The ASCEMBL trial is a phase 3 clinical study focusing on new treatment approaches for Chronic Myeloid Leukemia (CML). This investigation evaluated asciminib in patients who had previously undergone multiple therapies for their condition. The study’s findings provide insights into improving care for a patient population with CML.
The Need for New CML Therapies
Chronic Myeloid Leukemia is a cancer characterized by the BCR-ABL1 gene, which produces a faulty protein driving uncontrolled cell growth. Primary treatment involves Tyrosine Kinase Inhibitors (TKIs) that target this protein. While TKIs have transformed CML into a manageable condition for many, a subset of patients faces challenges.
Patients can develop resistance to existing TKIs, meaning the drugs lose effectiveness and the disease progresses. Intolerance is another issue, where patients experience severe side effects that necessitate discontinuing or switching treatments. These limitations highlight a need for new therapeutic options that can overcome resistance and offer a better tolerability profile for patients who have exhausted standard TKI regimens.
Asciminib’s Unique Mechanism of Action
Asciminib, the drug evaluated in the ASCEMBL trial, features a distinct approach compared to other TKIs. Most approved TKIs bind to the ATP-binding site of the BCR-ABL1 protein, blocking its energy source. This binding site is a common target, but mutations can arise, leading to drug resistance.
Asciminib is a STAMP inhibitor, or Specifically Targeting the ABL Myristoyl Pocket. This mechanism involves binding to an allosteric site on the BCR-ABL1 protein, distinct from the ATP-binding site. By binding to this alternative pocket, asciminib inactivates the protein even when mutations are present at the ATP-binding site. This allows asciminib to work in patients whose disease has become resistant to traditional TKIs due to such mutations.
Primary Results of the Trial
The ASCEMBL trial was a phase 3, open-label, randomized study comparing asciminib to bosutinib, another TKI. It included patients with Philadelphia chromosome-positive CML in chronic phase who had previously received two or more TKI therapies. A total of 233 patients were randomized, with 157 receiving asciminib and 76 receiving bosutinib. The primary objective was to assess the major molecular response (MMR) rate at 24 weeks.
At 24 weeks, asciminib demonstrated a superior MMR rate of 25.5% compared to 13.2% for bosutinib. This difference in MMR rates, adjusted for baseline major cytogenetic response status, was 12.2%, favoring asciminib (p=0.029). The median time to achieve MMR was also shorter with asciminib at 12.7 weeks versus 14.3 weeks for bosutinib.
Safety and Tolerability Findings
Adverse events of all grades were reported in 89.7% of patients on asciminib, compared to 96.1% on bosutinib. Grade 3 or higher adverse events occurred in 50.6% of patients treated with asciminib, which was lower than the 60.5% observed in the bosutinib group.
Only 5.8% of patients in the asciminib arm stopped treatment due to side effects, whereas 21.1% of those receiving bosutinib discontinued. Common grade 3 or higher adverse events with asciminib included thrombocytopenia (low platelet count) and neutropenia (low neutrophil count). In contrast, bosutinib was associated with higher rates of diarrhea and increased liver enzyme levels (alanine aminotransferase).
Impact on CML Treatment Guidelines
The results from the ASCEMBL trial led to the accelerated approval of asciminib (brand name Scemblix) by the U.S. Food and Drug Administration (FDA) on October 29, 2021. This approval was for adult patients with Philadelphia chromosome-positive CML in chronic phase who had been previously treated with two or more tyrosine kinase inhibitors. The FDA also granted full approval for adult patients with CML in chronic phase who carry the T315I mutation, a specific resistance mutation.
Asciminib offers an alternative for patients who have developed resistance or intolerance to multiple prior TKI therapies, a group with limited treatment choices and historically poor outcomes. The availability of asciminib addresses an unmet need in the CML treatment landscape.