Acalabrutinib Approved in Europe for Chronic Lymphocytic Leukemia


November 10, 2020 - The European Union approved the next-generation BTK inhibitor acalabrutinib for use in adult patients with chronic lymphocytic leukemia.

Paolo Ghia, MD

The European Union has approved the next-generation BTK inhibitor acalabrutinib (Calquence) for use in adult patients with chronic lymphocytic leukemia (CLL), according to an announcement from AstraZeneca.1

The regulatory decision was based on data from two phase 3 clinical trials: ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318). Results from ELEVATE-TN showed that acalabrutinib plus obinutuzumab (Gazyva) significantly improved median progression-free survival (PFS) compared with chlorambucil/obinutuzumab; the median PFS was not yet reached in the investigational arm versus 22.6 months in the control arm (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).2 In ASCEND, the median PFS with acalabrutinib was not reached versus 16.5 months with either rituximab (Rituxan) plus idelalisib (Zydelig; RI) or bendamustine (BR; HR, 0.31; 95% CI, 0.20-0.49; P <.0001).3

“One of our biggest hurdles in treating CLL is finding tolerable treatment options that manage the disease long term, which typically impacts older patients with comorbidities,” Paolo Ghia, MD, director of Strategic Research Program on CLL at the Università Vita-Salute San Raffaele, stated in a press release. “Today’s news marks great progress for patients in Europe, as the phase 3 clinical trials for [acalabrutinib] showed a significant improvement in comparison with current standard treatments.”

In the global, multicenter, open-label ELEVATE-TN trial, investigators set out to examine the safety and efficacy of acalabrutinib monotherapy or in combination with obinutuzumab compared with chlorambucil/obinutuzumab in a total of 535 treatment-naïve patients with CLL.

Participants were randomized 1:1:1 to 3 treatment arms: 100 mg of acalabrutinib twice daily plus obinutuzumab until disease progression or intolerable toxicity (n = 179), single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity (n = 179), and obinutuzumab/chlorambucil (n = 177).

Baseline characteristics were comparable across the arms. The median age of participants was 70 years, 63% had unmutated IGVH, 47% had Rai stage III or IV disease, 18% had 11q deletion, and 14% had either a 17p deletion or a TP53 mutation.

The primary end point of the trial was PFS in the 2 combination-therapy arms, as assessed by an independent review committee (IRC). Secondary objectives of the trial comprised IRC-assessed PFS in the acalabrutinib monotherapy arm versus chlorambucil/obinutuzumab, objective response rate (ORR), time to next treatment, and overall survival (OS).

Additional results showed an estimated PFS rate of 93% at 24 months with acalabrutinib/obinutuzumab, 87% with acalabrutinib monotherapy, and 47% with obinutuzumab/chlorambucil. The ORR was 94% in the acalabrutinib/obinutuzumab arm, 86% in the acalabrutinib-monotherapy arm, and 79% in the obinutuzumab/chlorambucil arm.4,5 The complete response (CR)/CR with incomplete blood count recovery rates were 14%, 1%, and 5%, respectively. The partial response (PR)/nodular PR rates were 80%, 85%, and 74%, respectively. At a median follow-up of 28.3 months, the median OS had not yet been reached in any of the arms.

Regarding safety, the most commonly reported grade 3 or higher toxicity across the arms was neutropenia (30%, acalabrutinib/obinutuzumab; 10%, single-agent acalabrutinib; and 41%, obinutuzumab/chlorambucil). All-grade infusion reactions were less frequently observed in patients who received the acalabrutinib/obinutuzumab combination versus obinutuzumab/chlorambucil, at 14% versus 40%, respectively.

Grade 3 or higher infections were reported in 21%, 14%, and 8% of patients who received acalabrutinib/obinutuzumab, single-agent acalabrutinib, and obinutuzumab/chlorambucil, respectively. Deaths were reported in 5%, 7%, and 9% of patients in the 3 treatment arms, respectively.

In the international, multicenter, open-label, phase 3 ASCEND trial, 310 previously treated patients with CLL were randomized 1:1 to receive either single-agent acalabrutinib at 100 mg twice daily until disease progression or intolerable toxicity (n = 155) or investigator’s choice of RI (n = 119) or BR (n = 36). Rituximab was given intravenously (IV) at a dose of 375 mg/m2 or 500 mg/m2 for up to 8 cycles; idelalisib was administered at a dose of 150 mg twice daily; and IV bendamustine was given at a dose of 70 mg/m2 for 6 cycles.

The median age of study participants was 67 years, 16% had del(17p), 27% had del(11q), and 42% of patients had Rai stage III/IV disease. The median number of prior therapies received was 1 in the investigational arm (range, 1-8) and 2 in the control arm (range, 1-10). Previous treatments included purine analogues (69%), alkylating drugs (85%), and CD20-directed approaches (80%). Stratification was based on del(17p) status, ECOG performance status (0-1 vs 2), and the number of previous lines of therapy received (1-2 vs 4 or more). Crossover from the control arm to the investigational arm was permitted upon confirmed progressive disease.

The primary end point of the trial was PFS per IRC assessment, while secondary objectives included PFS per physician assessment, IRC- and physician-assessed ORR and duration of response. Other secondary end points included OS, patient-reported outcomes, and time to next treatment.

Additional results showed that the estimated 12-month PFS rate in the acalabrutinib-monotherapy arm was 88% versus 68% in the arms that received investigator’s choice of treatment. Moreover, an improvement in median PFS with acalabrutinib over the control regimens was observed across all patient subsets analyzed, including del(17p), TP53 mutation, and Rai stage.4,5

The 12-month OS rates were similar between the acalabrutinib and control arms, at 94% and 91%, respectively. IRC-assessed ORR was also not found to be significantly different, at 81% versus 75% in the investigator and control arms, respectively.

With regard to safety, serious toxicities were observed in 29% of those who received single-agent acalabrutinib versus 56% of those given IR and 26% of those who received BR. Deaths were reported in 10%, 11%, and 14%, of patients who received acalabrutinib monotherapy, IR, and BR, respectively.

“This approval represents a key development for patients in Europe who until now have had limited chemotherapy-free treatment options,” Dave Frederikson, executive vice president of the Oncology Business Unit at AstraZeneca, added in the release. “As our first European approval in blood cancers, [acalabrutinib] provides a new tolerable treatment option with uncompromised efficacy and the potential to positively impact the quality of life for thousands of patients living with CLL.”

In November 2019, the FDA approved acalabrutinib for the treatment of adult patients with CLL or small lymphocytic leukemia based on data from ELEVATE-TN and ASCEND. The BTK inhibitor is also approved for CLL in several other countries worldwide, according to AstraZeneca.


1. Calquence approved in the EU for the treatment of chronic lymphocytic leukaemia. News release. AstraZeneca. November 9, 2020. Accessed November 10, 2020.

2. Sharman JP, Egyed M, Jurcazk W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

3. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

4. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. News release. FDA. November 21, 2019. Accessed November 10, 2020.

5. Calquence. Prescribing Information. AstraZeneca Pharmaceuticals LP; 2020. Accessed November 10, 2020.

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