Frontline Approaches in CML Headline 2025 Conference

FRONTLINE TYROSINE KINASE inhibitor (TKI) therapy in chronic myelogenous leukemia (CML) has been well established, with 4 TKIs currently available: imatinib (Gleevec), dasatinib (Sprycel), bosutinib (Bosulif), and nilotinib (Tasigna). Current guidelines promote all 4 agents as viable options for the management of chronic phase (CP) CML.¹ Despite these agents’ overall success among patients, there remain many patients whose disease does not respond adequately to 2 or more of these treatments and who experience burdensome adverse events (AEs) while undergoing therapy. In addition, patients may experience intolerance or resistance, particularly among those who are treated with 2 prior TKIs.² These challenges make the need to explore novel therapies of paramount importance.

Findings from the recent phase 3 ASC4FIRST trial (NCT04971226)³ evaluating the second-line TKI asciminib in patients with newly diagnosed CML may offer another option given recent regulatory developments. The FDA has granted asciminib accelerated approval for the treatment of adult patients with newly diagnosed Philadelphia chromosome–positive CML in CP.⁴ Targeted Therapies in Oncology interviewed study ASC4FIRST coinvestigator Jorge E. Cortes, MD, the Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer and director of the Georgia Cancer Center at Augusta University, about the f indings and other insights on CML.

“Aside from the findings themselves, this is the first study in which we randomized the experimental drug asciminib vs any other drug that is approved for the indication of newly diagnosed frontline CML,” Cortes said. “That’s a good element of the trial design.” Traditionally, one experimental agent is compared with one established agent or with placebo.

In the trial, patients with newly diagnosed CML were randomly assigned to receive either asciminib 80 mg once daily or an investigator- selected TKI. A second random assignment was also implemented. Patients were also stratified by European Treatment and Outcome Study longterm survival score category (low, intermediate, or high risk) and TKI therapy selected by investigators before random assignment (imatinib and second-generation TKIs).

For the primary end point of the study, which was the major molecular response (MMR) rate at 48 weeks, the MMR rate was 68% (95% CI, 61%-74%) in the asciminib arm and 49% (95% CI, 42%-56%) in the investigator-selected TKIs arm. This resulted in a percentage difference of 19% (95% CI, 10%-28%; P < .001). Within the imatinib stratum, the MMR rate in the asciminib arm was 69% (95% CI, 59%-78%) compared with 40% (95% CI, 31%-50%) in the investigator-selected TKI arm for a percentage difference of approximately 30% (95% CI, 17%-42%; P < .001).

“These findings clearly demonstrated superiority [for the experimental agent] in terms of the response rate against imatinib and against all TKIs. This is very encouraging,” Cortes said.

Clearly, the number of treatment options adds complexity to the treatment decision-making process, but Cortes is encouraged. “We’re going to have to develop algorithms and [treatment] strategies,” Cortes said.

The investigators also noted a favorable safety profile for the agent, especially when compared with imatinib and other second-generation TKIs. In particular, treatment discontinuation among patients treated with asciminib, imatinib, and second-generation TKIs was 4.5%, 11.1%, and 9.8%, respectively.³ The percentage of patients who experienced 1 dose reduction or interruption also favored asciminib (39.5%) vs imatinib (49.5%) and second-generation TKIs (63.7%).³

Another question Cortes brought up had to do with switching to asciminib, even in a patient who was experiencing a good response but not a deep molecular response, which is needed for treatment discontinuation. “Would this be a viable method to get the benefit of treatment discontinuation? I think it would be important to delineate,” Cortes said.

Congress on Hematologic Malignancies

Looking to the 29th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, being held from February 25 to March 2, 2025, in Miami Beach, Florida, Cortes, who is also cochair, emphasized that the mix of the most current data and advances and showing how the data are applicable in the clinic is a major benefit for attendees. “The faculty shares the latest updates and demonstrates how they are applicable,” Cortes said.

Kicking off the conference with 4 presentations focused on chimeric antigen receptor (CAR) T-cell therapy and its application across leukemia and lymphoma settings sets a strong tone, according to Cortes (AGENDA). “There are a lot of developments in CAR T-cell therapy that will be presented at the onset, making it one of my favorite sections of the meeting,” Cortes said.

In addition to the planned presentations, Cortes also mentioned the conversations that occur between the presentations, especially regarding advances that are on the horizon. “I’m sure we’re going to discuss asciminib and its use in the front line,” Cortes said. “I’m sure there will be conversations about menin inhibitors [as well], because their development is ramping up,” Cortes said.

“There are a lot of data to understand and new data coming out. I think it will be a fantastic meeting,” Cortes concluded.