Improved Long-Term Tolerability and Efficacy of Asciminib-Based Combination Therapies in Newly Diagnosed CML Patients-the Fascination Trial

Introduction: “The Frontline asciminib in combination” - FASCINATION study (NCT03906292) is a multicenter, prospective, open-label, interventional phase II trial to evaluate efficacy and tolerability of asciminib as first-line treatment in combination with conventional ATP-competing BCR::ABL1 inhibitors for patients (pts) with chronic myeloid leukemia (CML) in chronic phase. The aim of the study is to improve the rate of deep molecular response and thereby increase the proportion of patients in treatment-free remission (TFR) over time. Here, we report the 3-year follow-up of the trial. Methods: Adult pts with newly diagnosed BCR::ABL1-positive CML were allocated to one of four combination cohorts: nilotinib 300 mg BID plus asciminib 20 mg BID (cohort 1) or asciminib 40 mg QD (cohort 2), dasatinib 100 mg QD plus asciminib 80 mg QD (cohort 3), or imatinib 400 mg QD plus asciminib 60 mg QD (cohort 4). The primary endpoint was the rate of MR4 (BCR::ABL1 transcripts ≤0.01% on the International Scale, IS) at month 12. Patients who did not achieve MR4 at month 24 stopped asciminib combination and were treated with an ATP competing TKI monotherapy at the discretion of the investigator. Subjects with MR4 continued the previous asciminib combination treatment for one year. Patients with MR4.5 were de-escalated to asciminib monotherapy 80 mg QD for one year. At month 36, asciminib treatment was stopped for all pts. Pts with MR4 or better for at least one year entered a TFR phase. Results: Between September 2019 and January 2022, 144 pts were recruited from 21 sites in Germany. Combination therapy was commenced in 125 pts (67% male). Median age at diagnosis was 46 years (range, 19-89). 57.6, 30.3, and 12.1% were low, intermediate, and high risk according to the ELTS score, respectively. BCR::ABL1 independent mutations were identified in 22 pts (18%), most commonly ASXL1 mutations (8 pts, 7%). A total of 114 pts were eligible for evaluation of molecular response at month 12. According to the intention to treat, rate of MR4at month 12 (primary endpoint) was 37.7%. At month 24, a total of 92 pts (73.6%) were allocated to further treatment arms based on their molecular response: 45 pts did not achieve MR4 at month 24 and continued with an ATP competing TKI monotherapy, 17 pts achieved MR4 and continued the previous combination treatment, 30 pts achieved MR4.5and were de-escalated to asciminib monotherapy. A total of 101 pts were eligible for evaluation of molecular response at month 36 (secondary endpoint). Rate of MMR, MR4, MR4.5, MR5 and MR5.5was 91%, 65%, 45%, 27% and 20%, respectively. Six of 8 pts with ASXL1 mutations achieved MR4 at month 12 and 7 pts at month 36, respectively. Within the 3-year follow-up, loss of MMR was observed in 5 pts with a BCR::ABL1-E275G mutation detected in one patient. Two pts progressed to blast phase and received allogeneic stem cell transplantations (month 7 and 13, respectively). Adverse events (AEs) grade 3-4 decreased from 37.6% of pts within the first year to 24.0% and 9.6% within the second and third year, respectively. Most commonly observed AEs were lipase increase (10 pts) and hypophosphataemia (6 pts). One patient died due to a myocardial infarction (month 24). A total of 37 pts (29.6%) entered the TFR phase at month 36. Conclusions: The combination of asciminib as frontline therapy with ATP competing BCR::ABL1 inhibitors was associated with a high rate of deep molecular response but moderate tolerability in the first year. The 3-year follow-up of the FASCINATION trial shows high efficacy (even in pts with ASXL1 mutations), no evidence for development of clinically relevant BCR::ABL1 mutations and improved tolerability without any unsuspected AEs. Further follow-up is needed to investigate TFR.