A New Era in Treating Newly Diagnosed Chronic Myeloid Leukemia: The Promise of Asciminib

Chronic Myeloid Leukemia (CML) has seen a remarkable transformation over the past two decades, transitioning from a fatal condition to a manageable chronic disease, largely thanks to tyrosine kinase inhibitors (TKIs). These agents, which target the BCR::ABL1 fusion protein that drives CML, have proven to effectively control disease progression for most patients. Despite these advancements, challenges persist for patients and their doctors, particularly in newly diagnosed patients who face a difficult balance between achieving efficacy and managing treatment-related side effects.

The recent FDA approval of asciminib (brand name Scemblix) marks a promising shift in how newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) are treated. Asciminib’s novel mechanism of action targets the ABL myristoyl pocket, differentiating it from traditional TKIs that focus on the ATP-binding site. This breakthrough offers a new treatment option with the potential to enhance both efficacy and tolerability.

The expanded indication of asciminib quadruples the population eligible for treatment, providing a critical new option for patients who may have struggled with side effects from other TKIs.

“What that means, what these approval means, what these results mean is that we have another option that is very valuable that seems to be very potent, very effective, but also that seems to be very safe with the information that we have so far,” Dr. Jorge Cortes, Director of the Georgia Cancer Center at Augusta University, tells SurvivorNet Connect.

The Current Landscape of CML Treatment

CML is characterized by the presence of the Philadelphia chromosome, a genetic abnormality that results in the BCR::ABL1 fusion gene. This gene encodes a constitutively active tyrosine kinase that drives uncontrolled cell proliferation. For years, the treatment of CML has relied on ATP-competitive TKIs like imatinib, nilotinib, dasatinib, and bosutinib.

While these agents have transformed CML into a manageable disease, many patients still experience suboptimal responses or significant side effects that lead to treatment discontinuation. Data suggests that nearly half of newly diagnosed CML patients do not meet efficacy milestones, and almost one in four patients discontinue or switch treatments within the first year due to intolerability​.

Asciminib: A Novel Mechanism Targeting the ABL Myristoyl Pocket

Asciminib represents a new class of therapy known as a STAMP inhibitor (Specifically Targeting the ABL Myristoyl Pocket). Unlike traditional TKIs that inhibit the ATP-binding site, asciminib specifically targets the myristoyl pocket of the ABL kinase. This unique mechanism aims to reduce off-target effects while maintaining potent inhibition of the BCR::ABL1 fusion protein.

“And now for the first time, we have so-called STAMP inhibitors called specific targeting of the myristoyl site. And, because it’s targeting a specific site and not competing with ATP, we don’t get all those off target effects. It doesn’t affect any other kinase besides the one we’re trying to affect in CML. And that gives us a much better tolerability profile than we see with the so-called ATP competitive TKIs, the ones that we’ve been dealing with for the last 25 years,” highlights Hematologist Dr. Tim Hughes, from Adelaide, Australia.

The FDA recently granted accelerated approval to asciminib for newly diagnosed Ph+ CML-CP patients based on data from the ASC4FIRST Phase III trial, recently published in the New England Journal of Medicine.

This trial demonstrated asciminib’s superior efficacy and favorable safety profile compared to standard-of-care (SoC) TKIs, making it an exciting new option for frontline therapy.

Key Findings from the ASC4FIRST Phase III Trial

The ASC4FIRST trial is a multicenter, open-label, randomized study that compared asciminib to investigator-selected standard-of-care TKIs (imatinib, nilotinib, dasatinib, and bosutinib) in 405 patients with newly diagnosed Ph+ CML-CP. The trial had two primary endpoints: the proportion of patients achieving Major Molecular Response (MMR) at week 48, both in comparison to all SoC TKIs and specifically to imatinib alone.

Efficacy Outcomes

• Nearly 20% more patients treated with asciminib achieved MMR at week 48 compared to those on SoC TKIs (68% vs. 49%, p < 0.001).
• When compared specifically to imatinib, nearly 30% more patients on asciminib achieved MMR (69% vs. 40%, p < 0.001)​
• Asciminib also demonstrated superior rates of deeper molecular responses (MR4) by week 48 (41% vs. 22% with SoC TKIs and 16% with imatinib).

Safety and Tolerability

• Patients on asciminib experienced significantly fewer grade ≥3 adverse reactions (25.5% vs. 33% for imatinib and 42% for second-generation TKIs).
• The rate of dose reductions was lower with asciminib (6%) compared to imatinib (14%) and second-generation TKIs (24%).
• The incidence of treatment discontinuation due to adverse reactions was nearly half for asciminib (4.5%) compared to imatinib (11%) and second-generation TKIs (9.8%).

These results underscore asciminib’s potential to not only improve molecular response rates but also enhance the overall treatment experience by minimizing side effects.

“The safety profile has looked very good from the phase I study. We now have 10 years of experience, and while there may be a small cardiovascular signal when we compare it to Imatinib, it’s actually very low. And we’re also seeing reassuringly that an early concern about elevated lipase and pancreatitis actually doesn’t appear to be any different from what we see with the second generation drug. So overall, the safety profile has looked very favorable for asciminib,” explains Dr. Hughes. 

Clinical Implications: A Potential Practice-Changing Therapy

The approval of asciminib has significant implications for the treatment of newly diagnosed CML patients. For years, clinicians have had to navigate the delicate balance between efficacy and tolerability with existing TKIs.

According to Dr. Cortes, the results from the ASC4FIRST trial represent a pivotal moment in CML treatment. He noted that “asciminib [Scemblix] achieved impressive results across all three parameters of efficacy, safety, and tolerability, which could be practice-changing for newly diagnosed patients.”

“Now that we have the availability of as asciminib as a frontline therapy, the question is really whether we start with a lower potent drug or go straight to the most potent drug right up front. And, in our own practice, we are tending to prefer as asciminib, as a frontline therapy because we know it gives us the best chance of achieving that optimal response that we’ve spoken about and achieving an optimal response puts you on the pathway towards a deep molecular response. And patients with a deep molecular response have the prospect of going on to achieving treatment-free remission,” completes Dr. Hughes.

Looking Ahead: Future Directions and Ongoing Trials

The ASC4FIRST trial remains ongoing, with further analysis planned at week 96 to assess sustained efficacy, deeper molecular responses (MR4.5), and additional secondary endpoints, including progression-free survival and overall survival. Additionally, the ASC2ESCALATE study is exploring asciminib’s use in patients who previously failed other TKIs due to treatment failure or intolerance.

This continued research could further expand the role of asciminib in the treatment landscape, potentially setting new standards for both newly diagnosed and previously treated patients

Conclusion: A New Era for CML Management

The approval of asciminib marks a significant milestone in the management of chronic myeloid leukemia. By combining high efficacy with a favorable safety profile, asciminib addresses a critical need for patients seeking effective treatment with fewer side effects. As clinicians integrate this novel therapy into practice, asciminib has the potential to change the trajectory for many patients living with CML, offering them better control over their disease with improved quality of life.

The future of CML treatment looks promising, with asciminib paving the way for innovative approaches that could redefine patient care. As more data from ongoing trials become available, the hope is that asciminib will continue to demonstrate its benefits, further solidifying its role in the frontline treatment of CML.