Relationship between venetoclax exposure, rituximab coadministration, and progression‐free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy

Abstract

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

“…23 An exposure progression-free survival (PFS) analysis demonstrated that higher exposures are likely to increase PFS. 24 With regard to safety, subjects receiving venetoclax doses up to 1200 mg once daily, where the exposures were approximately 2.5-fold higher than those achieved at the approved dose of 400 mg once daily, did not experience dose-limiting toxicities. 6,25,26 Consistently, exposure-safety analyses indicated that higher venetoclax exposures had no effect on QT interval and were not associated with an increase in grade 3 or higher adverse events of neutropenia and infection.…”

“…In an exposure–efficacy analysis conducted using data from subjects with CLL (predominantly whites), the rate of objective response was shown to be similar, with a 0.5‐ to 2.0‐fold change in venetoclax exposure from that typically achieved at the 400‐mg once‐daily dosage regimen . An exposure progression‐free survival (PFS) analysis demonstrated that higher exposures are likely to increase PFS . With regard to safety, subjects receiving venetoclax doses up to 1200 mg once daily, where the exposures were approximately 2.5‐fold higher than those achieved at the approved dose of 400 mg once daily, did not experience dose‐limiting toxicities .…”

“…Blood samples for the venetoclax assay were collected prior to dosing (0 hour) and 2,4,6,8,10,12,14,16,24,36,48, and 72 hours after dosing. Plasma concentrations of venetoclax were determined using a validated liquid/liquid extraction followed by high-performance liquid chromatography-tandem mass spectrometric detection method.…”

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

“…Recently, venetoclax was approved by the US FDA for treatment of newly diagnosed AML in adults who are aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy in combination with HMAs or LDAC under accelerated approval pathway. Previous studies have evaluated the venetoclax exposure response relationships in subjects with CLL, non‐Hodgkin's lymphoma, or multiple myeloma . The findings of the analyses reported herein provide the rationale and justification for the dose of venetoclax used in the pivotal, global, randomized, double‐blind, placebo‐controlled phase III study in combination with azacitidine versus azacitidine alone (NCT02993523) and in combination with LDAC vs LDAC alone (NCT03069352), conducted in treatment‐naïve elderly patients with AML who are ineligible for standard induction therapy.…”

Quantitative Prediction of the Effect of CYP3A Inhibitors and Inducers on Venetoclax Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model

“…In any case, higher average venetoclax concentrations (through 1200 mg once daily) were not associated with an increase in adverse events (grade ࣙ3) of neutropenia or infection rates or increases in the QT interval. 28,29 Additionally, venetoclax exposures below those achieved with 400 mg venetoclax may reduce progression-free survival in subjects with R/R CLL, 30 so dose reductions greater than the increases in exposures due to drug-drug interactions could result in decreased efficacy.…”