The phase III ASCEND trial has met its primary endpoint, as findings from the study showed that patients with previously treated chronic lymphocytic leukemia had a statistically significant and clinically meaningful improvement in PFS with acalabrutinib compared with the combination of rituximab and either idelalisib or bendamustine.
Jose Baselga, MD
The phase III ASCEND trial has met its primary endpoint, as findings from the study showed that patients with previously treated chronic lymphocytic leukemia (CLL) had a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with acalabrutinib (Calquence) monotherapy treatment compared with the combination of rituximab (Rituxan) and either idelalisib (Zydelig) or bendamustine.1
Additionally, the safety and tolerability of acalabrutinib was found to be consistent with the known adverse event (AE) profile of the BTK inhibitor.
As a result of these interim data, AstraZeneca, the developer of acalabrutinib, has decided to end the trial early, with full findings to be presented at an upcoming medical meeting.
“Calquence is the first BTK inhibitor to show benefit in a phase III trial as a monotherapy compared to current standard-of-care combinations used in relapsed or refractory chronic lymphocytic leukemia,” José Baselga, MD, executive vice president, R&D Oncology, AstraZeneca, said in a press release. “We look forward to presenting detailed results at a forthcoming medical meeting.”
The international, multicenter, open-label, phase III ASCEND trial (NCT02970318) randomized 310 patients with previously treated CLL 1:1 to receive single-agent acalabrutinib at 100 mg twice daily until disease progression or rituximab plus either idelalisib or bendamustine.
To be eligible for enrollment, patients must have been ≥18 years or older, had an ECOG performance status of 0 to 2, received ≥1 prior systemic therapy, had CD20-positive disease, and had active disease meeting ≥1 of the International Workshop on CLL 2008 criteria for required treatment. Prior exposure to a BTK inhibitor; major surgery within 30 says 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 is PFS assessed via an independent review committee (IRC); key secondary endpoints include physician-assessed PFS, IRC- and physician-assessed overall response rate (ORR) and duration of response (DOR), overall survival (OS), time to next treatment, and patient-reported outcomes.
Moreover, the phase III ELEVATE-TN (ACE-CL-007; NCT02475681) trial is comparing the efficacy of obinutuzumab (Gazyva) and chlorambucil, acalabrutinib plus chlorambucil, or acalabrutinib alone in treatment-naïve patients with CLL.
Phase II data that were presented at the 2018 ASH Annual Meeting highlighted the benefit with acalabrutinib in both patients with newly diagnosed and relapsed/refractory CLL. In the open-label study, patients achieved ORRs as high as 100% with either of 2 doses of acalabrutinib.2
The study involved a total of 48 patients, 16 with high-risk treatment-naïve CLL and 32 with relapsed/refractory disease, who were randomized to 2 different dosing schedules, administered on 28-day cycles, and followed until disease progression or of toxicity.
Among 45 efficacy-evaluable patients, all 7 treatment-naïve patients who received acalabrutinib at 100 mg twice daily responded, as did 14 of 15 patients with relapsed/refractory disease. Of 23 patients who received 200 mg daily, 7 of 9 treatment-naïve patients and 12 of 14 patients with relapsed/refractory disease responded.
Acalabrutinib was associated with an ORR of 89% in the 45 evaluable patients (85% in all 48 enrolled patients), including 96% ORR with the 100-mg twice-daily dosage and 83% ORR with the 200-mg daily dose.
Additionally, the median DOR, PFS, and OS had not been reached. The 18-month DOR was 95% in the 100-mg twice-daily cohort and 100% in the 200-mg daily group. The 18-month PFS rate was 91% and 94% with the 100 mg twice daily and 200 mg daily groups, respectively, and the 18-month OS rates were 100% for patients who received acalabrutinib at 100 mg twice daily and 94% for those who were given the BTK inhibitor at 200 mg daily.
Regarding safety, there were acceptable toxicity with both dosages and no patients required dose delays or modification. Moreover, 3 of 48 safety-evaluable patients discontinued treatment because of AEs.
Acalabrutinib was previously approved by the FDA in October 2017 for the treatment of adult patients with relapsed/refractory mantle cell lymphoma who have received ≥1 prior therapy.