The National Medical Products Administration in China has approved acalabrutinib for use in adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have previously received at least 1 therapy.
The National Medical Products Administration in China has approved acalabrutinib (Calquence) for use in adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma who have previously received at least 1 therapy.1
The regulatory decision was supported by data from an open-label, single-arm phase 1/2 trial (NCT03932331) being conducted in China, and the phase 3 ASCEND trial (NCT02970318).
Data from the early-phase trial showed that acalabrutinib elicited an objective response rate (ORR) of 83.3% in Chinese adults with relapsed or refractory CLL. At a median follow-up of 20.2 months, the median progression-free survival (PFS) with the agent was not yet reached; the 12-month PFS rate was 90.7% and. the 18-month PFS rate was 78.8%.
Additionally, data from the final analysis of ASCEND indicated that acalabrutinib (n = 155) prolonged investigator-assessed PFS compared with idelalisib (Zydelig) plus rituximab (Rituxan; n = 119) or bendamustine plus rituximab (n = 36).2 After approximately 4 years of follow-up, the median PFS with acalabrutinib was not yet reached vs 16.8 months with idelalisib or bendamustine plus rituximab (HR, 0.28; 95% CI, 0.20-0.38; P < .0001). The estimated PFS rates at 42 months were 62% (95% CI, 53.2%-69.1%) and 19% (95% CI, 12.9%-26.1%), respectively.
When broken down further, the median PFS with idelalisib plus rituximab was 16.2 months (HR, 0.30; 95% CI, 0.22-0.42; P < .0001) and was 18.6 months with bendamustine plus rituximab (HR, 0.24; 95% CI, 0.16-0.38; P < .0001); the 42-month PFS rates in these arms were 23% and 5%, respectively.
Notably, acalabrutinib was also found to resulted in prolonged PFS vs idelalisib or bendamustine plus rituximab in those with del(17p) (HR, 0.13; 95% CI, 0.06-0.29; P < .0001) and unmutated IGHV (HR, 0.29; 95% CI, 0.20-0.41; P < .0001), as well as across prespecified subgroups.
“Many people living with CLL experience relapse and need additional treatment options to help manage their disease,” Professor Li Jianyong, director of Haematology, People’s Hospital of Jiangsu Province, and leader of China CLL Working Group, stated in a press release.1 “I’m delighted that with this approval, patients now have access to an established treatment that has already demonstrated effectiveness in many patients across the globe.”
The multicenter, randomized, open-label, phase 3 ASCEND trial enrolled patients with a diagnosis of CLL as defined by the International Workshop on Chronic Lymphocytic Leukemia who are at least 18 years of age, have received 1 or more prior systemic therapies for their disease, and have an ECOG performance status ranging from 0 to 2.2 Those with known central nervous system lymphoma or leukemia, who have significant cardiovascular disease, or who have previously received a BCL-2 or BCR inhibitor, were excluded.
Patients were able to have previously received bendamustine if the investigator’s choice for treatment was idelalisib plus rituximab. Retreatment with bendamustine was permitted if previous response to the agent persisted for longer than 2 years.
Study participants (n = 310) were randomly assigned 1:1 to receive oral acalabrutinib at 100 mg twice daily (n = 155) or investigator’s choice of idelalisib given orally at 150 mg twice daily or bendamustine given intravenously at 70 mg/m2 plus rituximab (n = 155). Rituximab was given intravenously at 375 mg/m2 on day 1 of the first cycle, with subsequent doses of 500 mg/m2 on day 1 of cycles 2 through 6. Treatment continued until disease progression or unacceptable toxicity.
Stratification factors included presence of del(17p) (yes vs no), ECOG performance status (0 to 1 vs 2) and number of prior therapies (1 to 3 vs 4 or more).
PFS served as the trial’s primary end point, and key secondary end points included ORR, overall survival (OS), and safety.
Disease characteristics at baseline were comparable across the groups. At the data cutoff date of September 3, 2021, the median time on study for those who received acalabrutinib was 46.5 months vs 45.3 months for those who received investigator’s choice of treatment.
In the total population, the median age was 67 years (range, 32-90), and 67.1% were male. Almost half (48.7%) had bulky disease defined as larger than 5 cm and 41.6% had Rai stage III to IV disease. Additionally, 7.4% of patients had an absolute neutrophil count of 1500/μL or less, 30.6% had hemoglobin of 11.0 g/dL or less, and 36.8% had platelet counts of 100,000/μL or less. Most patients (73.5%) had unmutated IGHV, 15.5% had del(17p), and 26.8% had del (11q).
The median number of prior therapies received was 2, with a range of 1 to 10. When broken down further, 48.1% of patients received 1 prior therapy, 27.7% received 2, 13.2% received 3, and 11.0% had received 4 or more.
Additional efficacy data showed that the median OS was not yet reached in either arm (HR, 0.69; 95% CI, 0.46-1.04; P = .0783). The 42-month OS rate in the acalabrutinib arm was 78% (95% CI, 71%-84%) vs 65% (95% CI, 56%-72%) in the idelalisib or bendamustine plus rituximab arm. The OS benefits observed with acalabrutinib proved to be consistent in those with del(17p) and/or a TP53 mutation and unmutated IGHV.
ORR data proved to be comparable between the investigative and control arms.
The median exposure to acalabrutinib was 44.2 months vs 11.5 months for idelalisib and 5.6 months for bendamustine. The incidence of grade 3 or higher toxicities, serious toxicities, treatment-related toxicities, and toxicities that resulted in discontinuation or dose withholding proved to be higher with idelalisib plus rituximab vs acalabrutinib or bendamustine plus rituximab.
The most frequently experienced any-grade adverse effects (AEs) included neutropenia, headache, diarrhea, and upper respiratory tract infection. The most common grade 3 or higher AEs reported with acalabrutinib included neutropenia, anemia, and pneumonia. Serious AEs reported in at least 5% of patients in the acalabrutinib, idelalisib, or bendamustine groups were pneumonia (9%; 10%; 3%), diarrhea (1%; 16%; 0%), and pyrexia (3%; 7%; 3%).
Regarding events of clinical interest, bleeding events and atrial fibrillation proved to be more common in those who received acalabrutinib, but major hemorrhage and hypertension proved to be low and comparable across the arms.
In November 2019, the FDA approved acalabrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma based on findings from ASCEND and the phase 3 ELEVATE-TN trial (NCT02475681).3 The agent is also indicated for CLL in the European Union and in other countries for treatment-naïve and relapsed/refractory disease.