ASC4REAL: Efficacy and Tolerability Comparison between Ascembl Study, a Phase 3 Randomized Clinical Trial (RCT), and Consolidated Real-World (RW) Evidence with Asciminib in CML Patients Beyond 2 TKIs
Authors: Khanna Anchit , Small Hannah , Lutchman Dhamend , Erlich Rafael , Marquez Gabriel , Yang Daisy , Jadhav Kejal 
Published: December 2024

Introduction: Despite advancements in managing chronic myeloid leukemia (CML), there are limited effective treatment options available in later lines of therapy. With each successive line of treatment, the rates of treatment failure increase, and sequential tyrosine kinase inhibitor (TKI) therapy is linked to higher resistance. It is worth noting that most TKIs currently used in clinical practice target the ATP binding site, which may lead to off-target effects and long-term tolerability issues. ASCEMBL is a phase 3 randomized controlled trial (RCT) evaluating the efficacy of asciminib (ASC), a novel allosteric TKI that targets the myristoyl pocket, in CML patients who have received two prior TKIs. While there is emerging efficacy and safety data for ASC, the limited number of patients in individual ASC real-world (RW) studies hampers a robust comparison with larger phase 3 RCTs. The data presented here builds upon previous efforts to aggregate RW evidence from studies conducted in multiple countries (Italy, Spain, the Netherlands, Australia, Russia, the United Kingdom, and Canada). This analysis expands the dataset to include US RW evidence as well as additional patient accrual and longer follow-up times in several of the original studies to contextualize and generalize the results of the ASCEMBL study.
Methods: A total of 10 RW studies were included in this analysis, with a total of 421 CML patients that received ASC after 2 or more prior TKIs. 9 of the RW studies were previously identified with a systematic literature search conducted in May 2023. In this previous search, data was extracted from published or publicly presented RW studies of patients that received ASC after 2 or more prior TKIs, and RW studies that had fewer than 10 patients were excluded. The 10th RW study (n=97), using US RW data, was presented following the previous search. Where updated data for the original 9 studies was published or publicly presented prior to July 2024, that updated data was used in this analysis. Data in the RW studies meeting the analysis criteria was generated during managed access programs or included from Flatiron Health's nationwide US electronic health record-derived de-identified database. The RW studies had a mean sample size of 42 patients, with a range of 20 to 97 patients. Key endpoints from the RW studies were compared to the ASCEMBL study (n=157), including major molecular response (MMR) rates, deep molecular response (DMR) rates, reason for ASC discontinuation, and adverse event occurrence. Data on patient MMR (n=393) and DMR (n=343) was available for a subset of the total RW patient population. DMR was operationalized as either MR4 (≤0.01% BCR::ABL1) or as MR4.5 (≤0.0032% BCR::ABL1) in the RW studies and as MR4 in the RCT.
Results: The average age of CML patients was slightly higher in the RW studies (59 years) than in the RCT (52 years). Importantly, compared to the RCT, RW studies showed similar or higher efficacy based on MMR and DMR rates, achieved in shorter time. RW studies reported a mean of 52% of patients achieving MMR (range: 37-70%) at a median 13 months (range: ≤12-24 months), and RCT reported 38% of patients achieving MMR at 22 months. RW studies reported a mean of 32% of patients achieving DMR (range: 16-70%) at a median 13 months (range: ≤12-24 months), and RCT reported 17% of patients achieving DMR at 22 months. Rate of discontinuation of ASC was comparable or lower in the RW setting. For discontinuation due to intolerance, RW studies reported a mean of 9% (range: 0-16%), and RCT reported 8%. For discontinuation due to resistance, RW studies reported a mean of 12% (range: 6-23%), and RCT reported 24%. Similarly, some adverse events, specifically thrombocytopenia and arterial occlusive events, were less frequent in the RW settings, while some such as myalgia and muscle spasms were slightly higher in the RW setting when compared with the RCT.
Conclusions: The aggregated RW evidence data across varied global contexts demonstrates asciminib is an effective and tolerable TKI for CML patients who have received two or more prior TKIs in the RW setting, supporting the results of the ASCEMBL RCT. Furthermore, the similarity of the RW results to the RCT results demonstrates the generalizability of the ASCEMBL RCT outcomes, indicating external validity despite the varying country and age contexts in the RW studies.