CML paper summary - July 2024

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

Hochhaus A et al. NEJM, May 2024
ClinicalTrials.gov no. NCT04971226

Introduction

The study investigated the efficacy and safety of asciminib, a novel BCR::ABL1 inhibitor targeting the ABL myristoyl pocket, in patients newly diagnosed with chronic myeloid leukemia (CML). The objective was to determine if asciminib offered superior efficacy and safety compared to current first-line ATP-competitive tyrosine kinase inhibitors (TKIs), including imatinib and second-generation TKIs.

Trial Design

The trial enrolled a total of 405 patients, who were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or the investigator-selected TKI - one of the approved frontline TKIs, which included imatinib, nilotinib, dasatinib, or bosutinib.

Patients were stratified by European Treatment and Outcome Study long-term survival risk categories (low, intermediate, or high) and the TKI selected prior to randomization (imatinib or a second generation TKI).

Study endpoints

The primary endpoints were the major molecular response (MMR) at week 48, both for asciminib versus all TKIs collectively and specifically against imatinib.

Results
Patient Demographics and Follow-up:

• 201 patients received asciminib, and 204 received a TKI.
• Median follow-up was 16.3 months for asciminib and 15.7 months for TKIs.

Efficacy:

• At week 48, 67.7% of patients in the asciminib group achieved MMR, compared to 49.0% in the Investigator-selected TKI group (difference: 18.9 percentage points; 95% CI, 9.6 to 28.2; P<0.001).
• In the imatinib stratum (comparing only the patients where the investigator selected imatinib prior to randomization), 69.3% of asciminib-treated patients achieved MMR versus 40.2% in the imatinib group (difference: 29.6 percentage points; 95% CI, 16.9 to 42.2; P<0.001).
• In the second-generation TKI stratum, MMR was 66.0% with asciminib and 57.8% with second-generation TKIs (difference: 8.2 percentage points; 95% CI, −5.1 to 21.5).

Safety:

• Asciminib had a markedly favorable safety and tolerability profile, with fewer grade ≥3 AEs and AEs leading to treatment discontinuation vs all IS-TKIs

Discussion

The study demonstrated that asciminib significantly improved MMR rates compared to the investigator-selected TKI and to imatinib, in newly diagnosed CML patients. The safety profile of asciminib was also favourable, with a low rate of discontinuations due to side effects.

These results suggest that asciminib could become a preferred frontline therapy for CML,

Long-term follow-up is necessary to confirm the durability of these responses and the potential for treatment-free remission.