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Background and objectives <p>The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy.</p> Methods <p>Data (<i>n</i> = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of <i>BCR::ABL1</i> mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells.</p> Results <p>Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (<i>n</i> = 36). Major molecular response (MMR) rates in 2L were predicted to be 61–67% at week 48 and 70–76% at week 96, with the 80 mg total daily dose.</p> Conclusions <p>A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.</p>

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Leveraging Model-Informed Drug Development to Predict Asciminib Efficacy in Second-Line Treatment of Chronic Myeloid Leukemia in Chronic Phase

  • 期刊论文

  • 发表日期：

    2026年2月11日

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  • Sherwin K. B. Sy,
  • Deok Yong Yoon,
  • Yiqun Yang,
  • Christelle Darstein,
  • Kohinoor Dasgupta,
  • Shruti Kapoor,
  • Shengyuan Wu,
  • Yasunori Kawakita,
  • Matthias Hoch,
  • Kai Grosch

摘要

Background and objectives

The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy.

Methods

Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells.

Results

Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61–67% at week 48 and 70–76% at week 96, with the 80 mg total daily dose.

Conclusions

A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.