STAMP Inhibitor Scemblix for CML

Scemblix produces superior responses in chronic myeloid leukemia – active in T315I mutations

Charles H. Weaver, MD
4–6 minutes
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STAMP inhibitor Scemblix (asciminib ABL001) for CML

About Scemblix

Scemblix is a precision cancer medicine targeting the ABL myristoyl pocket (STAMP) in patients with CML. Asciminib was designed to help overcome mutations on the ATP-binding site of BCR-ABL1, which may help address resistance that occurs in later treatment lines of CML. (2)

FDA Approval

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Scemblix as a first-line treatment for adults newly diagnosed with Philadelphia chromosome-positive CML in chronic phase (Ph+ CML-CP). This approval marks a significant expansion of Scemblix’s use, potentially benefiting four times as many patients as before as it is now indicated in newly diagnosed or previously treated PH+ CML in chronic phase. Scemblix is also approved in PH+ CML in chronic phase in patients with the T315I mutation. Scemblix has shown superior efficacy compared to all standard of care therapies, along with a favorable safety profile. The FDA’s decision to grant accelerated approval as a first-line treatment was based on results from the ASC4FIRST Phase III trial, which compared Scemblix to other tyrosine kinase inhibitors (TKIs). Key findings include:

  • Nearly 20% more patients on Scemblix achieved major molecular response (MMR) compared to standard TKIs
  • Scemblix showed superior efficacy with fewer severe side effects and treatment discontinuations

Previous Studies

Data presented at the December 2020 American Society of Hematology Annual Meeting (ASH) from the Phase III ASCEMBL clinical trial demonstrated that the novel precision cancer medicine Scemblix (asciminib, ABL001) nearly doubled the major molecular response (MMR) rate compared to Bosulif® (bosutinib) in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP).1,-3 This led to US Food and Drug Administration approval of Scemblix  for the treatment Ph+ CML-CP.3

More recently, findings from the phase 3 ASC4FIRST clinical trial presented during the 2024 ASCO Annual Meeting demonstrated that Scemblix significantly improves molecular response rates in individuals with Ph–positive chronic phase CML. In a comparative trial the major molecular response (MMR) rate was 67.7% for Scemblix treated patients compared to 49% among patients who were treated with older TKI drugs selected by their treating physician.4,5

“A significant number of patients [with CML]—more than half—do not get the deep molecular responses and the type of outcomes that we aim for now that treatment-free remission is becoming increasingly important,” Jorge E. Cortes, MD, the director of the Georgia Cancer Center at Augusta University, said during the press event. “Asciminib is a TKI with a novel mechanism of action that binds to the myristoyl pocket, raising the possibility of greater selectivity and less toxicity. The drug has been approved for patients who have received multiple prior therapies, and in a randomized trial in that setting [it] showed improved efficacy and safety. [Therefore], we decided to bring it to the frontline setting to see if something similar could be observed.”

Scemblix for Advanced CML

In patients with Ph+ CML-CP who had experienced resistance or intolerance to at least two TKIs, the ASCEMBL trial showed that2

  • Scemblix nearly doubled the molecular response rate compared to Bosulif® (bosutinib) at 24 weeks (25% vs. 13%)
  • The proportion of patients who discontinued treatment due to side effects was more than three times lower with Scemblix. 
  • The most common side effects were, respectively: upper respiratory tract infections, musculoskeletal pain; decrease in platelet and neutrophil counts, and a decrease in hemoglobin.

Tyrosine kinase inhibitors were one of the first precision cancer medicines developed and changed the management of CML. The advent and expansion of multiple TKI therapies has resulted in tremendous progress for patients living with CML over the last three decades. Some patients however in later treatment lines still can develop resistance leading to disease progression. There is currently no established standard-of-care in the third line setting of CML treatment.

About ASCEMBL

The ASCEMBL clinical trial was designed to compare Scemblix to Bosulif, and established and effective treatment for patients with Ph+ CML-CP previously treated with two or more tyrosine-kinase inhibitors TKI’s.

In the ASCEMBL clinical trial, 233 patients were treated with either asciminib 40 mg twice daily or Bosulif 500 mg once a day and directly compared. Patients were evaluated 24 weeks from initiation of therapy and 41% of asciminib treated patients achieved a cytogenetic complete remission compared to 24% of those treated with Bosulif. Treatment discontinuation due to side effects was less common with asciminib occurring in 5.8% compared to 21.1% for patients taking Bosulif.

References

  1. Hochhaus A, et al. Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs). Oral presentation at: ASH Annual Meeting; Dec. 8, 2020.
  2. Schuld P., et al. Structural and Biochemical Studies Confirming the Mechanism of Action of Asciminib, an Agent Specifically Targeting the ABL Myristoyl Pocket (STAMP). Blood. 2020;136:34-35.
  3. Rea D, et al. A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After≥ 2 Prior TKIs. Blood. 2021. DOI: 10.1182/blood.2020009984. PMID: 34407542.
  4. Hughes TP, Hochhaus A, Takahashi N, et al. ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): primary results. J Clin Oncol. 2024;42(suppl 17):LBA6500. doi:10.1200/JCO.2024.42.17_suppl.LBA6500
  5. A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP. ClinicalTrials.gov. Updated May 3, 2024. Accessed May 29, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04971226

  6. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia

  7. Hochhaus A, Wang J, Dong-Wook K, et al. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024.

  8. Scemblix (Asciminib) Package Insert. https://www.novartis.com/us-en/sites/novartis_us/files/scemblix.pdf. Revised October 2024.

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