Acalabrutinib is a novel, highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor that demonstrated improved progression-free survival (PFS) in the phase 3 ASCEND trial compared with idelalisib or bendamustine/rituximab therapy in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). A previous phase 1/2 multicenter study (NCT02029443) showed promising activity and tolerability in patients with R/R CLL/small lymphocytic lymphoma (SLL). An updated analysis of the phase 1/2 trial with 42-month extended follow-up was conducted to assess the durability of response and long-term tolerability of acalabrutinib, and its results were presented at the 2019 ASH annual meeting.
Eligible patients were aged ≥18 years, had CLL or SLL, and had R/R disease after ≥1 prior treatments, with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. In the phase 2 part of the study, patients received oral acalabrutinib 100 mg twice daily until progressive disease or unacceptable toxicity. Study end points included overall response rate (ORR), PFS, duration of response (DOR), and safety, with post hoc analysis of event-free survival (EFS).
At data cutoff (January 4, 2019), a total of 134 patients with R/R CLL/SLL were treated with acalabrutinib for a median of 41 months (range, 0.2-58 months). The median age was 66 years (range, 42-85 years); the majority of patients had ECOG PS ≤1 (97%), 39% had bulky lymph nodes ≥5 cm, 73% had unmutated IGHV, 23% had chromosome 17p13.1 deletion, 18% had chromosome 11q22.3 deletion, and 35% had complex karyotype (≥3 abnormalities). The median number of prior therapies was 2 (range, 1-13).
The most common adverse events (AEs) were diarrhea (52%), headache (46%), and upper respiratory tract infection (37%). Grade ≥3 AEs occurred in 66% of patients and included neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% grade ≥3) and major bleeding events (5% all grades; 3% grade ≥3). Treatment discontinuation due to AEs was reported in 17 patients. AEs leading to discontinuation occurring in ≥1 patients included pneumonia (n = 4), anemia (n = 2), neutropenia (n = 2), and thrombocytopenia (n = 2).
In terms of efficacy, the ORR (partial response with lymphocytosis [PR-L] or above) was 94% (95% confidence interval [CI], 89-97), including complete responses in 4% of patients, PRs in 84%, and PR-Ls in 6% of patients. The median DOR, PFS, and EFS were not reached. The estimated 45-month DOR was 63% (95% CI, 52-72), 45-month PFS was 62% (95% CI, 51-71), and 45-month EFS was 58% (95% CI, 48-67). Similar responses were achieved in high-risk subgroups, including unmutated IGHV (77/81 [95%]), chromosomal deletions (del[17p], 25/27 [93%]; del[11q], 20/21 [95%]), and complex karyotype (18/20 [90%]). Following relapse during acalabrutinib treatment, whole exome sequencing detected BTK C481X mutations in 6 of 9 (67%) tested patients that were not detectable at baseline; of these, 4 had expansion to high allele frequency of the BTK mutation at progression.
Based on the updated phase 2 study results, the investigators concluded that acalabrutinib monotherapy was well tolerated and effective in the treatment of patients with CLL/SLL.
Furman RR, et al. ASH Abstract 3039. Session 642.