Overall, the findings of this study provide evidence for the use of asciminib add-on as a treatment option to achieve DMR in patients with CML-CP who have received imatinib for ≥ 1 year without achieving DMR. Asciminib add-on may be a promising strategy to help these patients achieve their treatment goals, including becoming eligible for TFR.

Asciminib add-on showed efficacy in the primary endpoint of MR4.5 at week 48; 19.0% and 28.6% of patients in the 40- and 60-mg asciminib QD add-on arms, respectively, achieved MR4.5 at week 48, compared with 0.0% in the continued imatinib arm and 4.8% in the switch to nilotinib arm. Of note, despite more patients in the continued imatinib arm being in MMR at baseline, none achieved MR4.5 at week 48. In comparison, patients in the asciminib add-on arms had higher baseline BCR::ABL1 levels. MR4.5 rates at week 96, a secondary endpoint, continued to provide evidence that both asciminib add-on doses were effective in achieving deep responses, with more patients in MR4.5 at week 96 with asciminib add-on than with continued imatinib or switch to nilotinib. Importantly, 28.6% of patients in the continued imatinib arm who crossed over to receive asciminib 60 mg QD add-on after not achieving MR4.5 at week 48 were still able to achieve MR4.5. No patients in the continued imatinib arm achieved MR4.5. This may be attributed to the prior treatment of randomized patients with imatinib for a median of 2.4 (range, 1.1–18.2) years without achieving DMR, as well as the limited sample size. Within the CML-study IV, 6.0% of patients receiving imatinib with MMR at 18 months achieved MR4.5 by 5 years, indicating that a small proportion of patients may achieve DMRs at later timepoints with continued imatinib.[22] These results suggest that early asciminib add-on therapy may enable patients who do not achieve DMR after ≥ 1 year of imatinib to more rapidly reach key treatment goals of deep remission. Given that a large percentage of patients worldwide are still initially treated with imatinib, and only approximately 30% of patients achieve TFR eligibility with imatinib by 10 years [10], asciminib add-on therapy may be a viable strategy to help patients who do not meet TFR criteria with imatinib to reach these treatment goals. Furthermore, the asciminib add-on strategy may be preferable to a switch to nilotinib, given that no AOEs were observed in the add-on arms.

Responses with asciminib add-on observed in this trial were rapidly achieved, with 14.3% and 19.0% of patients in the 40- and 60-mg asciminib QD add-on arms, respectively, achieving MR4.5 at week 24, compared with 0.0% and 9.5% in the continued imatinib and switch to nilotinib arms, respectively. However, there appears to be other subgroups of patients with different BCR::ABL1IS kinetics (Additional file 1, Figures S1a and S1b). One group appears to have a more gradual decrease in expression over time; these patients have not yet achieved DMR, but may be able to achieve DMR with longer asciminib add-on treatment, although further investigation is needed. The other group appears to have no change in BCR::ABL1IS levels. This nonresponse may be due to the presence of resistance mutations; though, per protocol, analysis to identify the presence of resistance mutations is only planned in patients who lose response.

Asciminib add-on was found to be tolerable, although it was associated with higher rates of any-grade AEs, grade ≥ 3 AEs, and AEs leading to discontinuation than imatinib monotherapy. This was expected, as these patients previously received imatinib 400 mg for ≥ 1 year without discontinuation due to intolerance.

Overall, the safety profile with the asciminib 40- and 60-mg QD add-on arms was favorable compared with nilotinib. Rates of AE of grade ≥ 3 were around 38% with either combination arm, compared with 10.0% in the continued imatinib arm and 42.9% in the switch to nilotinib arm. Rates of any-grade AEs leading to discontinuation were 4.8% and 14.3% with asciminib 40- and 60-mg QD add-on, respectively, 0% with continued imatinib, and 33.3% with switch to nilotinib. Notably, rates of pancreatic enzyme elevations were similar in asciminib add-on arms compared with the switch to nilotinib arm. Overall, these findings are consistent with those from previous studies of asciminib monotherapy and support the favorable safety and tolerability profiles of asciminib add-on therapy [13, 14, 16, 18]. No new safety signals were observed over time with asciminib 40 or 60 mg QD add-on to imatinib, compared with previous studies of asciminib monotherapy [13, 14, 16, 18]. These findings provide further support for the manageable safety profile of asciminib add-on to imatinib in patients with CML-CP.

The approved dose of asciminib as monotherapy for CML-CP without the T315I mutation is 80 mg QD or 40 mg BID [11, 12]. However, prior phase I studies demonstrated an increase in asciminib exposure (area under the curve [AUC] and maximum drug concentration [Cmax]) when administered with imatinib, but no effect of asciminib on imatinib exposure [21]. The asciminib 40-mg QD dose in combination with imatinib provided comparable Cmax but up to 40% decrease in AUC relative to asciminib 40 mg BID. Likewise, the asciminib 60-mg QD dose in combination with imatinib provided comparable AUC, with 1.5- to 1.85-fold increase in Cmax. Despite these differences in pharmacokinetic profiles, this trial was not designed to compare between asciminib add-on arms, and did not elucidate a difference in efficacy and safety between doses.

Another treatment option for patients who are unable to achieve DMR after ≥ 1 year of imatinib therapy might be to switch to asciminib. The addition of the asciminib monotherapy arm to the ASC4MORE study will help to establish whether asciminib alone is sufficient for patients to reach their treatment goals, while further assessing the relative safety and tolerability of asciminib monotherapy in patients who have received a prior TKI.

Although polymerase chain reaction results depicting BCR::ABL1IS kinetics appear to objectively support the clinical benefit observed, this study was not formally designed to compare efficacy results between the arms and was not blinded. The study was not powered for hypothesis testing and the small sample size limits further interpretation of these promising results. These limitations may affect interpretation of efficacy; however, this trial was designed to gain an early understanding of the potential for the asciminib add-on strategy to be a safe and effective alternative to switching to a second-generation TKI. The asciminib monotherapy arm was added after recruitment for the other arms was completed and therefore, there are no direct comparisons for this arm with the asciminib add-on arms, limiting interpretation of the study results. Further validation is required before incorporating the asciminib add-on strategy into clinical practice.

There is a need for shared treatment decision-making between patients and physicians that considers several factors. While second-generation TKIs show an advantage over imatinib in terms of efficacy, it does not translate into significantly improved survival outcomes [23]. An increased rate of AEs and AEs leading to discontinuation were reported in the asciminib add-on arms compared with the continued imatinib arm, although this was expected as these patients had tolerated imatinib for over a year without intolerance leading to discontinuation. Asciminib add-on also had a favorable safety profile compared with nilotinib, with faster and deeper response rates than both imatinib and nilotinib. However, the increased pill burden of asciminib add-on therapy should be considered when selecting a therapeutic strategy. Therefore, patients and physicians should consider the benefit–risk profile of asciminib add-on on an individual basis.

ASC2ESCALATE (NCT05384587) is another phase II trial investigating alternative asciminib dosing strategies in patients with CML-CP who discontinued initial TKI therapy [24]. Moreover, in addition to ASC4FIRST, several other studies are assessing asciminib monotherapy as first TKI, including ASCEND, ASC4START (NCT05456191), and ASC2ESCALATE, which also includes a cohort of newly diagnosed patients [19, 24,25,26].