Pharmacokinetics, Safety, and Efficacy of Acalabrutinib in Chinese Patients with Relapsed/Refractory Mantle Cell Lymphoma and Other B-Cell Malignancies: An Open-Label, Multicenter Phase 1/2 Trial

Background: Acalabrutinib (Acala), a highly selective covalent inhibitor of Bruton tyrosine kinase with minimal off-target activity, is approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The pivotal studies that supported Acala's approval were conducted predominantly in Europe and North America, with limited representation from Asian populations. This phase 1/2 study (NCT03932331) assessed the pharmacokinetics (PK), safety, and efficacy of Acala in Chinese patients (pts) with R/R MCL and other advanced B-cell malignancies.

Methods: In phase 1, adult pts with R/R B-cell malignancies received a single dose of Acala 100 mg orally (day 1/cycle 0) followed by a 2-day washout period and subsequent treatment with Acala 100 mg orally twice daily in 28-day cycles, until progressive disease (PD) or treatment discontinuation (TD) for any other reason. Blood samples were collected to assess PK characteristics of Acala and its major metabolite, ACP-5862. In phase 2, adult pts with R/R MCL and ECOG status ≤2 received Acala 100 mg orally twice daily in 28-day cycles until PD or TD. Primary efficacy endpoint was overall response rate (ORR) per Lugano classification for non-Hodgkin lymphoma (Cheson 2014) assessed by blinded independent central review (BICR). Secondary endpoints were investigator (INV)-assessed ORR; BICR- and INV-assessed time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Results: Patients were enrolled at 14 sites in China from April 29, 2020, to March 2, 2021. In phase 1, 14 pts were screened and 12 received treatment (CLL, n=4; follicular lymphoma, n=4; MCL, n=1; diffuse large B-cell lymphoma, n=1; SLL, n=2). At data cutoff (May 6, 2022), 7 pts were receiving Acala and 5 had TD (PD, n=4; AE, n=1). Acala exhibited time-independent PK and moderate to high variability (parent drug and metabolite), rapid drug absorption, approximately 2-fold higher exposure of metabolite than parent drug, rapid elimination of Acala and ACP-5862, and no significant accumulation of either parent drug or metabolite after multiple dosing (Table 1). In phase 2 (MCL cohort), 45 pts were screened; 34 were enrolled (phase 1, n=1; phase 2, n=33), all received ≥1 dose of Acala, and were included in the safety and efficacy analyses. The MCL cohort was predominantly male (88.2%), median age was 63 y, 73.5% had ECOG status 0, 64.7% had extranodal disease, 35.3% had bone marrow involvement, 5.9% had high simplified MCL International Prognostic Index score, and median number of prior anticancer therapy regimens was 3 (range 1-5). Median duration of treatment was 14.0 mo (range 1.2-23.6). ORR by BICR was 82.4% (95% CI 65.5-93.2); CR rate was 35.3%, median TTR was 1.8 mo (range 1.6-3.7), and estimated 12-mo DOR rate was 62.7% (95% CI 41.5-78.0); median DOR was not reached. INV assessments were generally concordant with BICR assessments for ORR (73.5% [95% CI 55.6-87.1]), CR rate (38.2%), median TTR (1.9 mo; range 1.6-3.7), and estimated 12-mo DOR rate (65.5% [95% CI 42.1-81.3]). Estimated 12-mo PFS rate was 51.5% (95% CI 33.3-67.0) by BICR and 58.3% (95% CI 39.9-72.9) by INV. Estimated 12-mo OS was 84.5% (95% CI 66.6-93.3).Twenty-nine pts (85.3%) reported AEs of any grade; 15 pts (44.1%) had grade ≥3 AEs, most commonly anemia (8.8%, n=3) and decreased neutrophil count (8.8%, n=3) (Table 2). AEs led to treatment discontinuation in 3 pts (8.8%) due to aplastic anemia (n=1), thrombocytopenia (n=1), and gastrointestinal infection (n=1). Six pts (17.6%) had serious AEs. Fatal AEs were reported in 2 pts (aplastic anemia [n=1], multiple organ dysfunction syndrome [n=1]). There were no cases of atrial fibrillation, major hemorrhage, hypertension, second primary malignancies, or tumor lysis syndrome.

Conclusions: This is the first study to evaluate Acala PK, safety, and efficacy in a Chinese population with R/R B-cell malignancies. Acala was rapidly absorbed and showed no signs of accumulation after multiple doses. Treatment with Acala provided high response rates in the R/R MCL cohort, with efficacy results similar to those of the pivotal, global ACE-LY-004 study in a predominantly Caucasian population with R/R MCL (Wang M et al. Lancet 2018;391:659-67). Acala had a tolerable safety profile in Chinese pts.

Yao:AstraZeneca: Current Employment. Xia:AstraZeneca: Current Employment. Wang:AstraZeneca: Current Employment; AbbVie: Ended employment in the past 24 months. Lai:AstraZeneca: Current Employment; Hutchison MediPharma: Ended employment in the past 24 months. Liu:AstraZeneca: Current Employment.