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Background <p>Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment options. The novel agent QBS72S, also known as QBS10072S, is designed to leverage the high expression of L-type amino acid transporter 1 (LAT1) on breast cancer cells and the blood-brain barrier. By conjugating an amino acid analogue with a DNA alkylating moiety, QBS72S can exploit LAT1 for specific delivery into the brain and metastatic tumor cells.</p> Methods <p>We designed a single-arm, Phase 2a study to test the preliminary efficacy and safety of QBS72S for breast-to-brain metastasis in two distinct cohorts: intraparenchymal metastasis (Cohort 1; no LMD), and LMD (Cohort 2; with or without intraparenchymal metastasis). The primary endpoint is overall response rate across evaluable participants in Cohort 1. Secondary endpoints include progression-free survival, overall survival, duration of response, and treatment-related adverse events in Cohort 1. Exploratory endpoints include correlation of LAT1 expression in formalin-fixed paraffin-embedded samples with treatment response, CSF pharmacokinetics, perfusion MRI, and novel CSF-based biomarkers.</p> Discussion <p>Adaptive clinical trial design enables rapid enrollment and tailored endpoints for patient cohorts with baseline disparate outcomes. Our LAT1 staining protocol will allow ongoing trials in glioblastoma (NCT02977780) and future studies in brain metastases to correlate&#xa0;LAT1 expression to drug efficacy. Our exploratory endpoints may facilitate identification of more rapid and reliable biomarkers of LMD treatment response and resistance.</p> Trial registration <p>ClinicalTrials.gov NCT05305365.</p>

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Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月15日

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  • Rukayat Taiwo,
  • Paul M. Harary,
  • Thy T. H. Trinh,
  • Monica Granucci,
  • Sophie Bertrand,
  • Brandon Carlson-Clarke,
  • Sophia B. Chernikova,
  • Kate Therkelsen,
  • Mili Arora,
  • Michelle E. Melisko,
  • Michael Iv,
  • Hannes Vogel,
  • Summer Han,
  • Christine Xie,
  • Susie Brain,
  • Vivian Lee,
  • Krishna L. Bharani,
  • Seema Nagpal,
  • Melanie Hayden Gephart

摘要

Background

Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment options. The novel agent QBS72S, also known as QBS10072S, is designed to leverage the high expression of L-type amino acid transporter 1 (LAT1) on breast cancer cells and the blood-brain barrier. By conjugating an amino acid analogue with a DNA alkylating moiety, QBS72S can exploit LAT1 for specific delivery into the brain and metastatic tumor cells.

Methods

We designed a single-arm, Phase 2a study to test the preliminary efficacy and safety of QBS72S for breast-to-brain metastasis in two distinct cohorts: intraparenchymal metastasis (Cohort 1; no LMD), and LMD (Cohort 2; with or without intraparenchymal metastasis). The primary endpoint is overall response rate across evaluable participants in Cohort 1. Secondary endpoints include progression-free survival, overall survival, duration of response, and treatment-related adverse events in Cohort 1. Exploratory endpoints include correlation of LAT1 expression in formalin-fixed paraffin-embedded samples with treatment response, CSF pharmacokinetics, perfusion MRI, and novel CSF-based biomarkers.

Discussion

Adaptive clinical trial design enables rapid enrollment and tailored endpoints for patient cohorts with baseline disparate outcomes. Our LAT1 staining protocol will allow ongoing trials in glioblastoma (NCT02977780) and future studies in brain metastases to correlate LAT1 expression to drug efficacy. Our exploratory endpoints may facilitate identification of more rapid and reliable biomarkers of LMD treatment response and resistance.

Trial registration

ClinicalTrials.gov NCT05305365.