ASH 2020: New safety and efficacy data of acalabrutinib in CLL and MCL

Dr. Jennifer Brown
Dana-Farber Cancer Institute
Boston, Massachusetts, US
Dr. Jennifer Woyach
Ohio State University
Comprehensive Cancer Center
Columbus, Ohio, US
Dr. Michael Wang
MD Anderson Cancer Center
University of Texas
Houston, Texas, US
28 Jan 2021
ASH 2020: New safety and efficacy data of acalabrutinib in CLL and MCL

Acalabrutinib, a next-generation, highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor, is approved for treatment of chronic lymphocytic leukaemia (CLL) and mantel cell lymphoma (MCL) in Hong Kong. At the 62nd American Society of Hematology Annual Meeting and Exposition (ASH 2020), researchers presented data from a pooled analysis of four trials showing a low risk of cardiac adverse events (AEs) in CLL patients treated with acalabrutinib, while another study demonstrated tolerability and efficacy of acalabrutinib-based triple combination regimens in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. In patients with R/R MCL, extended follow-up data presented at ASH 2020 confirmed the safety and sustained efficacy of acalabrutinib that supports its long-term use.

Pooled analysis: Low risk of cardiac AEs in CLL

“The first-generation BTK inhibitor ibrutinib is associated with cardiovascular [CV] toxicities, potentially due to off-target kinase inhibition,” said Dr Jennifer Brown of Dana-Farber Cancer Institute, Boston, Massachusetts, US. [Mol Cancer 2018;17:57; Blood 2019;134:1919-1928] “Acalabrutinib, on the other hand, has demonstrated greater selectivity for BTK than ibrutinib in in vitro studies, and may therefore be associated with an improved safety profile.” [J Pharmacol Exp Ther 2017;363:240-252; N Engl J Med 2016;374:323-332; N Engl J Med 2013;369:32-42; N Engl J Med 2014;371:213-223]

An analysis of data from 762 patients with TN or R/R CLL (median age, 67 years; median number of prior regimens, 1) treated with ≥1 dose of acalabrutinib monotherapy in four phase I/II–III trials showed that cardiac AEs were infrequent during a median follow-up of 25.9 months. [Brown JR, et al, ASH 2020, abstract 3146]

“Cardiac AEs of any grade and grade ≥3 occurred in 17 percent and 5 percent of patients, respectively,” said Brown. “Most patients [91 percent] with cardiac AEs had pre-existing CV risk factors, including hypertension [67 percent], hyperlipidaemia [29 percent] and arrhythmias [22 percent].”

The most common cardiac AEs were atrial fibrillation (AF; any grade, 4 percent; grade ≥3, 1 percent), palpitations (any grade, 3 percent; grade ≥3, 0 percent), and tachycardia (any grade, 2 percent; grade ≥3, 0 percent). Among patients who experienced AF/atrial flutter, 18 percent had a prior history of arrhythmia/AF/atrial flutter.

“The 4 percent incidence of AF with acalabrutinib, reported after a median follow-up of 25.9 months, was comparable to the AF incidence [6.1 percent] reported previously in a general CLL population with no prior history of AF after a median follow-up of 7.3 years,” pointed out Brown. [Leuk Lymphoma 2017;58:1630-1639]

“The rate of cardiac AE onset was generally constant over time. The median time to onset of cardiac AEs was 10.1 months, while that of AF/atrial flutter and hypertension was 17.1 months and 6.5 months, respectively,” she added. (Figure 1) “Twenty-five percent of grade ≥3 cardiac AEs were reported during the first 6 months of acalabrutinib treatment.”

HK-AST-435mo Calquence Fig 1

After a median follow-up of 25.9 months, 72 percent of patients remained on acalabrutinib treatment. Among 27 percent of patients who discontinued acalabrutinib, the most common reasons for discontinuation were disease progression (11 percent) and AEs (9 percent).

Among patients who experienced cardiac AEs, only 0.9 percent discontinued acalabrutinib treatment. “In patients who experienced grade ≥3 cardiac AEs, 49 percent remained on acalabrutinib treatment at data cut-off, while 16 percent discontinued acalabrutinib due to grade ≥3 cardiac AEs,” noted Brown. “Grade ≥3 cardiac AEs were managed with concomitant medications in 71 percent of the cases and resolved in 84 percent of the cases.” 

“Overall, these findings suggest a low risk of cardiac AEs with acalabrutinib in CLL patients,” she concluded. “The safety of acalabrutinib vs ibrutinib in CLL patients with del(17p) or del(11q) is being investigated in the phase III, randomized ACE-CL-006 trial.” 

Acalabrutinib triple combination therapy: High CR & uMRD rates in CLL

Acalabrutinib in combination with the anti-CD20 monoclonal antibody obinutuzumab demonstrated durable responses in patients with TN or R/R CLL in the phase Ib ACE-CL-003 trial, and improved progression-free survival (PFS) vs obinutuzumab plus chlorambucil in patients with TN CLL in the phase III ELEVATE-TN trial. [Cancer Discov 2020;10:394-405; Lancet 2020;395:1278-1291]

New data from the ACE-CL-003 trial showed high rates of complete response (CR) and undetectable minimal residual disease (uMRD) with acalabrutinib in combination with venetoclax and rituximab (AVR) in R/R CLL patients (n=12; median age, 66.5 years; median number of prior therapies, 1), as well as with acalabrutinib in combination with venetoclax and obinutuzumab (AVO) in TN CLL patients (n=12; median age, 60.5 years), after median follow-up of 27.7 months and 26 months, respectively. [Woyach JA, et al, ASH 2020, abstract 1312]

“The trial’s primary endpoint was safety. At data cut-off, 92 percent of patients in the R/R cohort and 83 percent of patients in the TN cohort remained on AVR or AVO treatment, respectively. AEs were as expected based on each individual agent’s safety profile, and were mostly grade 1/2,” reported Dr Jennifer Woyach of the Ohio State University Comprehensive Cancer Center, Columbus, Ohio, US. “Few patients [8 percent in each cohort] discontinued treatment due to AEs.”

The most common AEs of interest were infections, including upper respiratory tract infections (50 percent in R/R patients, 67 percent in TN patients), nasopharyngitis (42 percent in TN patients) and sinusitis (42 percent in TN patients). Grade ≥3 cardiac AEs occurred in 8 percent of patients.

In terms of efficacy, objective response rate (ORR) was 92 percent in R/R patients and 100 percent in TN patients after 16 cycles of AVR or AVO treatment, respectively. At data cut-off, 50 percent of patients in each cohort achieved CR (33 percent of R/R patients, 50 percent of TN patients) or CR with incomplete marrow recovery (CRi; 17 percent of R/R patients). 

“All patients with CR or CRi achieved uMRD [10-4] in peripheral blood [PB] at the time of CR/CRi or earlier. The overall uMRD rate was 71 percent. At cycle 10, MRD negativity [≤0.01 percent] in PB was achieved in 67 percent of R/R patients and 75 percent of TN patients,” said Woyach.

Median duration of response (DoR), PFS and overall survival (OS) were not yet reached in either cohort. Estimated 18-month PFS and OS rates were 100 percent in both cohorts.

“The pharmacokinetics [PK] of acalabrutinib, its active metabolite and venetoclax in the triple combination setting were consistent with the PK profiles observed with monotherapy,” Woyach noted.

“These results suggest that triple combination therapy with acalabrutinib plus an anti-CD20 antibody and a BCL-2 inhibitor is feasible based on tolerability, yielding high CR and uMRD rates in both R/R and TN CLL,” she concluded.

Long-term safety and efficacy of acalabrutinib in R/R MCL

The single-arm phase II ACE-LY-004 study previously demonstrated efficacy and safety of acalabrutinib in patients with R/R MCL (n=124; median age, 68 years; median number of prior therapies, 2) after a median follow-up of 26 months. [Leukemia 2019;33:2762-2766] New data after an additional year of follow-up demonstrated sustained efficacy and a largely unchanged AE profile, supporting long-term use of acalabrutinib in R/R MCL treatment. [Wang M, et al, ASH 2020, abstract 2040]

After a median follow-up of 38.1 months, 19 percent of patients remained on acalabrutinib treatment and 44 percent remained in follow-up for survival assessment.

“The ORR remained 81 percent, while CR rate increased from 43 percent at 26 months to 48 percent at 38 months,” reported Dr Michael Wang of MD Anderson Cancer Center, University of Texas, Houston, Texas, US. 

The median DoR was 28.6 months, while estimated 36-months DoR rate was 41.9 percent. Median DoR in patients with Ki-67 index <50 percent and ≥50 percent was 36.7 months and 15.3 months, respectively. In patients who had received one, two and ≥3 prior regimens, median DoR was 25.6 months, 33.8 months and 25.9 months, respectively.

“Median PFS was 22 months. More than one-third of patients were progression-free at 36 months,” said Wang. (Figure 2) “Median OS was not yet reached, and estimated 36-months OS rate was 60.5 percent.”

HK-AST-435mo Calquence Fig 2

Subgroup analysis showed longer median PFS in patients with Ki-67 index <50 percent than those with Ki-67 index ≥50 percent (35.8 months vs 6.4 months). Median PFS was also longer in patients who did not receive prior proteasome inhibitor (PI) therapy (24.8 months vs 13.8 months in those previously treated with PIs). ORR was generally similar across subgroups, except for patients with Ki-67 index <50 percent vs ≥50 percent (89.1 percent vs 62.5 percent) and those without vs with prior PI therapy (85 percent vs 66.7 percent).

“Six of 30 patients [20 percent] with available samples achieved CR and uMRD, and maintained uMRD at the last assessment,” said Wang.

“The AE profile of acalabrutinib was largely unchanged with an additional year of follow-up,” he highlighted. “AEs led to dose delays and modifications in 40 percent and 2 percent of patients, respectively.”

During the additional year of follow-up, the most common grade 3/4 AEs of interest were infections, bleeding events and cardiac AEs (2 percent each). Rates of these grade 3/4 AEs at any time during the study were 17 percent, 4 percent and 5 percent, respectively.

“With efficacy and tolerability largely maintained during the additional year of follow-up, these data support the long-term use of acalabrutinib in patients with R/R MCL,” Wang concluded.

 

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