On February 19, the U.S. Food and Drug Administration (FDA) approved the Bruton’s tyrosine kinase inhibitor acalabrutinib (Calquence) tablets and capsules in combination with the BCL2 inhibitor venetoclax (Venclexta) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
AMPLIFY Trial
Efficacy was evaluated in AMPLIFY (ClinicalTrials.gov identifier NCT03836261), a randomized, multicenter trial in adult patients previously untreated for CLL without del(17p) or a TP53 mutation. Patients were randomly assigned to receive acalabrutinib and venetoclax (AV) or investigator’s choice of chemotherapy (fludarabine plus cyclophosphamide plus rituximab [FCR] or bendamustine plus rituximab [BR]).
The major efficacy outcome measure was progression-free survival as assessed by independent review committee for the AV arm vs the investigator’s choice arm (FCR/BR). The median duration of progression-free survival follow-up was 42.6 months. Median progression-free survival was not estimable (95% confidence interval [CI] = 51.1 months to not estimable) in the AV arm and 47.6 months (95% CI = 43.3 months to not estimable) in the FCR/BR arm (hazard ratio = 0.65, 95% CI = 0.49–0.87, P = .0038). With a median follow-up of 41.0 months, there were 18 (6%) deaths in the AV arm and 42 (14%) in the FCR/BR arm.
The acalabrutinib prescribing information includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, secondary primary malignancies, cardiac arrhythmias, and hepatotoxicity. The venetoclax prescribing information includes warnings and precautions for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity. In AMPLIFY, serious adverse reactions occurred in 25% of patients receiving AV, and serious or grade 3 or higher infections in 14%.
The recommended regimen for acalabrutinib in combination with venetoclax consists of up to 14 cycles of acalabrutinib and 12 cycles of venetoclax starting at cycle 3. Each cycle is 28 days. The recommended acalabrutinib dose is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles of treatment. Start venetoclax at 20 mg according to the 5-week ramp-up dosing schedule in the prescribing information. Following the ramp-up, the recommended venetoclax dose is 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of cycle 14.
Expedited Programs
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The applications were granted Orphan Drug designation.
