Acalabrutinib Demonstrates Superior PFS Over Standard-0f-Care in Relapsed/Refractory CLL

Paolo Ghia, MD, PhD

Acalabrutinib (Calquence) sustained superiority in terms of extended progression-free survival with a tolerable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia, which was inclusive of patients with high-risk features, results from the phase 3 ASCEND trial (NCT02970318) show.

Combination therapies such as PI3K inhibitors IdR or BR are standard treatments for patients with relapsed/refractory CLL, but they are associated with toxicities that may be treatment-limiting,” Paolo Ghia, MD, PhD, a professor of Medical Oncology and the director of the Strategic Research Program on CLL and the B Cell Neoplasia Unit at Università Vita-Salute San Raffaele University. “Acalabrutinib, on the contrary, is a next-generation, highly selective, covalent BTK inhibitor with less off-target kinase inhibition than ibrutinib (Imbruvica), [which] potentially results in an improved safety profile.”

Results presented during the 2020 SOHO Annual Meetingshowed that after a median of 22 months, treatment with acalabrutinib resulted in a prolongation of PFS compared with the investigator’s choice therapy, confirming earlier data from a preplanned interim analysis. The median PFS with acalabrutinib per investigator assessment had not been reached versus 16.8 months with either idelalisib (Zydelig) plus rituximab (Rituxan; IdR) or bendamustine plus rituximab (BR). Moreover, the estimated 18-month PFS rate was 82% with acalabrutinib versus 48% with IdR/BR.

Moreover, when acalabrutinib was compared with IdR, the median PFS per investigator assessment was not reached versus 16.2 months, respectively (hazard ratio [HR], 0.27; P = .0001). When compared with BR, the median PFS was not reached with acalabrutinib versus 18.6 months with BR (HR, 0.29; P = .0001).

Patients with high-risk features, such as del(17p) and TP53 mutations as well as unmutated IGHV, also experienced prolonged PFS benefit with acalabrutinib. In those with del(17p) and TP53 mutations, the HR for investigator-assessed PFS benefit with acalabrutinib versus IdR/BR was 0.11; the HR was 0.29 in those without those mutations present. In patients with unmutated IGHV, the hazard ratio for investigator-assessed PFS with acalabrutinib versus the standard-of-care regimens was 0.26; the HR was 0.30 in those with mutated IGHV.

“Interestingly, acalabrutinib had a prolonged PFS in patients with high-risk features, [including those with] del(17p) mutations, TP53 mutations, and unmutated IGHV,” Ghia explained. “Similarly, acalabrutinib prolonged PFS in other prespecified patient subgroups besides those with high-risk genetic features, [such as] those over 55 years of age or those with stage III or IV bulky disease or complex karyotype.”

In the randomized phase 3 trial, investigators set out to assess the safety and efficacy of single-agent acalabrutinib compared with investigator’s choice of IdR/BR in patients with relapsed/refractory CLL. The trial enrolled a total of 310 patients who had been diagnosed with relapsed/refractory disease. Participants were stratified based on the presence of a del(17p) mutation, their ECOG performance status (0-1 vs 2), and the number of prior lines of therapy (1-3 vs 4 or more).

Participants were randomized 1:1 to receive 100 mg of oral acalabrutinib twice daily (n = 155) or 150 mg of oral idelalisib twice daily plus rituximab (n = 119) or 70 mg/m2 of intravenous bendamustine plus rituximab (n = 36). The primary end point of the trial was PFS, and key secondary end points included overall response rate, overall survival (OS), and safety.

The median age of the study population was 67 years, and the majority, or 67.1%) were men (n = 208). Just under half, or 48.7%, of patients had bulky disease (n = 151). Additionally, 41.6% of the total study population had Rai stage III or IV disease (n = 129). The median number of prior therapies received was 2 (range, 1-10); 48.1% (n = 149) received 1 prior line, 27.7% (n = 86) received 2, 13.2% (n = 41) received 3, and 11.0% (n = 34) received 4 or more. Previous treatments included purine analogues (68.7%), alkylators other than bendamustine (85.2%), bendamustine (30.6%), anti-CD20 monoclonal antibodies (80.3%), stem cell transplant (0.6%), and other (4.8%).

Moreover, 78.4% of patients (n = 243) had unmutated IGHV at baseline, 15.8% (n = 49) had a del(17p) mutation, 26.8% (n = 83) had del(11q) mutation, and 31.0% (n = 96) had a complex karyotype.

Additional data from the trial showed that the median OS had not been reached in either arm of the trial (HR, 0.78; 95% CI, 0.44-1.40; P = .4094). The estimated 18-month OS rate was 88% with acalabrutinib (95% CI, 81%-92%) and 88% with IdR/BR (95% CI, 81%-92%).

Investigator-assessed duration of response (DOR) was found to be longer with acalabrutinib compared with IdR/BR. The median DOR was not reached (HR, 0.19; 95% CI, 0.11-0.33]) with acalabrutinib versus 18.0 months with IdR/BR. The 18-month DOR was estimated to be 85.4% with acalabrutinib (95% CI, 77%-91%) and 49.4% (95% CI, 40%-58%) with IdR/BR.

The median duration of exposure differed between the treatment arms; patients who received acalabrutinib were exposed for a median duration of 21.9 months (95% CI, 1.1-27.9) versus 11.5 months with IdR (95% CI, 0.1-27.2) and 5.6 months with BR (95% CI, 1.0-7.1). The relative dose intensity was 99.3% (95% CI, 48.3-100) in the acalabrutinib cohort, 90% (95% CI, 46.6-100) in the IdR cohort, and 96.4% (95% CI, 14.5-102.5) in the BR cohort.

With regard to safety, 27% of patients in the acalabrutinib arm (n = 42) discontinued treatment. Results for discontinuation included adverse effects (AEs; n = 24), disease progression (n = 16), death (n = 1), and other (n = 1). Seventy-seven percent of patients who received IdR (n = 92) discontinued treatment; 66 due to AEs, 17 due to disease progression, 5 per investigator discretion, 1 due to withdrawal of consent, and 3 due to other reasons. No deaths were reported on the IdR arm. Additionally, 19% of patients discontinued treatment with BR (n = 7); 6 due to AEs and 1 due to progressive disease; no deaths were reported in this cohort. Richter transformation was reported in 3% of patients in the acalabrutinib arm (n = 4) and 3% of patients in the IdR/BR arm (n = 5; n = 4, IdR; n = 1, BR).

“The median treatment exposure acalabrutinib with was approximately double that of IdR and 4 times that of BR. Of course, BR was administered for 6 months only; [that’s why] the median treatment exposure was much shorter,” explained Ghia. “However, in the case of IdR, the shorter treatment exposure was actually because of AEs. In fact, AEs were the most common reason for treatment discontinuation in all groups.”

IdR treatment was found to be associated with higher incidences of grade 3 or higher AEs, serious AEs, treatment-related AEs (TRAEs), drug discontinuations, and dose modifications compared with acalabrutinib and BR. Grade 3 or higher AEs were reported in 55% of patients on acalabrutinib (n = 85), 90% of patients on IdR (n = 106), and 49% of patients on BR (n = 17). Grade 5 AEs occurred in 7% of patients in the acalabrutinib cohort (n =10), 5% of those in the IdR cohort (n = 6), and 6% of those in the BR cohort (n = 2).

Among those in the acalabrutinib arm, 33% experienced serious all-grade AEs (n = 50), 70% experienced TRAEs (n = 107), 4% had AEs that led to a dose reduction (n = 6), 38% had doses withheld due to toxicities (n = 58), and 14% had AEs that resulted in drug discontinuation (n = 22). By comparison, 58% of the IdR arm experienced serious all-grade AEs (n = 66), 95% had TRAEs (n = 112), 13% reported AEs that led to a dose reduction (n = 15), 66% had doses withheld due to AEs (n = 78), and 59% had AEs that lead to drug discontinuation (n = 70). Finally, 26% of the BR arm experienced serious all-grade AEs (n = 9), 69% reported TRAEs (n = 24), 14% had AEs that led to dose reduction (n = 5), 20% had doses withheld due to AEs (n = 7), and 17% experienced AEs that resulted in drug discontinuation (n = 6).

Serious AEs that were reported in 5% or more of patients in any group included pneumonia (acalabrutinib, 6%; IdR, 10%; BR, 3%), diarrhea (acalabrutinib, 1%; IdR, 14%; BR, 0%), and pyrexia (acalabrutinib, 1%; IdR, 7%; BR, 3%). Any-grade and grade 3 or higher neutropenia was additionally reported in the acalabrutinib cohort at 21% and 17%, respectively; in the IdR cohort at 46% and 40%, respectively; and in the BR cohort at 34% and 31%, respectively.

Events of clinical interest (ECIs) reported with acalabrutinib included any-grade bleeding events, such as hemorrhage (29%; n = 44), which occurred at a higher incidence than what had been observed with IdR/BR (8%; n =12). However, investigators noted that the incidence of any-grade major hemorrhaging was low and comparable across the cohorts.

“The final results of the ASCEND study confirm the findings of the interim analysis and support the efficacy and safety of acalabrutinib versus standard-of-care regimens, such as IdR or BR in patients with relapsed/refractory CLL,” concluded Ghia.

_Reference:

_{Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in relapse/refractory chronic lymphocytic leukemia: ASCEND final results. Poster presented at 2020 SOHO Annual Meeting; September 9-12; 2020; Virtual. Oral Abstract: CLL-091.}