Discussion
hard-to-treat, cardiovascular disorders, CML, CML-CP
DISEASE PROGRESSION, CML, SECONDARY, EVENTS, CARDIOVASCULAR DISORDERS
After an additional 16.4 months of follow-up since the ASCEMBL primary analysis, asciminib showed increasingly superior efficacy compared with bosutinib in patients with CML-CP treated with ≥2 prior TKIs—more patients on asciminib achieved clinically relevant and highly durable responses (The MMR rate at week 96 for asciminib was more than double that for bosutinib, meeting the key secondary objective. The statistically significant difference (95% CI) in MMR rates between the two arms increased from 12.2% (2.19–22.30, two-sided Achieving MMR is associated with a very low risk of disease progression, a high likelihood of subsequent deeper responses, and enhanced survival [A sustained clinical benefit was seen with asciminib as demonstrated by the increasing number of patients who achieved Encouragingly, deep molecular response rates increased over time and continued to be higher with asciminib than with bosutinib. MRConclusions on the impact of Interpretation of the safety results also warrants consideration that the duration of exposure was much longer for asciminib (approximately three times longer) than for bosutinib by the data cutoff, leading to a longer time for AE reporting. The median duration of exposure for asciminib increased since the primary analysis from 10.0 months to 23.7 months [The burden of AEs with asciminib (both incidence and prevalence) decreased over time in patients who continued treatment beyond 6 months. Consistent with reports on other TKIs [The decreased burden of AEs over time was consistent with the lower EAIR of AEs with asciminib than with bosutinib. Regardless of the longer duration of exposure for asciminib vs bosutinib, the risk of AEs did not increase, allowing more than half of the patients receiving asciminib (53.5%) to remain on therapy with the continued benefit of deepening responses, which was especially relevant in these hard-to-treat patients who were previously treated with ≥2 TKIs. Fewer patients remained on bosutinib therapy (19.7%), similar to that at the primary cutoff, when 61.8% vs 28.9% of patients were still receiving treatment with asciminib vs bosutinib, respectively [The safety and tolerability of bosutinib in ASCEMBL is comparable to that of bosutinib in the BYOND study [Overall, the risk of AOEs with asciminib did not increase with longer-term follow-up. The EAIR of AOEs with asciminib decreased from 3.3 per 100-patient years in the primary analysis to 3.0 in the current analysis. The EAIR of AOEs with bosutinib also decreased from 2.0 to 1.4; however, most patients receiving bosutinib discontinued early, thus preventing a meaningful comparison between the two arms. Patients were not stratified by cardiovascular disorders and prior TKI exposure at baseline, hence baseline risk for AOEs was not equivalent between treatment arms. The risk of developing AOEs is seen with most ATP-competitive TKIs, is heightened in patients who have other risk factors for these events, and increases with an increase in comorbidities [Overall, after >2 years of follow-up in ASCEMBL, asciminib remained consistently superior to bosutinib with clinically relevant and durable efficacy. Treatment was ongoing in >50% of patients receiving asciminib, allowing for greater potential benefit from long-term asciminib therapy and opportunity to achieve deeper levels of response. These high response rates to a specific inhibitor emphasize that BCR::ABL1 remains the driving force in most patients with CML-CP, even in later lines of therapy, and highlight the need for highly potent, well-tolerated, and targeted TKIs.Collectively, these updated results from ASCEMBL are a confirmation of the enduring clinical benefit of asciminib after longer exposure and continue to illustrate that asciminib has transformed CML treatment as a new standard of care for patients with CML-CP treated with ≥2 prior TKIs and support its ongoing development in earlier lines of therapy.