.05 for the primary objective of assessing the effect of FCGR3A V158F on PFS in ofatumumab-treated CLL subjects and at p<0.0167 for all other objectives.