Asciminib: a revolution in the tyrosine kinase inhibitors era

Chronic myeloid leukemia (CML) management has evolved into an era where treatment goals extend beyond survival to include deep molecular response (DMR) and treatment-free remission (TFR) (1). Actual treatment with tyrosine kinase inhibitors (TKIs) has shown to increase life-expectancy (2) and clinical evidence suggests that in a substantial number of patients who achieve a stable DMR treatment with TKIs can be safely discontinued (3,4). Hence, TFR is increasingly regarded as a feasible treatment goal in about 20% to 40% patients with CML (5). However, a proportion of patients with CML in chronic-phase (CP) and treated with TKIs still remain in stable major molecular remission (MR3) or less (stable MR2), do not achieve a DMR, and, consequently necessitate lifelong TKIs therapy (6) as well as long-term molecular monitoring (7). Therefore, a clinical unmet need is still how to optimize proactive management strategies to expand a DMR achievement and to increase TFR candidates.

Asciminib (ASC), a new oral specific BCR::ABL1 inhibitor with a novel mechanism of action, is a paradigm shift (8). Approved indications of ASC by the United States Food and Drug Administration (FDA) for the treatment of adult patients with CML include: (I) newly diagnosed Philadelphia chromosome-positive (Ph+) CML-CP (accelerated approval based on major molecular response rate); (II) previously treated Ph+ CML-CP; (III) Ph+ CML-CP with the T315I mutation. At the moment, however, European Medicines Agency (EMA) has approved ASC from the second line onwards. In contrast to all other BCR::ABL1 inhibitors that bind within the ATP-binding site of the ABL kinase domain, ASC inhibits ABL tyrosine kinase activity by binding to a distinct and specific allosteric site that targets the ABL myristoyl pocket and induces the formation of an inactive kinase conformation (9). ASC has been designed to enhance clinical efficacy and reduce off-target effects as compared with current ATP-competitive TKIs. Further, the peculiar mechanism of action of ASC strongly suggests that simultaneous targeting of both the myristate and ATP binding pockets of BCR::ABL1 might be more effective than targeting a single site. This model of action raises the potential to combine ASC with other TKIs (10) to achieve a greater pharmacological control of BCR::ABL1 since dual inhibition of BCR::ABL1 might lead to disease eradication and increase DMR achievement. To this address this issue, clinical protocols exploring ASC add-on therapies are warranted. In this view, the recently published ASC4MORE study (11) explored the efficacy of two different ASC doses (40 mg QD and 60 mg QD) add-on to imatinib (IM) standard dose versus IM alone versus switch to nilotinib (NIL: 300 mg BID) in those patients with CML-CP who previously received conventional IM-therapy for more than 1 year without obtaining a DMR with the primary endpoint of assessing a DMR (MR4.5) at week 48. All patients received a prior IM treatment for a median of 2.4 years, whilst the median follow-up of the study was 32 months and the four study arms enrolled patients showing both MR3 and MR2 responses. However, more patients in the ASC add-on arm were in MR2, compared to those in the continued IM and switch to NIL arms. Study results demonstrated the superiority of the ASC add-on strategy to IM in achieving the primary endpoint of the protocol. At week 48, a MR4.5 was achieved by 19% [90% confidence interval (CI): 6.8–38.4%] and 28.6% (90% CI: 13.2–48.7%) of the 70% of patients in the ASC 40 and 60 mg add-on schedule as compared to 0% in IM alone or 4.8% in the switch to NIL.

In addition, a fast MR4.5 response was achieved with the add-on combinations since median time to MR4.5 achievement was 24.6, 12.4, 66.4 and 36.3 weeks for ASC 40 mg plus IM, ASC 60 mg plus IM, IM alone, and NIL respectively. Notably, these MR4.5 rates achieved with ASC add-ons are also comparable to those obtained with ASC treatment (80 mg QD) as first-line therapy in newly diagnosed patients with CML-CP at week 48 (12) compared to investigator-selected TKIs, such as IM or second-generation TKIs (16.9% vs. 4.9% IM vs. 12.7% second-generation TKIs). Therefore, the ASC4MORE findings, although restricted to four small cohort of patients, suggest that ASC might be successfully used in a proactive way to achieve a DMR in those patients who remain in both stable MR3 or MR2.

Another important issue to highlight from the ASC4MORE study is the rate of discontinuation from randomization treatment. Overall, 14.3%, 23.8%, 76.2%, and 47.6% of the patients in the ASC 40 mg add-on, ASC 60 mg add-on, IM alone, and switch to NIL, respectively, discontinued the assigned treatment. Main reasons for discontinuation were: (I) patient decision (9.5%) in the ASC 40 mg add-on; (II) adverse event (AE) (14.3%) in the ASC 60 mg add-on; (III) physician decision (66.7%) in IM alone; (IV) AE in switch to NIL (33.3%). However, even if the high rate of discontinuation in the IM arm can be attributed to cross-over, discontinuation rates from ASC add-on arms were significantly reduced as compared to NIL.

As for safety, both ASC add-on arms showed again lower rates of AEs of grade ≥3 leading to discontinuation as compared to NIL. Most of the described AEs were like those previously reported (13) and no new findings were observed.

In conclusion, the ASC4MORE study explored the potential of the ASC combination therapy with IM demonstrating superior efficacy against NIL as a proactive agent, and further supports the feasibility of ASC add-on strategies to optimize CML clinical management.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-68/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-68/coif). The authors have no conflicts of interest to declare.

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