Single-Agent Acalabrutinib Showcases Potential Practice-Changing Data in Relapsed/Refractory CLL

Paolo Ghia, MD, PhD

Chemotherapy-free treatment with single-agent acalabrutinib (Calquence) provided a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with physicians’ choice of standard therapy in patients with previously treated chronic lymphocytic leukemia (CLL), according to data from the phase III ASCEND trial that were presented at the 2019 European Hematology Association Congress.

At a median follow-up of 16.1 months, the study’s primary endpoint of PFS was met, as the median PFS with the BTK inhibitor was not reached compared with 16.5 months in the physician’s choice control arm (HR, 0.31; 95% CI, 0.20-0.49; P <.0001), leading to a 69% reduction in the risk of progression or death. Moreover, at 12 months, 88% of patients on acalabrutinib showed no disease progression compared with 68% in the control arm.

“The ASCEND study demonstrated that acalabrutinib is more effective and tolerable compared with standard combination therapies,” said lead study author Paolo Ghia, MD, professor of medical oncology, Università Vita-Salute San Raffaele in Milan, Italy. “These data may change the current practice of how we treat patients with relapsed or refractory disease.”

In the international, multicenter, open-label, randomized phase III ASCEND study (NCT02970318), the efficacy and safety of single-agent acalabrutinib was compared with control treatment, which comprised rituximab (Rituxan) plus physician’s choice of either idelalisib (Zydelig) or bendamustine (BR) in patients with relapsed/refractory CLL. Patients were randomized 1:1 to receive oral acalabrutinib at 100 mg twice daily until progression (n = 155) or standard rituximab at 375 mg/m² or 500 mg/m² intravenously (IV) for up to 8 cycles plus investigator’s choice of treatment of 150 mg of idelalisib twice daily (n = 119) or plus 6 cycles of bendamustine at 70 mg/m2 IV (n = 36).

The median age was 67 years (range, 32-90), 16% of patients had del(17p) and 27% had del(11q); 42% of patients had Rai stage III/IV CLL. The median number of prior therapies in the acalabrutinib arm was 1 (range, 1-8) and 2 in the control group (range, 1-10). Prior therapies included purine analogues (69%), alkylating agents (85%), and anti-CD20 therapies (80%). Patients were stratified according to del(17p) status, ECOG status (0-1 vs 2), and the number of prior lines of therapy received (1-3 vs ≥4). Crossover from the investigators’ choice arm was permitted upon confirmed progression.

The primary endpoint was PFS per independent review committee (IRC) and secondary endpoints included OS, IRC-assessed overall response rate (ORR), and safety.

“This is the first randomized study to evaluate acalabrutinib in patients with relapsed/refractory CLL,” said Ghia. “It is also the first randomized study directly comparing acalabrutinib with chemoimmunotherapy or the combination of idelalisib and rituximab, so the comparison involves different pathways.”

Results showed that PFS was improved with acalabrutinib compared with control across all patient subgroups, including del(17p), TP53 mutation, and Rai stage.

“We must think about new science to find predictors,” Ghia said. “The future of this agent like all agents used in CLL is to avoid clonal selection, perhaps by using combinations to provide a clear deep response.”

Regarding secondary endpoints, 12-month OS rates were 94% and 91%, respectively. IRC-assessed ORR also was not significantly different at 81% with acalabrutinib versus 75% with control (P <.22).

Crossover from the control arm to acalabrutinib was recorded for 23% of patients. In the acalabrutinib arm, 15 deaths occurred compared with 18 in the rituximab-regimen arms. Moreover, while the OS and ORR were similar, there was a more favorable safety profile for acalabrutinib than with rituximab plus either idelalisib or bendamustine.

The most commonly reported all-grade AEs occurring in ≥15% of patients treated with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), and anemia or cough (15% each).

“Headache was most often reported adverse event, which was self-resolving,” said Ghia.

In the rituximab/idelalisib arm, headache, neutropenia, diarrhea, anemia, and cough were reported in 6%, 45%, 47%, and 15% of patients, respectively. With BR, neutropenia, diarrhea, anemia, and cough were reported for 34%, 14%, 11%, and 6% of patients, respectively, while 23% each on the BR arm reported infusion-related reaction and fatigue.

Grade ≥3 AEs with acalabrutinib, rituximab/idelalisib, and BR included neutropenia (16% vs 40% vs 31%, respectively), anemia (12% with acalabrutinib vs 9% with BR), and pneumonia (5% with acalabrutinib) diarrhea (24% with idelalisib/rituximab) and constipation (6% with BR).

AEs of interest included atrial fibrillation, which occurred in 5.2% versus 3.3%, bleeding in 26% versus 7.2%—including major hemorrhage in 1.9% versus 2.6%&mdash;of patients on acalabrutinib versus BR, respectively. Grade ≥3 infections were reported in 15% versus 24% of patients in the respective groups. Second primary malignancies, excluding nonmelanoma skin cancer, were observed in 6.5% of acalabrutinib- and 2.6% of BR-treated patients. Discontinuation due to AEs occurred in 11% of acalabrutinib-treated patients.

Acalabrutinib is currently approved by the FDA for treatment of patients with mantle cell lymphoma following ≥1 prior therapy.

Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (idr) or bendamustine (br) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2606.