The advent of Novartis's GLEEVEC (imatinib), the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), allowed patients with Philadelphia-positive chronic myeloid leukemia (CML) to attain nearly normal life expectancy. However, the necessity for long-term or indefinite daily therapy has introduced new complications and toxicities linked to extended use of first-generation TKIs. As a result, lower molecular response rates, heightened side effects, and resistance to initial treatment have emerged as major challenges.

Second- and third-generation TKIs are now addressing the challenges faced in treating chronic phase (CP) CML. Primary data from the pivotal Phase III ASC4FIRST study, presented at the EHA 2024, indicated that Novartis's third-generation TKI, SCEMBLIX (asciminib), may be safer and more effective than standard-of-care TKIs for patients with newly diagnosed CP CML.

In the Phase III ASC4FIRST trial, SCEMBLIX was compared to investigator-selected TKIs, including GLEEVEC and second-generation TKIs. Patients received either 80 mg of SCEMBLIX once daily or an investigator-selected TKI at standard doses. The study met its primary endpoint, showing a major molecular response (MMR) at 48 weeks of 67.7% for SCEMBLIX, compared to 49% for all investigator-selected TKIs. Although the increase in MMR with SCEMBLIX was not significantly higher than that with second-generation TKIs, 89.6% of SCEMBLIX-treated patients achieved early molecular responses by week 12, compared to 70.1% with investigator-selected TKIs. Additionally, 38% of patients treated with SCEMBLIX achieved deep molecular responses at 48 weeks, compared to 20.6% with investigator-selected TKIs.

Regarding toxicities, SCEMBLIX exhibited a favorable safety and tolerability profile, with fewer Grade 3 or higher adverse events and a lower discontinuation rate of 4.5%, versus 11.1% for Gleevec and 9.8% for second-generation TKIs. Although the differences in side effect rates are minimal, the 10-year positive clinical trial safety data for later lines of therapy supports SCEMBLIX as potentially practice-changing in terms of safety. Coupled with its positive efficacy data, SCEMBLIX presents as an appealing alternative treatment, enhancing the quality of life for patients experiencing toxicities from second-generation TKIs or having comorbidities that make second-generation TKI-associated side effects less suitable.

KOL insights

“After almost 1.5 years of median follow-up, asciminib demonstrated superior efficacy and favorable safety and tolerability compared to investigator-selected TKI and compared to imatinib in patients with newly diagnosed CML. We need longer follow-up to further elucidate the benefits and potential long-term safety profile of asciminib as a treatment for newly diagnosed CML.” – MD, United States

Conclusion

Talking about the current treatment landscape of CML, there are a number of approved therapies.  First generation GLEEVEC is used to treat around 50% of patients, and any of the 2nd-generation TKIs  are used to treat the remaining 50%. Despite all of these advancements, people with CML still have significant unmet needs. Nearly 40% of patients still require medication changes within the five years following their initial switch, despite the usage of GLEEVEC and second-generation TKIs. Furthermore, adverse events such as pleural effusions and GI and CV adverse events have been linked to the long-term usage of second-generation TKIs. Additionally, in line with the overall advancement of cancer therapy, including CML, the current objective is to provide patients with effective yet well-tolerated treatment. This is the reason why SCEMBLIX was specifically created to provide potentially increased efficacy while reducing the off-target effects that arise from 1st and 2nd-generation TKIs targeting multiple kinases in an attempt to interact with the ATP binding site on the BCR-ABL protein, whereas SCEMBLIX targets the myristoyl pocket.

 

The Phase III ASC4FIRST trial compared SCEMBLIX to investigator-selected TKIs, including GLEEVEC and 2nd-generation TKIs. Despite minimal differences in side effect rates, SCEMBLIX's long-term positive safety data supports its potential to be practice-changing.