Abstract 3023: Exposure versus efficacy/safety of acalabrutinib and its pharmacologically active metabolite, ACP-5862, for the treatment of chronic lymphocytic leukemia
Authors: Edlund Helena , Vishwanathan Karthick , Yin Ming , Raman Rakesh , de Kock Miné , He Zhongqing , Liu Huan , Baek Marshall , Al-Huniti Nidal , Ware Joseph , Sharma Shringi 
Published: September 2020

Abstract
Background: Acalabrutinib is a selective BTK inhibitor approved for the treatment of Mantle Cell Lymphoma. Relationship between plasma exposures to acalabrutinib and ACP-5862 versus clinical efficacy and safety were evaluated in subjects with B-cell malignancies, following administration of acalabrutinib monotherapy or in combination with obinutuzumab.
Methods: Acalabrutinib and ACP-5862 exposures (AUC24h,ss) were generated using population pharmacokinetic (PK) analysis. To account for the contribution of ACP-5862 to overall activity, an exposure metric (total active AUC24h,ss) accounting for relative BTK potency and protein binding was estimated. Efficacy data from the pivotal Phase 3 study in previously untreated (PU) CLL subjects (n=274), who received acalabrutinib 100 mg twice daily (BID) as monotherapy or in combination, were included. Safety data pooled across 8 studies in PU or relapsed/refractory (R/R) subjects with B-cell malignancies (n=567), who received acalabrutinib 100, 175, 200, and 250 once daily or 100 mg and 200 mg BID as monotherapy or in combination, were included. Efficacy endpoints including best overall response rate (BOR), progression -free survival (PFS) and sum of products of the greatest perpendicular diameters (SPD) of index lesions were evaluated. Safety endpoints including all AEs Grade ≥2 in severity, and Grade ≥2 events of clinical interest such as, anemia, cardiac events, diarrhea, headache, hemorrhage, hepatic events, hypertension, infections, neutropenia, and thrombocytopenia were evaluated. Kaplan-Meier survival and logistic regression analyses were conducted for key efficacy and safety endpoints.
Results: Median acalabrutinib/ACP-5862/total active AUC24h,ss were similar between responders versus non-responders, and across the 4 response categories (i.e. complete response, partial response, stable disease or progressive disease). No correlation between AUC24h,ss and PFS or SPD were noted. With the exception of Grade ≥2 anemia, no significant relationship between AUC24h,ss and safety outcomes was observed. Model-based analyses revealed baseline hemoglobin levels and line of therapy as highly significant predictors of Grade ≥2 anemia (p&lt;0.0001) but not PK exposure (AUC24h,ss; p=0.08), indicating the lack of an exposure-dependent relationship. The results were consistent across acalabrutinib monotherapy or combination with obinutuzumab treatment arms.
Conclusions: No clinically meaningful correlation between PK exposures and selected efficacy and safety outcomes was observed. In pivotal studies, the 100 mg BID acalabrutinib regimen demonstrated an acceptable safety profile and robust efficacy (consistent with ≥95% BTK occupancy over a dosing interval) in PU and R/R CLL. Overall, these data support a fixed 100 mg BID acalabrutinib dose for the treatment of subjects with CLL.
Citation Format: Helena Edlund, Karthick Vishwanathan, Ming Yin, Rakesh Raman, Miné de Kock, Zhongqing He, Huan Liu, Marshall Baek, Nidal Al-Huniti, Joseph Ware, Shringi Sharma. Exposure versus efficacy/safety of acalabrutinib and its pharmacologically active metabolite, ACP-5862, for the treatment of chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3023.