Abstract
Introduction: Venetoclax, a potent BCL-2 inhibitor, is approved for CLL and AML and is currently under development for treatment of multiple myeloma and other hematological malignancies. The objective of this analysis was to assess the exposure-response relationships of venetoclax from a phase 1/2 study (NCT01794520) evaluating venetoclax monotherapy and in combination with dexamethasone in relapsed or refractory (R/R) multiple myeloma (MM) subjects to inform dose selection for the CANOVA Phase 3 study (NCT03539744). Methods: A total of 117 subjects receiving venetoclax at 300, 600, 800, 900, or 1200 mg either as monotherapy or in combination with dexamethasone were included in the analysis. VenDex was only administered in t(11;14)-positive subjects. Individual subject venetoclax exposures (average area under the concentration time curve [AUCavg] up to the event of interest or discontinuation of venetoclax were determined based on the population pharmacokinetic analysis using the post-hoc empirical Bayes parameter estimates. The impact of venetoclax exposures on efficacy (objective response [OR] progression-free survival [PFS], time to progression [TTP], and overall survival [OS]) as well as safety (treatment-emergent adverse effects [grade ≥ 3] of neutropenia, serious infection, and any grade of serious treatment-emergent adverse effects) was explored. Safety analysis was conducted for total population and for the t(11;14)-negative and t(11;14)-positive subpopulations. Results: Venetoclax exposure relationships to PFS and TTP indicated a trend of longer progression free survival with higher exposures. Moreover, cumulative logistic regression analyses for clinical response rates (stable disease or better [≥SD], partial response or better [≥PR], and very good partial response or better [≥VGPR]) demonstrated a statistically significant (p<0.05) relationship with venetoclax exposure in the t(11;14)-positive subpopulation. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures and serious infection (grade ≥ 3) or serious treatment-emergent adverse events (any grade) in the total population as well as the t(11;14)-positive and t(11;14)-negative subpopulations at the exposure range evaluated. Venetoclax exposures were comparable between the two subpopulations. With respect to grade ≥3 neutropenia, lack of a significant exposure-response relationship was only observed in the t(11;14)-positive subpopulation. Higher rates of grade ≥3 neutropenia trended with higher venetoclax exposures in the t(11;14)-negative subpopulation. Conclusion: In t(11;14)-positive R/R MM subjects, higher venetoclax exposures resulted in improved efficacy without an increase in safety events compared to lower exposures. These findings support dosing venetoclax at 800 mg QD dose in combination with dexamethasone in this patient population in the CANOVA Phase 3 Study.
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