Second-Gen BTKi Drugs Outperform Ibrutinib in CLL/SLL: Real-World Study Shows Promise for Acalabrutinib and Zanubrutinib
Acalabrutinib and zanubrutinib showed longer median TTD and TTNT compared to ibrutinib in CLL/SLL patients. Cardiovascular adverse effects were less frequent with acalabrutinib and zanubrutinib than with ibrutinib.
Microscopic image of CLL cells
Acalabrutinib (Calquence) and zanubrutinib (Brukinsa) monotherapy were both deemed to be superior to ibrutinib (Imbruvica) regarding safety and efficacy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to data from a real-world analysis presented during the 2024 EHA Congress.
At a median follow-up of 20.5 months (range, 0.4-46.0), 14.2 months (range, 0.1-46.0), and 6 months (range, 1.1-26.6) in the frontline ibrutinib (n = 1389), acalabrutinib (n = 1223), and zanubrutinib (n = 203) groups, respectively, the respective median times to treatment discontinuation or death (TTD) were 13.7 months (95% CI, 12.2-16.0), 19.2 months (95% CI, 15.1-25.3), and 19.3 months (95% CI, 14.1-not reached [NR]). The median times to next treatment or death (TTNT) were 30.2 months (95% CI, 26.2-35.5) in the ibrutinib arm, 35.8 months (95% CI, 29.8-NR) in the acalabrutinib arm, and NR (95% CI, 16.7-NR) in the zanubrutinib arm. In the overall population (n = 2815), the median TTD and TTNT were 16.2 months (95% CI, 14.4-19.1) and 32.3 months (95% CI, 29.1-36.0), respectively.
“This study demonstrated better real-world safety and [efficacy] outcomes for acalabrutinib and zanubrutinib vs ibrutinib [in patients with CLL/SLL],” Jing-Zhou Hou, MD, PhD,a clinical hematological oncologist at the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania, and coauthors wrote in a poster presentation of the findings. “The proportions of patients continuing treatment and the median TTNT was longer for patients who received zanubrutinib. Additional research is needed to explain and validate observed differences favoring zanubrutinib over acalabrutinib.”
To conduct their study, investigators collected data across 55 practices and over 1600 providers in the community oncology setting in the US from the IntegraConnect-PrecisionQ deidentified database. The analysis included adult patients with CLL/SLL who initiated treatment with a BTK inhibitor from January 1, 2020, to July 31, 2023, with follow-up through October 31, 2023. Eligible patients had at least 5 CLL/SLL visits or more CLL/SLL visits than non-CLL/SLL visits, and all patients had at least 2 evaluation and management visits.
The study outcomes were cardiovascular adverse effects (AEs), TTNT, and TTD. The study objective was, “To investigate the clinical characteristics, treatment patterns, and AEs among BTK inhibitor-treated patients with CLL/SLL in the real-world setting.”
The baseline patient characteristics were well balanced between the ibrutinib, acalabrutinib, and zanubrutinib groups; the median age was 71 years (range, 35-90), 72 years (range, 36-90), and 72 years (range, 33-90), respectively. Most patients in each group were male (63.6 vs 63.0% vs 60.6%), White (60.6% vs 63.4% vs 62.6%), and had an ECOG performances status of 1 or less (62.0% vs 61.3% vs 66.0%). Cardiac comorbidities were reported in 16.6%, 15.7%, and 10.3% of patients, respectively.
Additional findings from the analysis demonstrated that patients in the ibrutinib (n = 1134), acalabrutinib (n = 903), and zanubrutinib (n = 176) arms with at least 3 months of follow-up experienced cardiovascular AEs in the first-line setting at rates of 8.7%, 5.9%, and 7.4%, respectively. Among patients in the ibrutinib (n = 972), acalabrutinib (n = 753), and zanubrutinib (n = 96) groups with at least 6 months of follow-up, significantly more patients who received ibrutinib experienced cardiovascular AEs; rates were 12.1%, 7.6%, and 7.3%, respectively. Patients who received ibrutinib (n = 790), acalabrutinib (n = 573), and zanubrutinib (n = 47) with at least 9 months of follow-up experienced a cardiovascular AE at rates of 14.6%, 9.4%, and 8.5%, respectively.
Investigators noted that “the median TTD in [the] first-line was shorter for ibrutinib than acalabrutinib or zanubrutinib. The associated probability of continuing treatment and not having new treatment were higher with zanubrutinib vs ibrutinib or acalabrutinib at month 6.”
In the ibrutinib arm, the 6-, 12-,18-, 24-, 30-, 36-, and 42-month probabilities of continuing the same treatment were 64.8% (95% CI, 62.2%-67.3%), 53.3% (95% CI, 50.5%-56.0%), 46.2% (95% CI, 43.3%-49.0%), 40.9%, (95% CI, 37.9%-43.8%), 36.5% (95% CI, 33.5%-39.6%), 32.0% (95% CI, 28.6%-35.4%), and 29.8% (95% CI, 26.0%, 33.6%), respectively. Among patients who received acalabrutinib, these respective rates were 64.8% (95% CI, 62.0%-67.4%), 57.7% (95% CI, 54.7%-60.6%), 51.2% (95% CI, 48.0%-54.4%), 46.9%, (95% CI, 43.3%-50.4%), 43.9% (95% CI, 39.9%-47.8%), 37.0% (95% CI, 30.6%-43.3%), and 37.0% (95% CI, 30.6%-43.3%). The 6-, 12-, 18-, and 24-month rates in the zanubrutinib arm were 81.6% (95% CI, 75.1%-86.6%), 64.1% (95% CI, 51.0%-74.6%), 51.0% (95% CI, 30.5%-68.4%), and 42.5% (95% CI, 20.6%-62.9%), respectively. A proportion of patients in the ibrutinib (55.8%), acalabrutinib (45.5%), and zanubrutinib (22.2%) arms discontinued treatment or died.
Among patients who received frontline ibrutinib, 12.7% discontinued therapy and switched to a second-generation BTK inhibitor. The 6-, 12-,18-, 24-, 30-, 36-, and 42-month probabilities of not receiving another treatment in the ibrutinib arm were 75.4% (95% CI, 73.0%-77.6%), 67.3% (95% CI, 64.6%-69.7%), 60.5% (95% CI, 57.7%-63.2%), 54.9% (95% CI, 51.9%-57.7%), 50.0% (95% CI, 46.9%-53.1%), 45.8% (95% CI, 42.3%-49.2%), and 39.9% (95% CI, 35.7%-44.0%), respectively. These respective rates were 71.3% (95% CI, 68.7%-73.8%), 66.3% (95% CI, 63.4%-69.0%), 60.3% (95% CI, 57.1%-63.3%), 56.1% (95% CI, 52.6%-59.4%), 53.9% (95% CI, 49.9%-57.6%), 49.2% (95% CI, 43.5%-54.7%), and 49.2% (95% CI, 43.5%-54.7%). The 6-, 12-, 18-, and 24-month probabilities were 85.3% (95% CI, 79.2%-89.8%), 75.0% (95% CI, 64.3%-82.9%), 63.3% (95% CI, 46.1%-76.3%), and 57.0% (95% CI, 37.2%-72.6%), respectively, in the zanubrutinib group.
