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First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced

Wei Li1, Yongsheng Wang2, Anwen Xiong1

  • 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Signal Transduction and Targeted Therapy
|November 3, 2024
PubMed

Insights

SY-5007, a novel RET inhibitor, demonstrated promising safety and efficacy in a phase 1 trial for patients with RET-altered solid tumors. Objective response rates reached 57.8%, with a median progression-free survival of 21.1 months, highlighting its therapeutic potential.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Oncogenic RET alterations represent a significant, tissue-agnostic therapeutic target in various cancers.
  • The development of potent and selective RET inhibitors is crucial for advancing cancer treatment strategies.

Purpose of the Study:

  • To evaluate the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of SY-5007.
  • To assess the pharmacokinetics and preliminary anti-tumor activity of SY-5007 in patients with RET-altered solid tumors.

Main Methods:

  • A first-in-human, phase 1 study involving dose-escalation and dose-expansion phases.
  • Enrolled 122 patients with diverse RET-altered solid tumors, including non-small cell lung cancer and medullary thyroid cancer.
  • Monitored treatment-related adverse events (TRAEs), pharmacokinetics, and anti-tumor responses, including objective response rate (ORR) and progression-free survival (PFS).

Main Results:

  • SY-5007 was generally well-tolerated, with common grade ≥3 TRAEs including hypertension and diarrhea.
  • Achieved an overall ORR of 57.8% in efficacy-evaluable patients, with a median PFS of 21.1 months.
  • Rapid clearance of circulating tumor DNA (ctDNA) correlated with improved treatment outcomes.

Conclusions:

  • SY-5007 exhibits a favorable safety profile and promising anti-tumor activity in patients with RET-altered solid tumors.
  • Serial ctDNA monitoring can provide insights into treatment response and potential resistance mechanisms.
  • Further investigation in larger trials is warranted to confirm these findings.

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