The FDA has granted accelerated approval to asciminib (Scemblix®, Novartis AG) for patients with Philadelphia chromosome–positive (Ph-positive) chronic myeloid leukemia (CML) who have disease in chronic phase and were previously treated with two or more tyrosine kinase inhibitors and for those whose disease is in chronic phase with the T315I mutation.
"Patients with CML in chronic phase CML resistant or intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes due to disease biology and inadequate efficacy and/or safety of current therapies," wrote Delphine Rea, MD, Professor at the Hôpital Saint-Louis AP-HP (Assistance Publique Hôpitaux de Paris) in France, and colleagues, in their publication of the ASCEMBL trial (NCT03106779), one of the two trials on which the approval was based. "Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs."
The ASCEMBL study, a phase 3, multicenter, randomized, active-controlled, open-label trial, enrolled 233 patients with Ph-positive CML who had chronic-phase disease and had been previously treated with two or more TKIs. Patients were randomized 2:1 to receive either asciminib 40 mg twice daily or bosutinib 500 mg once daily until unacceptable toxicity or treatment failure. The primary end point was major molecular response at 24 weeks. Asciminib produced a molecular response rate of 25% compared with 13% in the bosutinib treatment arm. After a median duration of follow-up of 20 months, the median duration of major molecular response was not reached.
The CABL001X2101 study (NCT02081378), a phase 1, multicenter, open-label trial, evaluated 45 patients with Ph-positive disease who had disease in the chronic phase and had a T315I mutation. Patients received asciminib 200 mg twice daily until unacceptable toxicity or treatment failure. The primary end point was major molecular response. At 24 weeks, asciminib produced a major molecular response in 42% of the patients; major molecular response was reached in 49% of the patients at 96 weeks. The median duration of treatment was 108 weeks.
The most common adverse events associated with asciminib, occurring in at least 20% of patients, were upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea. The most common laboratory abnormalities were decreased platelet counts, increased triglycerides, decreased neutrophil counts and hemoglobin, and increased creatine kinase, alanine aminotransferase, lipase, and amylase.
"Asciminib demonstrated superior efficacy versus bosutinib and an improved safety profile in patients with chronic-phase CML after at least two prior TKIs," concluded Dr. Rea and colleagues in their August 2021 publication of the ASCEMBL results in Blood. "Asciminib has the potential to transform [the] standard of care in this population throughout its novel mechanism of action."
The recommended dose of asciminib for patients with Ph-positive CML in chronic phase and previously treated with two or more tyrosine kinase inhibitors is 80 mg taken orally once daily at approximately the same time each day or 40 mg twice daily at approximate 12-hour intervals. For patients with Ph-positive CML in chronic phase with the T315I mutation, the recommended dose of asciminib is 200 mg taken orally twice daily at approximate 12-hour intervals.
For More Information
Rea D, Mauro MJ, Boquimpani C, et al (2021). A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after ≥2 prior TKIs. Blood. [Epub ahead of print] DOI:10.1182/blood.2020009984
Memorial Sloan Kettering Cancer Center (2021). A phase I study of ABL001 in patients with chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Available at: https://www.mskcc.org/cancer-care/clinical-trials/14-168
Clinicaltrials.gov (2021). Study of efficacy of CML-CP patients treated with ABL001 versus bosutinib, previously treated with 2 or more TKIs. NLM identifier: NCT03106779.
Clinicaltrials.gov (2021). A phase I study of oral ABL001 in patients with CML or Ph+ ALL. NLM identifier: NCT02081378.
Scemblix® (asciminib) prescribing information (2021). Novartis AG. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215358s000Orig1lbl.pdf
US Food & Drug Administration (2021). FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asciminib-philadelphia-chromosome-positive-chronic-myeloid-leukemia
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