Results from the phase III ASCEMBL trial with asciminib (Novartis), presented during the all-virtual 62nd American Society of Hematology (ASH) Annual Meeting, held December 5 – 8, 2020, shows that the experimental drug, also known as ABL001, was nearly twice as effective as a standard-of-care treatment regimen for patients who had recurrent Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) despite two previous courses of tyrosine kinase inhibitors (TKIs).
Tyrosine kinases are involved in multiple cellular processes, including cell signaling, cellular growth, and cell cycle. Hyperactivation of these kinases is often found in cancer cells. This makes tyrosine kinases an important drug target.
The Abelson tyrosine (ABL) kinases were initially identified as drivers of leukemia. Abl1 and Abl2 regulate diverse cellular processes during development and normal homeostasis. They can be activated by multiple stimuli leading to cytoskeletal reorganization required to promote cellular proliferation and cell survival in leukemia. As a result, researchers are evaluating multiple opportunities to inhibit ABL for the treatment of leukemia.
By specifically targeting the myristoyl pocket on the BCR-ABL1 protein, asciminib, a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor works through a different biological mechanism of action than existing TKIs, which comprise most available CML treatments and are designed to bind to the ATP site of the BCR-ABL1 oncoprotein.
Tyrosine kinase inhibitors
Today, five TKI drugs are currently available for treating CML. The disease is typically treated with one of several first-line TKIs. If the cancer persists, another TKI might be used. If both treatments fail or if patients cannot tolerate these options, there are limited alternatives left and patients may face a reduced chance of survival.
“Though some patients with CML may be told they have a ‘good cancer’ because of the wonderful advances in care that have been made over the years, this doesn’t capture the full picture for everyone with the disease,” said Greg Stephens, Executive Director and Founder of the US National CML Society.
Despite the significant advances in the treatment of chronic myeloid leukemia, many patients treated with two or more TKIs experience intolerance. The analysis of studies in patients who had previously failed two TKIs, showd that up to 55% reported intolerance to treatment. 
In addition, resistance rates for patients in later treatment lines remain high. Available data suggest that in the second-line setting, at least three out of five patients are unable to achieve MMR and up to 56% of patients do not achieve complete cytogenetic response (CCyR) within two years of follow-up 
With few remaining treatment options, and no currently established standard-of-care in the third-line setting per treatment guidelines, patients who are resistant or intolerant to two or more TKIs are at a high risk of progression 
“Asciminib may provide a good opportunity for a third-line treatment in CML patients,” said senior study author Professor Dr. Andreas Hochhaus, of the University Hospital, Jena, Germany, who also presented the study results during the Late-Breaking Abstracts session on Tuesday, December 8 at 7:30 a.m. Pacific time.
“The ASCEMBL data show that, with ABL-specific inhibition, asciminib has a reduced rate of side effects that lead to discontinuation or dose adjustment compared to the TKI drug bosutinib, while improving the response rate and speed of response,” Hochhaus observed.
“The results of the ASCEMBL study are very encouraging to the CML community, and help underscore the crucial need for additional treatment options to address real challenges that patients face,” Stephens added.
The researchers enrolled 233 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia in chronic phase (CML-CP) who had been previously treated with two or more TKIs. Participants were randomly assigned to receive asciminib (157 patients) or bosutinib (76 patients) as third-line treatment and followed for a median of just under 15 months.
The presented trial results demonstrated that at 24 weeks, 25.5% of the participating patients receiving asciminib achieved a major molecular response (MMR; an indicator that cancer cells have been reduced to extremely low levels), compared with 13.2% among those receiving bosutinib (Bosulif®; Pfizer), meeting the trial’s primary endpoint (25.5% vs. 13.2%, respectively ([95% CI, 2.19-22.3]; 2-sided P=0.029) in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine-kinase inhibitors (TKIs)
Patients taking asciminib were also twice as likely to achieve a deep molecular response, an indicator of more thorough eradication of cancer cells.
Adverse events of grade 3 or higher occurred in about half of patients taking asciminib and 60% of those taking bosutinib. “The tolerability profile was very good,” Hochhaus sais.
“It offers a nice proof that the more specific an inhibitor is, the fewer side effects you see.”
Important compartive data
“These important comparative data are impressive, and they reinforce the critical role asciminib may play, if approved, in overcoming the treatment challenges we face in later treatment lines of chronic-phase CML,” said Michael J. Mauro, Member and Myeloproliferative Neoplasms Program Leader at Memorial Sloan Kettering Cancer Center and Professor at Weill Cornell Medicine.
“While the advent and expansion of TKI therapies has resulted in tremendous progress for patients living with CML over the last decades, many of our patients in later treatment lines still face inadequate response, disease progression and intolerable side effects,” Mauro, who provided consulting services to Novartis, concluded.
Submission to the U.S. Food and Drug Administration and the European Medicines Agency of the European Union is planned for 2021. Additional trials are ongoing.
The study was funded by Novartis.
Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs – NCT03106779
Highlights of prescribing information
Bosutinib (Bosulif®; Pfizer)[Prescribing Information]
 Hochhaus A, Boquimpani C, Rea D, Minami Y, Lomaia E, Voloshin S, Turkina AG, et al. Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs)[Abstract LBA-4]
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Featured image: Audience during the San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy: © 2019 – 2020 American Society of Hematology / Todd Buchanan. Used with permission.