Abstract 3023: Exposure versus efficacy/safety of acalabrutinib and its pharmacologically active metabolite, ACP-5862, for the treatment of chronic lymphocytic leukemia

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