This phase 1b/2 trial evaluated acalabrutinib, a highly selective, covalent, Bruton’s tyrosine kinase inhibitor in combination with the CD20 antibody obinutuzumab. Adult patients with treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL) receiving at least 1 prior therapy were eligible for study participation. In 28-day cycles, acalabrutinib was given orally at a dose of 100 mg twice daily, or 200 mg once daily until disease progression. Obinutuzumab was given in standard fashion for 6 cycles starting with cycle 2. The primary end points were overall response rate (ORR) and safety, and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival and minimal residual disease (MRD). Assessment of MRD in peripheral blood and in bone marrow was performed using flow cytometry.
A total of 19 treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib plus obinutuzumab. The median age of all patients was 61 years. A substantial proportion of treatment-naïve and relapsed/refractory patients had high-risk disease characteristics, including del17p (22% and 19%, respectively), del11q (28% and 35%, respectively), complex karyotype (42% and 56%, respectively), and unmutated IGHV (53% and 65%, respectively).
Common all-grade adverse events were upper respiratory tract infection (73%), weight gain (72%), maculopapular rash (66%), cough (64%), diarrhea (64%), headache (56%), and nausea (54%). The most frequently occurring grade 3 or 4 adverse events were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight, and cellulitis (9% each). There were 2 grade 3 bleeding events and 1 grade 3 atrial fibrillation event.
In terms of efficacy, after median follow-up of 39.4 and 42.1 months in the treatment-naïve and relapsed/refractory groups, respectively, the ORR was 95% and 92% for treatment-naïve and relapsed/refractory patients, respectively, with 6 (32%) treatment-naïve patients and 2 (8%) relapsed/refractory patients showing complete response. Median DOR and PFS was not reached for either treatment group. Higher MRD-negativity rates were seen in the bone marrow of treatment-naïve (26%) versus relapsed/refractory (15%) patients.
The researchers concluded that acalabrutinib plus obinutuzumab was well tolerated and yielded high response rates that were durable and deepened over time in treatment-naïve and relapsed/refractory patients with CLL.
Abstract 7500; Woyach JA, et al.