Acalabrutinib in Combination with Venetoclax and Obinutuzumab or Rituximab in Patients with Treatment-Naïve or Relapsed/Refractory Chronic Lymphocytic Leukemia

Background: Acalabrutinib (A) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for marketing by the US FDA in patients (pts) with chronic lymphocytic leukemia (CLL). While responses to A monotherapy are durable in CLL, response depth may be enhanced with combination therapy and potentially allow treatment discontinuation. The safety and efficacy of A plus a CD20 antibody (obinutuzumab [O] or rituximab [R]) and the BCL-2 inhibitor venetoclax (V) were examined in a phase 1b study (CL-003; NCT02296918) in relapsed/refractory (R/R) or treatment-naïve (TN) CLL pts.

Methods: Pts were aged ≥18 years with intermediate or high-risk CLL (R/R or TN) and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prior BTK inhibitor treatment was allowed for R/R pts if discontinuation was not due to CLL progression. R/R CLL pts received oral (PO) A 100 mg twice daily (BID) until progression, plus intravenous (IV) R 375 mg/m² for 9 infusions (cycles 2–7), plus V PO daily per standard dosing (cycles 3–15). TN CLL pts received PO A and V (as above) plus IV O per standard dosing (cycles 2–7). The primary endpoint was safety. Secondary endpoints included investigator-assessed overall response rate (ORR, partial response [PR] or better) at cycle 16, complete response (CR) rate, undetectable minimal residual disease (uMRD) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics (PK).

Results: Twelve pts were included in each cohort (R/R: male, n=9 [75%], median [range] age: 66 [55–72] y; TN: male, n=9 [75%], median [range] age: 61 [42–73] y). All pts had ECOG PS ≤1; 6/8 (75%) R/R and 8/10 (80%) TN pts had unmutated IGHV (<2% variance from germline sequence). The median number of prior therapies in R/R pts was 1 (range, 1–3).

At a median follow-up of 23.2 mo (range: 19.8–25.3) in R/R pts and 22.0 mo (range: 19.5–24.4) in TN pts, 11 (92%) and 10 (83%) pts remained on treatment, respectively. Reasons for treatment discontinuation were adverse events (AEs) in 1 pt (8%) in each cohort (R/R: grade 1 purpura; TN: grade 2 head discomfort), and withdrawal by 1 pt (8%) in the TN cohort. The median number of treatment cycles in R/R pts was 23 (range: 14.9–27.5) for A, 6 (6–6) for R, and 13 (10.0–13.7) for V, and in TN pts was 23 (18.0–24.8) for A, 6 (6–6) for O, and 13 (13.0–13.5) for V.

Reported AEs were similar to the individual agents’ toxicity profiles (Table 1). Among AEs of interest, 7 R/R pts (58%) and 4 TN pts (33%) had cardiac AEs; grade ≥3 cardiac AEs were reported in 1 pt (8%). Atrial fibrillation was reported in 1 pt (grade 3; R/R pt with prior atrial fibrillation history). No ventricular arrhythmias were reported. Three R/R pts (25%) and 7 TN pts (58%) had hypertension AEs; none were grade ≥3. The most frequent infections (≥40%) were upper respiratory tract infection (URTI; 50%) in R/R pts and URTI (67%), sinusitis (42%), and nasopharyngitis (42%) in TN pts. Grade ≥3 infections occurred in 3 TN pts (lung infection, n=2 [17%]; prostate infection, staphylococcal bacteremia, staphylococcal sepsis, n=1 [8%] each) and no R/R pts. Six R/R pts (50%) and 3 TN pts (25%) had infusion-related reactions; none were grade ≥3. One R/R pt (8%) and 6 TN pts (50%) had decreased neutrophil counts; all were grade ≥3. No tumor lysis syndrome AEs, Richter transformations, or deaths were reported.

After 16 cycles, ORR was 92% (95% CI: 62–100) in R/R pts and 100% (95% CI: 74–100) in TN pts. At the time of data cutoff, 50% of pts in each cohort had achieved CR or CR with incomplete marrow recovery (CRi). All pts with CR or CRi achieved uMRD (10^-4) in peripheral blood (PB) at the time of CR/CRi or earlier. Overall, 8 (67%) R/R and 9 (75%) TN pts achieved uMRD (10^-4) in PB at cycle 10 (Table 2). Median DOR, PFS, and OS were not reached in either group. Estimated 18-mo PFS and OS rates were 100% (95% CI: not estimable) in both cohorts. The PK of A and its active metabolite, ACP-5862, were consistent when given as monotherapy or with V, R, or O. The PK of V remained within the range observed with monotherapy (Salem et al. J Clin Pharmacol. 2017;57:484-492) when given with A.

Conclusions: Combination therapy with A plus an anti-CD20 antibody and BCL-2 inhibitor leads to a tolerable safety profile with high CR and uMRD rates in both R/R and TN CLL pts, with minimal to no drug-drug interactions.