Since the introduction of imatinib almost 18 years ago, similar next-generation tyrosine kinase inhibitors have been approved for chronic myeloid leukemia (CML), including dasatinib, nilotinib, bosutinib, and ponatinib. These drugs attack a similar target, making it more likely that resistance to one of them will also occur with the others.
The novel first-in-class inhibitor asciminib, which specifically targets the ABL myristoyl pocket (STAMP), improved outcomes compared with bosutinib in patients with chronic-phase CML previously treated with two or more tyrosine kinase inhibitors, according to the results of the phase III ASCEMBL trial reported as a late-breaking abstract at the virtual 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1
At 24 weeks, the study met its primary endpoint of major molecular response: 25.5% with asciminib vs 13.2% with bosutinib. After adjusting for baseline major cytogenetic response status, the absolute between-arm difference in major molecular response was 12%, favoring asciminib (P = .029).
“In this first controlled study comparing treatments of resistant/intolerant patients with CML, asciminib demonstrated statistically significant and clinically meaningful superiority in efficacy compared with bosutinib [primary objective], deeper molecular response rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option, particularly in resistant/intolerant patients who received two or more prior tyrosine kinase inhibitors,” stated lead author Andreas Hochhaus, MD, of the Jena University Hospital, Jena, Germany.
These results support the use of asciminib as a new treatment option, particularly in resistant/intolerant patients who received two or more prior tyrosine kinase inhibitors.— Andreas Hochhaus, MD
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Background
Most patients with CML respond to initial tyrosine kinase inhibitor therapy and are switched to another tyrosine kinase inhibitor at disease progression. With sequential therapy, resistance driven by point mutations in the ABL kinase domain can develop, particularly the “gatekeeper” T315I mutation, which represents a clinical challenge. Ponatinib is currently the only tyrosine kinase inhibitor that can overcome the T315I mutation, but its use is limited by side effects.
Asciminib is an orally bioavailable BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Asciminib acts as an allosteric inhibitor engaging a vacant pocket at the site of the kinase domain normally occupied by the myristoylated N-terminal of ABL1. By binding to this site, asciminib restores inhibition of kinase activity.
In addition to the development of resistance in some patients treated with approved tyrosine kinase inhibitors, up to 25% of patients with CML may develop unacceptable side effects, including vascular and pulmonary toxicities.
Study Details
ASCEMBL randomly assigned 223 patients with chronic-phase CML previously treated with two or more tyrosine kinase inhibitors in a 2:1 ratio to receive asciminib at 40 mg twice daily vs bosutinib at 500 mg once daily. Randomization was stratified by major cytogenetic response at baseline. Both intolerant and refractory patients were enrolled, excluding those with known bosutinib-resistant T315I or V299L mutations at baseline. Crossover to asciminib at bosutinib treatment failure (as per investigator’s judgment) was permitted.
At baseline, at least one BCR-ABL1 mutation was present in 12.7% of the asciminib group and 17.1% of the bosutinib group. The median age of patients was 52 years, and 51% were female. About 75% were White, 14% were Asian, and 5% were Black.
As of data cutoff on May 25, 2020, treatment was ongoing in 97 patients (61.8%) in the asciminib group and 23 patients (30.3%) in the bosutinib group. Treatment discontinuation was reported in 37.6% of the asciminib group and 69.7% of the bosutinib group. The most common reason for treatment discontinuation was lack of efficacy: 21% in the asciminib group and 31.6% in the bosutinib group. Treatment discontinuation due to adverse events was reported in 5.1% and 21.1%, respectively.
Lack of efficacy (as measured by BCR-ABL1 > 10% or Philadelphia chromosome–positive metaphases > 65%) after 6 months of therapy was observed in 10.8% of asciminib-treated patients and 25% of bosutinib-treated patients. A total of 22 of 24 patients who discontinued bosutinib due to lack of efficacy switched to asciminib.
The median duration of follow-up was 14.9 months. Deep molecular responses (ie, MR4 and MR4.5, respectively) were observed in 10.8% and 8.9% of those in the asciminib group and 5.3% and 1.3% of those in the bosutinib group.
Subgroup analysis of major molecular response at 24 weeks demonstrated the superiority of asciminib over bosutinib across most major demographic and prognostic subgroups, including sex, race, age, number of prior tyrosine kinase inhibitors therapies, and presence of BCR-ABL1 mutation at start of treatment.
Asciminib had an improved side-effect profile compared with bosutinib. Adverse events of all grades were reported in 89.7% and 96.1%, respectively; grade 3 or higher adverse events occurred in 50.6% and 60.5%, respectively. Dose adjustments or interruptions due to adverse events were needed more often in the bosutinib-treated patients.
Additional Commentary
Robert A. Brodsky, MD
Robert A. Brodsky, MD, ASH Secretary, Professor and Director of the Division of Hematology at Johns Hopkins School of Medicine, Baltimore, highlighted the importance of this new treatment option at a premeeting press conference. “The ASCEMBL study demonstrated the efficacy and safety of asciminib, a first-in-class STAMP inhibitor, vs bosutinib in chronic-phase CML previously treated with two or more tyrosine kinase inhibitors. Most patients do well on one tyrosine kinase inhibitor or another, but there are patients who cannot tolerate these drugs or who become resistant,” he explained.
“The phase III study showed statistically significant and clinically meaningful efficacy of asciminib compared with bosutinib, achieving deeper responses and improved safety. These data are likely to change practice for treatment of patients with chronic-phase CML who are refractory to or intolerant of tyrosine kinase inhibitors,” Dr. Brodsky told listeners.
“Asciminib is relevant for a small subgroup of patients who cannot tolerate or are refractory to tyrosine kinase inhibitors. A total of 95% of patients with chronic-phase CML are never going to have to get this drug. For many patients, other available tyrosine kinase inhibitors work quite well and are often tantamount to a cure, controling the disease for a very long time such that they don’t often die of CML,” he noted.
DISCLOSURE: Dr. Hochhaus has received research funding from Novartis, Pfizer, Incyte, and Bristol Myers Squibb. Dr. Brodsky has served on an advisory board for Achillion Pharmaceuticals; has received research funding from Achillion Pharmaceuticals and Alexion Pharmaceuticals; has served as a consultant to Alexion Pharmaceuticals; and has received honoraria from UpToDate.
REFERENCE
1. Hochhaus A, Boquimpani C, Rea D, et al: Efficacy and safety from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib in patients with chronic myeloid leukemia in chronic phase previously treated with ≥ 2 tyrosine kinase inhibitors. 2020 ASH Annual Meeting & Exposition. Abstract LBA-4. Presented December 8, 2020.
