Asciminib Yields Promising Efficacy vs SOC Agents in CML

The efficacy and tolerable safety profile of asciminib (Scemblix) make it a promising potential agent that could be used in the frontline setting if approved for patients with chronic myeloid leukemia (CML), according to Jorge Cortes, MD, who noted that successful treatment discontinuation may also be possible with the agent.

“The question is, will it be approved by the FDA? If it is approved, then who is the right candidate to receive asciminib? How do we incorporate it [into care]?” Cortes asked in an interview with OncLive^®. “We have 4 drugs approved for frontline CML treatment—how do you choose? We’re going to have to learn about that [and] develop algorithms and strategies.”

Based on data from the phase 3 ASC4FIRST trial (NCT04971226) which evaluated asciminib vs standard of care investigator-selected TKIs, the FDA granted priority review to the agent for the treatment of those with newly diagnosed Philadelphia chromosome (Ph)–positive CML in chronic phase on July 29, 2024.¹

Recently published data in the New England Journal of Medicine from the study revealed that patients with newly diagnosed disease achieved a 48-week major molecular response (MMR) rate of 67.7% when treated with asciminib (n = 201) vs 49.0% among those in the standard of care TKI arm (n = 204; 95% CI, 9.6%-28.2%; adjusted 2-sided P < .001). Additionally, patients in an asciminib analysis population (n = 101) experienced a 48-week MMR rate of 69.3% vs 40.2% in the analysis set of patients who received imatinib (Gleevec; n = 102), for a treatment difference of 29.6% (95% CI, 16.9%-42.2%; two-sided adjusted P < .001).²

In the interview, Cortes highlighted key takeaways from the ASC4FIRST trial, how asciminib could affect care for patients with CML, and how the agentcompares to available frontline TKIs. Cortes is the director for the Georgia Cancer Center and the Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer in Augusta.

OncLive: What is key to note on the recently published ASC4FIRST study data with asciminib?

Cortes: This is a very interesting trial. One thing that I like about the trial, aside from the results themselves, is the design. This is the first time that there is a study where we randomly assigned patients with newly diagnosed CML [to receive] the experimental drug, in this case asciminib, vs any other drug that’s approved for that same indication. Usually, we’ve been selective in randomizing [the experimental agent] against one drug. In this case, any of the drugs that are approved for that indication were a part of the control arm, which is good because that way it was a fair comparison. It’s this drug, [asciminib], vs anything else I could do for my patients. That was a good element of the design.

The study clearly demonstrated superiority in terms of the response rate [and] MMR rate at 48 weeks in both primary end points [with asciminib vs] imatinib and vs all TKIs. That is very encouraging. Now it’s only 48-week [data], so we need to wait for longer results, [but] we do know that these early responses historically have correlated well with long-term outcomes, particularly with the achievement of the deeper molecular responses [and] eligibility for treatment-free remission, which is what we ultimately want to get to with a better drug. Whether it turns out to be a better drug [is yet to be determined], but as a primary end point [at] an early time point, it is very exciting [data], and the difference was quite significant [with asciminib vs imatinib or all other TKIs]. It is suggestive that [treatment with asciminib] could lead us to have more patients who would eventually meet the criteria for treatment discontinuation and hopefully discontinue treatment successfully.

The other element that I find very attractive from the results of the trial is the safety profile. The safety of asciminib was very good and there was nothing major [reported] in terms of adverse effects [AEs]; the incidence of both hematologic and non-hematologic toxicities was equivalent or less than [that observed with] the other TKIs, showing that it’s a clean drug in this setting. It’s very exciting.

How could asciminib affect the care of patients with CML?

I see it benefiting patients who are interested in stopping treatment at some point; if we are [trying to increase the] probability of having a patient be eligible for [discontinuation], that could be a patient to use [asciminib in]. But also, patients who may be more prone to AEs and who we are concerned about [experiencing AEs such as] arterio-occlusive events, diarrhea, and pleural effusions [may benefit from the agent] because of its very clean toxicity profile.

[Questions on a potential approval and candidates to receive the agent are ones] that I don’t think we can answer immediately, but it is good to have a drug that has all these potential benefits, [and] I would like to use [it] as the first drug in most of my patients.

What are the next steps with asciminib in CML?

There’s a bit of a hole in the approval [with asciminib currently] which is the second-line [setting] for patients [with Ph-positive CML in chronic phase] who have received second-generation TKIs as initial therapy. How can we treat those patients if they have resistance? Because moving from a second-generation [TKI] to another second-generation TKI doesn’t help much. Generally, the approvals for asciminib and ponatinib [Iclusig] do not apply to that [early or frontline] setting, they’re supposed to be [administered] after 2 prior TKIs in the US.

Getting more information as to the benefit in that [frontline] setting would be important, and [we] also [want to determine] whether you can switch to asciminib in a patient who is having a good response, but not the deep molecular response that they need for treatment discontinuation. Could that be another way of [giving therapy] and getting the benefit of treatment discontinuation? [There is a] study [that] is ongoing, but those are questions that would be important to address.

How does asciminib compare with the currently available frontline TKIs in the CML landscape?

In my view, it’s the most potent of these drugs, maybe as potent as ponatinib. Ponatinib is a very potent drug, so it probably falls into that category of [one of] the most potent TKIs, but asciminib also has the advantage of a very clean safety profile. It’s well tolerated and although we have the perception that it’s a new drug, we’ve been using asciminib for 10 years. The phase 1 study started in 2014, so we have patients who have been receiving this drug for 10 years, and we do have long-term follow-up. It is a clean drug, and I like that because even if some patients are not going to be able to stop therapy, at least they have something that provides as little toxicity and respects quality of life as much as possible.

References

1. Novartis Scemblix granted FDA priority review for the treatment of adults with newly diagnosed CML. News release. Novartis. July 29, 2024. Accessed October 14, 2024. https://www.novartis.com/news/media-releases/novartis-scemblix-granted-fda-priority-review-treatment-adults-newly-diagnosed-cml
2. Hochhaus A, Wang J, Kim DW, et al; ASC4FIRST Investigators. Asciminib in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2024;391(10):885-898. doi:10.1056/NEJMoa2400858