FDA Grants Acalabrutinib Breakthrough Designation for CLL

The FDA has granted a breakthrough therapy designation to acalabrutinib (Calquence) for the treatment of patients with chronic lymphocytic leukemia.

José Baselga, MD, PhD

The FDA has granted a breakthrough therapy designation to acalabrutinib (Calquence) for the treatment of patients with chronic lymphocytic leukemia (CLL).1

The designation is based on findings from the interim analyses of the phase III ELEVATE-TN and ASCEND (ACE-CL-309) studies, which showed that acalabrutinib either as a single agent or in combination significantly reduced the risk of disease progression or death compared with standard regimens. Regarding safety, the tolerability of the BTK inhibitor in both trials was found to be consistent with prior studies, stated AstraZeneca, the developer of acalabrutinib, in a press release.

“This is an important regulatory milestone for our work in hematology and for patients living with chronic lymphocytic leukemia, a life-threatening disease,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, stated in the press release. “The Breakthrough Therapy Designation acknowledges the growing body of evidence that supports Calquence as a highly-selective Bruton tyrosine kinase inhibitor with the potential to offer patients a new, differentiated, chemotherapy-free treatment option with a favorable safety profile.”

In the randomized, multicenter, open-label, phase III ELEVANTE-TN (ACE-CL-007) trial, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab (Gazyva) versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL. Patients were randomized (1:1:1) into 3 arms: chlorambucil plus obinutuzumab, 100 mg of acalabrutinib twice daily in combination with obinutuzumab until disease progression or unacceptable toxicity, and acalabrutinib, or single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients had to have an ECOG performance status of 0, 1, or 2; a diagnosis of CD20-positive CLL; active disease that met at least 1 of the following International Workshop on Chronic Lymphocytic Leukemia 2008 criteria for requiring treatment, and must have met specific laboratory parameters related to platelet count, total bilirubin, and creatinine clearance.

The primary endpoint is progression-free survival (PFS) in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm, as assessed by an independent review committee (IRC). Secondary endpoints included IRC-assessed PFS in the acalabrutinib-alone arm versus chlorambucil/obinutuzumab, as well as objective response rate (ORR), time to next treatment, and overall survival (OS).

Previously, AstraZeneca announced that single-agent acalabrutinib showed a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab/chlorambucil.2 Due to these positive data, the company stated that it will end the trial early. Full findings of ELEVATE-TN will be presented at an upcoming medical meeting.

In the international, multicenter, open-label, phase III ASCEND trial, 310 previously treated patients with CLL were randomized 1:1 to receive single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity (n = 155), or rituximab (Rituxan) at 375 mg/m2 or 500 mg/m2 intravenously (IV) for up to 8 cycles in combination with idelalisib (Zydelig; n = 119) at 150 mg twice daily or IV bendamustine at 70 mg/m2 (n = 36) for 6 cycles.

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 CD20-directed therapies (80%). Patients were stratified according to del(17p) status, ECOG performance 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 disease progression.

The primary endpoint is PFS assessed by an IRC, and key secondary endpoints include physician-assessed PFS, IRC- and physician-assessed ORR and duration of response, as well as OS, patient-reported outcomes and time to next treatment.

Results showed that, at a median follow-up of 16.1 months, the median PFS with acalabrutinib was not reached compared with 16.5 months in the control arms (HR, 0.31; 95% CI, 0.20-0.49; P <.0001), translating to a 69% reduction in the risk of progression or death.3 At 12 months, 88% of patients on acalabrutinib showed no disease progression compared with 68% in the control arm.

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

Regarding safety, 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).

Grade ≥3 AEs with acalabrutinib, rituximab/idelalisib, and bendamustine rituximab (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).

Acalabrutinib is currently approved by the FDA for the treatment of patients with relapsed/refractory mantle cell lymphoma.


  1. Calquence Granted US Breakthrough Therapy Designation for Chronic Lymphocytic Leukemia. AstraZeneca. Published August 14, 2019. https://bit.ly/2MfbCja. Accessed August 14, 2019.
  2. Calquence Phase III ELEVATE-TN trial Met Primary Endpoint at Interim Analysis in Previously-Untreated Chronic Lymphocytic Leukemia. AstraZeneca. Published June 6, 2019. https://bit.ly/2Xy8t06. Accessed June 6, 2019.
  3. 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.