Positive Scemblix Data ‘May Change the Treatment Paradigm in CML’


Scemblix outperformed standard tyrosine kinase inhibitor treatment in patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Frontline Scemblix (asciminib) improved outcomes over standard-of-care tyrosine kinase inhibitors (TKIs) in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML), according to data from the phase 3 ASC4FIRST trial presented at the 2024 American Society of Clinical Oncology Annual Meeting.

TKIs — including Scemblix — are a type of drug that works by blocking tyrosine kinases, which are enzymes found on many cancer cells involved in cellular signaling, according to research published by the National Institutes of Health.

Scemblix Improves Major Molecular Response Rates

Primary results shared during a press briefing showed that, at a data cutoff of Nov. 28, 2023, patients with Philadelphia chromosome (Ph)–positive chronic phase CML who received Scemblix (201 patients) achieved a 48-week major molecular response (MMR) rate of 67.7% compared with 49.0% among patients who were treated with an investigator-selected TKI (204 patients); this represented an 18.9% improvement. According to the American Cancer Society, a MMR is when the amount of the BCR-ABL gene (which causes CML to grow and divide) in the blood or bone marrow is 1/1000th or less of what is expected in someone with untreated CML.

Study Highlights:

  • A new drug called Scemblix may be more effective than standard treatments for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML).
  • Scemblix is a type of tyrosine kinase inhibitor (TKI) that works by blocking enzymes involved in cancer cell growth.
  • In a trial, patients with CML who received Scemblix had a higher rate of major molecular response (a measure of how well treatment is working to reduce leukemia cells) after 48 weeks than those who received standard TKI treatment.

Furthermore, in the Gleevec (imatinib) group of both arms, the 48-week MMR rates were 69.3% in the Scemblix group (101 patients) compared with 40.2% in the comparator arm (102 patients), for an improvement of 29.55%.

“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,” Dr. Jorge E. Cortes, the director of the Georgia Cancer Center at Augusta University, said during the press event. “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.”

ASC4FIRST was a study that enrolled adult patients with newly diagnosed Ph-positive chronic phase CML who had not received prior treatment with a TKI.

Prior to dividing patients into different treatment groups, investigators selected a TKI in consultation with the patient in the event that the patient was assigned to the comparator TKI arm. Patients were stratified by prerandomization TKI selection (Gleevec vs second-generation TKI) and European Treatment and Outcome Study (EUTOS) long-term survival risk category (low vs intermediate vs high). The EUTOS score categorizes patients’ risk based on factors such as age, sex, spleen size and blood cell counts.

Eligible patients were randomly assigned to receive either Scemblix at a dose of 80 mg daily or a TKI of the investigator’s choice. Within the investigator-selected TKI arm, patients were further divided to receive a second-generation TKI or Gleevec; the investigational arm included Gleevec and second-generation TKI groups.

Secondary Goals of ASC4FIRST

The main goal of the trial was measuring 48-week MMR rate. Secondary end points included 96-week MRR rate, time to discontinuation due to side effects, MMR at scheduled data collection time points, complete hematological response rate (the return of normal blood levels), duration of MMR, event-free survival (time patients live without complications from their disease), progression-free survival (time from treatment patients live without disease worsening) and overall survival (time from treatment until death of any cause), among others.

Additional findings from ASC4FIRST showed that more patients who received Scemblix experienced deep molecular responses compared with those treated with investigator-selected TKIs. The MR4 rates, which measure the percentage of patients whose have 0.01% CML cells, at week 48 were 38.8% vs 20.6%, respectively, and the 48-week MR4.5 (0.003125% CML cells) rates were 16.9% vs 8.8%, respectively.

In the Gleevec groups, the MR4 rates were 42.6% in the Scemblix arm (101 patients) and 17.8% in the TKI arm (102 patients); the MR4.5 rates were 17.8% and 4.9%, respectively. In the second-generation TKI stratum, the MR4 rates were 35.0% and 26.5% in the investigational (100 patients) and control (102 patients) arms, respectively; the MR4.5 rates were 16.0% and 12.8%, respectively.

In terms of safety, the most common non-hematologic any-grade side effects observed among all patients treated with Scemblix (200 patients) were diarrhea (15.5%), fatigue (14%) and headache (13.5%). Patients who received Gleevec (99 patients) experienced diarrhea (26.3%), nausea (21.2%), and swelling around the eyes or face (20.2%) most frequently. Any-grade side effects in the second-generation TKI group (102 patients) included diarrhea (25.5%), headache (21.6%) and rash (21.6%).

Any-grade blood-related side effects in all patients who received Scemblix vs Gleevec vs second-generation TKIs consisted of thrombocytopenia (decrease in a type of white blood cell called thrombocytes; 28.0% vs 28.3% vs 34.3%), neutropenia (decrease in a type of white blood cell called neutrocytes; 25.0% vs 31.3% vs 34.3%), low white blood cell count (19.0% vs 29.3% vs 19.6%), low healthy red blood cells (11.5% vs 26.3% vs 22.5%) and lymphopenia (decrease in lymphocytes; 6% vs 16.2% vs 6.9%).

Most patients in the Scemblix-Gleevec group (84.2%) and second-generation TKI group (88.0%) were still receiving study treatment at the data cutoff. Comparatively, these rates were 61.8% and 75.5%, respectively, in the investigator-selected TKI Gleevec group and investigator-selected second-generation TKI group.

“This is the first study to compare a new drug, in this case [Scemblix], with any of the TKIs that are approved in the frontline setting of chronic phase CML,” Cortes said in conclusion. “We demonstrated a statistically superior response in terms of MMR at 48 weeks, both against imatinib and against all TKIs, and a safety and tolerability profile that favors [Scemblix] against all of the TKIs, suggesting that this strong benefit-risk profile may change the treatment paradigm in CML.”

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