The introduction of the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), Novartis‘s Gleevec (imatinib), enabled patients with Philadelphia-positive chronic myeloid leukemia (CML) to achieve a near-normal life expectancy. However, the need for long-term or indefinite daily therapy has led to new issues and toxicities associated with prolonged first-generation TKI use. Consequently, lower molecular response rates, increased side effects, and resistance to first-line treatment have become significant challenges.
These challenges are now being addressed by second- and third-generation TKIs in chronic phase (CP) CML. Primary data from the pivotal Phase III ASC4FIRST study presented at the European Hematology Association conference, being held 13 – 16 June, suggests that Novartis’ third-generation TKI, Scemblix (asciminib), may be safer and more effective than standard-of-care TKIs in patients with newly diagnosed CP CML. Scemblix is the first FDA-approved CML treatment distinct from its TKI counterparts, as it uniquely targets the myristoyl pocket of ABL, inhibiting BCR-ABL-mediated proliferation and enhancing apoptosis.
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In the Phase III ASC4FIRST trial, Scemblix was evaluated against investigator-selected TKIs, including Gleevec and second-generation TKIs. Patients received 80 mg of Scemblix once daily or an investigator-selected TKI at standard label doses. The study achieved its first primary endpoint, with a major molecular response (MMR) at 48 weeks of 67.7% for Scemblix, compared to 49% with all investigator-selected TKIs. While the increase in MMR with Scemblix did not significantly surpass that achieved with second-generation TKI treatment, 89.6% of patients treated with Scemblix showed early molecular responses by week 12, compared to 70.1% with investigator-selected TKIs. Additionally, 38% of Scemblix-treated patients displayed deep molecular responses at 48 weeks, compared to 20.6% with investigator-selected TKIs. In terms of toxicities, Scemblix was found to have 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. While the differences in side effect rates are minimal, Dr. Andreas Hocchaus emphasised that 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, it emerges as an appealing alternative treatment to enhance the quality of life for patients who experience toxicities from second-generation TKIs or have comorbidities that make second-generation TKI-associated side effects less suitable.
Given the potential for long-term or indefinite therapy, an improved trial design is needed with overall survival and progression-free survival as endpoints to evaluate the survival benefit and safety of continuous treatment. Additionally, the high cost of therapy is a major consideration for physicians when choosing a treatment. Currently, Scemblix does not offer attractive treatment value for CML, with an approximate annual cost of $264,000 for a dosage of 40 mg twice daily.
With continued success, Scemblix’s global total sales are projected to reach $2.38bn by 2030, based on GlobalData’s analyst consensus forecast. The sales may be negatively impacted if concerns about the lack of long-term follow-up data and the high cost of therapy are not addressed.
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Novartis AG