Population Pharmacokinetic and Exposure-Response Analyses of Ibrutinib Combined With Bendamustine and Rituximab in Patients With Mantle Cell Lymphoma.

Abstract

Efficacy and safety of ibrutinib 560 mg once daily or placebo combined with bendamustine and rituximab (BR) were assessed in patients with mantle cell lymphoma in a randomized phase 3 study (SHINE). The analysis described explores the ibrutinib population pharmacokinetics (PK) and exposure-response (E-R) relationships of selected efficacy and safety endpoints. Ibrutinib PK was consistent with previous assessments, characterized by an open two-compartment disposition model with sequential zero-first order oral absorption after a lag time. Ibrutinib treatment was efficacious in extending PFS versus placebo (HR: 0.75; 95% CI: 0.59 to 0.96), although similar OS, CRR, and ORR were observed. PFS benefit was similar across the quartiles of ibrutinib exposure, suggesting that systemic exposures obtained provide maximal clinical response. There was no association between ibrutinib exposure and incidence of major hemorrhage, Grade ≥ 3 liver function test abnormalities, Grade ≥ 3 neutropenia, Grade ≥ 2 diarrhea, treatment-emergent adverse events (TEAEs) leading to death, and TEAEs leading to ibrutinib dose reduction. However, the incidence of all Grade ≥ 3 TEAEs, all serious TEAEs, TEAEs leading to ibrutinib discontinuation, Grade ≥ 1 atrial fibrillation, any hemorrhage, and Grade ≥ 3 infection was higher in the ibrutinib than placebo arm. Of these, only atrial fibrillation and any hemorrhage increased with increasing exposure. Overall, ibrutinib 560 mg, combined with BR, consistently improves PFS across the ibrutinib exposure range evaluated. According to the results of the exposure-response analysis, for patients who develop specific toxicities, dose reduction according to the prescribing information may improve the ibrutinib tolerability while keeping adequate exposure to maintain efficacy.