Venetoclax in biomarker‐selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety

Author:

Badawi Mohamed1ORCID,Coppola Sheryl1ORCID,Eckert Doerthe2,Gopalakrishnan Sathej2ORCID,Engelhardt Benjamin2,Doelger Eva2,Huang Weize3,Dobkowska Edyta4,Kumar Shaji5,Menon Rajeev M.1ORCID,Salem Ahmed Hamed6ORCID

Affiliation:

1. Clinical Pharmacology AbbVie, Inc North Chicago Illinois USA

2. Clinical Pharmacology AbbVie Deutschland GmbH & Co. KG Ludwigshafen Am Rhein Germany

3. Clinical Pharmacology Genentech Inc South San Francisco California USA

4. Clinical Development Pharmacyclics Switzerland GmbH An AbbVie Company Schaffhausen Switzerland

5. Division of Hematology Mayo Clinic Rochester Minnesota USA

6. Clinical Pharmacy Ain Shams University Cairo Egypt

Abstract

AbstractVenetoclax, a potent BCL‐2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure–response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression‐free survival [PFS] and overall survival [OS]) as well as safety (treatment‐emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment‐emergent adverse effects) was evaluated. In the t(11;14)‐positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure‐safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment‐emergent adverse events or any grade serious treatment‐emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)‐positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Funder

AbbVie

Genentech

Publisher

Wiley

Subject

Cancer Research,Oncology,Hematology,General Medicine

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