Novartis announced positive, longer-term results from the pivotal Phase III ASC4FIRST trial with Scemblix (asciminib) showing superior major molecular response (MMR) rates at week 96. The study compared the MMR rate of Scemblix to investigator-selected standard-of-care (SoC) tyrosine kinase inhibitors (TKIs) (imatinib, nilotinib, dasatinib and bosutinib) and to imatinib alone in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at the week 96 evaluation, the study's key secondary endpoints. The longer-term results showed an increasing difference in Scemblix MMR rate vs.

SoC, vs. imatinib and vs. 2G TKIs (nilotinib, dasatinib and bosutinib).

Results were presented at the 66 American Society of Hematology Annual Meeting & Exposition (ASH). The median follow-up was 2.2 years for Scemblix and investigator-selected SoC TKIs. Over 22% more patients treated with once-daily Scemblix achieved MMR at week 96 vs.

all investigator-selected SoC TKIs, and nearly 30% more patients achieved MMR at week 96 vs. imatinib alone. The Scemblix MMR rate was 15.1% (95% CI: 2.3, 28.0; not crossing zero) higher vs.

2G TKIs (72% vs. 56.9%). Patients treated with Scemblix also achieved deeper rates of molecular responses (MR4 and MR4.5) compared with investigator-selected SoC TKIs.

The safety profile of Scemblix at 96-weeks was consistent with the 4-year follow-up of the Phase III ASCEMBL trial, with no new safety concerns observed to date. Fewer grade =3 AEs and dose adjustments to manage AEs were reported for Scemblix, and discontinuation due to AEs was more than 50% lower for Scemblix vs. both imatinib and 2G TKIs.

The most frequent AEs (=15%) were diarrhea, headache, fatigue, musculoskeletal pain, and rash. Novartis also presented at ASH interim data from the Phase II ASC2ESCALATE dose-escalation study in both the second line (2L) and newly diagnosed Ph+ CML-CP settings. In the analysis of 2L patients at week 24 (n=28) Scemblix demonstrated MMR rates of 42.9% and deep molecular responses (MR4 25% and MR4.5 10.7%), with a consistent safety and tolerability profile.

The most common AEs (>15%) were nausea, hypertension, and vomiting. Scemblix was recently granted accelerated approval in the US to treat newly diagnosed adults with Ph+ CML-CP, which together with its approval in previously treated adult patients with Ph+ CML-CP expands the population of Scemblix-eligible patients by four-fold. In addition, the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of CML, recommending asciminib as a category 1 ?

preferred treatment for newly diagnosed Ph+ CML-CP and across all risk categories. ASC4FIRST (NCT04971226) is a Phase III, head-to-head, multi-center, open-label, randomized study of oral Scemblix 80 mg QD vs. IS first- or second-generation TKIs (imatinib, nilotinib, dasatinib or bosutinib) in 405 adult patients with newly diagnosed Ph+ CML-CP.

The trial met both primary endpoints with Scemblix demonstrating superior MMR rates at week 48 vs. investigator-selected SoC TKIs (imatinib, nilotinib, dasatinib and bosutinib) (67.7% vs. 49.0%) and imatinib alone (69.3% vs.

40.2%) as well as the secondary, non-powered endpoint for the 2G TKI stratum of (66% vs 57.8%). The study remains ongoing with further efficacy and safety readouts planned. ASC2ESCALATE (NCT05384587) is a Phase II, multicenter, single-arm, dose-escalation study of oral Scemblix 80 mg QD in both the second line (2L) and newly diagnosed (1L) Ph+ CML-CP settings in the US.

While Scemblix is already approved across lines of therapy, this is the first prospective trial to assess asciminib in the 2L setting and a dose-escalation strategy of asciminib as 2L and 1L treatment for patients with CML-CP not meeting molecular milestones. The proportion of patients achieving MMR at 12 months in the 2L setting will be measured as the primary endpoint. The study remains ongoing and has completed enrollment with 196 patients (100 patients in 2L, 96 patients in 1L).

Scemblix is the first CML treatment that works by Specifically Targeting the ABL Myristoyl Pocket (referred to as a STAMP inhibitor in scientific literature). Other currently approved CML treatments are TKIs that target the ATP-binding site (ATP-competitive). In the US, Scemblix was granted accelerated approval to treat newly diagnosed adults with Ph+ CML-CP and is also approved for previously treated adult patients with Ph+ CML-CP.

Outside the US, it is approved in more than 75 countries, including the EU, to treat those who have previously been treated with two or more TKIs with Ph+ CML-CP. In some countries, including the US, Scemblix is also approved in patients with Ph+ CML-CP with the T315I mutation. Scemblix is being studied across multiple treatment lines for Ph+ CML-CP, both as a monotherapy and in combination.