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FDA Grants Breakthrough Designation to Acalabrutinib Monotherapy for CLL

Lisa Astor
Published Online:4:55 PM, Wed August 14, 2019
The FDA has granted a breakthrough therapy designation to acalabrutinib (Calquence) monotherapy for the treatment of adult patients with chronic lymphocytic leukemia (CLL).The breakthrough designation was given based on the results of interim analyses from 2 phase III trials: ELEVATE-TN and ASCEND. 

“This is an important regulatory milestone for our work in hematology and for patients living with CLL, a life-threatening disease. The Breakthrough Therapy Designation acknowledges the growing body of evidence that supports Calquence as a highly-selective Bruton tyrosine kinase [BTK] inhibitor with the potential to offer patients a new, differentiated, chemotherapy-free treatment option with a favorable safety profile,” José Baselga, MD, PhD, executive vice president, Oncology Research & Development, AstraZeneca—the company developing acalabrutinib, said in a statement. 

A breakthrough therapy designation expedites the development and regulatory review of the BTK inhibitor by the FDA. 

The company expects to move on regulatory submissions for acalabrutinib as a treatment for patients with CLL later this year based on the results from both the ELEVATE-TN and ASCEND trials. 

ELEVATE-TN is a multicenter, open-label phase III trial (ACE-CL-007) investigating the combination of acalabrutinib and obinutuzumab (Gazyva) in comparison with obinutuzumab/chlorambucil or acalabrutinib monotherapy in patients with newly diagnosed CLL (NCT02475681).

The multicenter, open-label trial randomized 535 treatment-naïve patients with CLL in a 1:1:1. In both acalabrutinib arms, the BTK inhibitor was administered at 100 mg twice daily until disease progression.

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). A key secondary endpoint is IRC-assessed PFS with single-agent acalabrutinib compared with chlorambucil plus obinutuzumab. Objective response rate (ORR), time to next treatment, and overall survival (OS) are additional secondary endpoints of the study.

Recently the trial met its primary endpoint in an interim analysis, demonstrating a statistically significant and clinically meaningful improvement in PFS with the use of acalabrutinib and obinutuzumab compared with obinutuzumab and chlorambucil, according to a press release from AstraZeneca.2

Acalabrutinib monotherapy also demonstrated a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab combined with chlorambucil in topline results of the trial.  

The international, multicenter, open-label, phase III ASCEND trial investigated the use of single-agent acalabrutinib compared with rituximab (Rituxan) and either idelalisib (Zydelig) or bendamustine in patients with relapsed or refractory CLL (NCT02970318). A total of 310 patients were enrolled and randomized 1:1 to receive 100 mg of acalabrutinib twice daily or one of the combination regimens.

To be eligible for enrollment, patients must have been ≥18 years of age, have an ECOG performance status of 0 to 2, received ≥1 prior systemic therapy, had CD20-positive disease, and had active disease meeting at least 1 of the criteria of the International Workshop on CLL 2008 for required treatment. Prior exposure to a BTK inhibitor; major surgery within 30 days of the first dose of the study drug; significant cardiovascular disease; and a history of drug-induced pneumonitis requiring anticoagulation or a strong CYP3A inhibitor were some of the exclusion criteria.

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

ASCEND also achieved its primary endpoint of improvement in PFS in an interim analysis, AstraZeneca announced in May.Acalabrutinib monotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS compared with the rituximab-based combinations. 

According to a presentation at the 2019 EHA Annual Congress, by IRC assessment of PFS, the acalabrutinib arm did not reach a median PFS compared with 16.5 months in the rituximab-based combination arm (HR, 0.31; 95% CI, 0.20-0.49; <.0001).The PFS benefit was consistent across patient subgroups favoring acalabrutinib monotherapy. 

The ORR by IRC assessment in the acalabrutinib arm was 81% (95% CI, 74%-87%) compared with 76% (95% CI, 68%-82%) with rituximab/idelalisib or rituximab/bendamustine (= .22). The median DOR was not reached in the acalabrutinib arm versus 13.6 months (95% CI, 11.9-not reached) in the rituximab-based therapy arm (HR, 0.33; 95% CI, 0.19-0.59; <.0001). 

At a median follow-up of 16.1 months, the OS had not yet been reached in either treatment arm (HR, 0.84; 95% CI, 0.42-1.66; = .6). Of note, 51% of the patients receiving rituximab-based combinations who had disease progression then crossed over to receive acalabrutinib. 

Treatment discontinuation due to adverse events (AEs) was observed in 11% of patients in the acalabrutinib arm; 49% of patients receiving rituximab and idelalisib and 17% receiving rituximab and bendamustine also discontinued due to AEs. Richter transformation occurred in 4 patients in the acalabrutinib arm and in 5 patients in the rituximab-based therapy arm. 

At least 1 AE of any grade was observed in 94% of patients in the acalabrutinib arm and in 99% and 80% of patients receiving the idelalisib and bendamustine combinations, respectively. Serious AEs were observed in 29%, 56%, and 26% of patients receiving acalabrutinib, rituximab/idelalisib, and rituximab/bendamustine, respectively. Grade 5 AEs were reported in 6 patients in the acalabrutinib arm and in 7 patients in the rituximab-based therapy arm. 

Acalabrutinib is currently approved by the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma. 
  1. Calquence granted US Breakthrough Therapy Designation for chronic lymphocytic leukaemia [press release]. Kenilworth, NJ: AstraZeneca; 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 leukaemia [press release]. Kenilworth, NJ: AstraZeneca; June 6, 2019. https://bit.ly/32DlDeY. Accessed August 14, 2019. 
  3. Calquence Phase III ASCEND trial met primary endpoint at interim analysis in relapsed or refractory chronic lymphocytic leukaemia and will stop early [press release]. Kenilworth, NJ: AstraZeneca; May 7, 2019. https://bit.ly/2H1bNJY. Accessed August 14, 2019. 
  4. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib or bendamustine by investigator choice in relapsed/refractory chronic lymphocytic leukemia: results from a pre-planned interim analysis of the phase 3 ASCEND study. Presented at: 2019 EHA Annual Congress; Amsterdam, Netherlands; June 13-16, 2019. Abstract LBA2606. 

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