FDA Approves Acalabrutinib for CLL

In Clinical Studies News by Barbara Jacoby

By: Jason M. Broderick

From: onclive.com

The FDA has approved acalabrutinib (Calquence) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1,2

The approval, which was done under the FDA’s Project Orbis initiative, was based on 2 phase III randomized trials—ELEVATE-TN and ASCEND.

“Today, as part of a US, Australian, and Canadian collaboration known as Project Orbis, the United States approved a new treatment option for those living with chronic lymphocytic leukemia or small lymphocytic lymphoma. The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international partners,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“We are pleased to continue working alongside our Australian and Canadian colleagues to facilitate new treatment options for patients and the FDA looks forward to working with other countries in future application reviews,” added Pazdur.

In the randomized, multicenter, open-label, phase III ELEVATE-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 (n = 177); 100 mg of acalabrutinib twice daily in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); or single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity (n = 179).

Baseline characteristics were similar across the 3 treatment arms. The median patient age for the trial was 70 years (range, 41-91), 63% of patients had an unmutated IGVH, 47% had Rai stage III or IV disease, 18% had 11q deletion, and 14% had 17p deletion or TP53 mutation.

The primary endpoint was 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).

The median PFS was 22.6 months (95% CI, 20-28) in the control arm, but was not yet reached in the acalabrutinib/obinutuzumab arm (HR, 0.10; 95% CI, 0.06-0.17; P <.0001) or the acalabrutinib monotherapy arm (HR, 0.20; 95% CI, 0.13-0.30 P <.0001).

The ORR was 79% in the obinutuzumab/chlorambucil arm, compared with 94% in the acalabrutinib combination arm and 86% in the monotherapy arm. The complete response (CR)/CR with incomplete blood count recovery rates were 5%, 14%, and 1%, and the partial response (PR)/nodular PR rates were 74%, 80%, and 85%, respectively.

The median OS was not yet reached in any of the 3 arms at a median follow-up of 28.3 months (range, 0-40.8).

Adverse event (AE)-related discontinuations occurred in 11% and 10% of patients in the acalabrutinib combination and monotherapy arms, respectively. Common grade ≥3 AEs occurring across the 3 treatment arms included neutropenia (37% in the acalabrutinib combination arm; 13% in the monotherapy arm, and 50% in the control arm), infection (22%, 14%, and 13%, respectively), anemia (12%, 10%, 14%), thrombocytopenia (12%, 3.4%, and 16%), uric acid increase (29%, 22%, 37%), and ALT increase (7%, 1.1%, 6%).

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 (range, 1-10) in the control group. 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 was PFS assessed by an IRC, and key secondary endpoints included 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. 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, commonly reported AEs occurring in ≥15% of patients treated with acalabrutinib were neutropenia (48%), anemia (47%), thrombocytopenia (33%), lymphocytosis (26%), diarrhea (18%), and ALT increase (15%).

Common grade ≥3 AEs with acalabrutinib, rituximab/idelalisib, and bendamustine/rituximab included neutropenia (23% vs 53% vs 40%, respectively), anemia (15%, 8%, 17%), lymphocytosis (19%, 18%, 2.9%), uric acid increase (15%, 11%, 23%).

Commenting on the approval, ​​​​Jeff Sharman, MD, a lead author on the ELEVATE-TN trial and director of Research at Willamette Valley Cancer Institute and Medical Director of Hematology Research for The US Oncology Network said, “Tolerability remains an issue in the current treatment landscape of chronic lymphocytic leukemia, which may require ongoing therapy for many years. In the ELEVATE-TN and ASCEND trials comparing Calquence to commonly used treatment regimens, Calquence demonstrated a clinically meaningful improvement in progression-free survival in patients across multiple settings, while maintaining its favorable tolerability and safety profile.”

The approval of acalabrutinib in CLL follows an FDA breakthrough therapy designation granted to the second-generation BTK inhibitor in August 2019.

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


  1. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. Published November 21, 2020. https://bit.ly/33bw74m. Accessed November 21, 2020.
  2. Calquence prescribing information. Revised November 21, 2020. https://bit.ly/35kyfID. Accessed November 21, 2020.