CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

Timothy P. Hughes, Jorge E. Cortes, Delphine Réa, Michael J. Mauro, Andreas Hochhaus, Dong Wook Kim, Koji Sasaki, Fabian Lang, Michael C. Heinrich, Massimo Breccia, Michael Deininger, Yeow Tee Goh, Jeroen J.W.M. Janssen, Moshe Talpaz, Philipp le Coutre, Shruti Kapoor, Silvia Cacciatore, Fotis Polydoros, Nithya Agrawal, Francois Xavier Mahon

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Abstract

Context: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib—a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket—demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). Objective: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. Design: Patients with T315I-mutated CML-CP and treated with ≥1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). Results: 48 patients were included; 25 patients (52.1%) received ≥3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR); 3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients; 34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for ≥96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by week 96. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added exposure (median duration of exposure, 2.08 years; range, 0.04-4.13 years). The most common (≥10%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%); none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. Conclusions: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP—a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

Original languageEnglish (US)
Pages (from-to)S300
JournalClinical Lymphoma, Myeloma and Leukemia
Volume22
DOIs
StatePublished - Oct 2022

Keywords

  • CML
  • Phase I
  • T315I
  • TKI
  • asciminib
  • chronic myeloid leukemia

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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