Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial

Signal Transduct Target Ther. 2025 Feb 28;10(1):62. doi: 10.1038/s41392-025-02155-5.

Abstract

HA121-28, a promising multikinase inhibitor, mainly targets rearranged during transfection (RET) fusions and selectively targets vascular endothelial growth factor receptor-2, endothelial growth factor receptor, and fibroblast growth factor receptor 1-3. The safety, pharmacokinetics, and efficacy of HA121-28 were assessed in advanced solid tumors (phase 1, ClinicalTrials.gov NCT03994484) and advanced RET fusion-positive non-small-cell lung cancer (RET-TKI naive NSCLC, phase 2, ClinicalTrials.gov NCT05117658). HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial. The recommended dose identified in phase 1 (450 mg) was administered for patients during phase 2. The primary endpoints were the maximum tolerated dose (MTD) in phase 1 and the objective response rate (ORR) in phase 2. 162 patients were enrolled in phase 1 and 48 in phase 2. A total of 600 mg once daily was set as MTD. Across 100-800 mg, the exposure of HA121-28 increased in a dose-dependent manner. Consistent between both trials, diarrhea, rash, and prolonged QTc interval, were the most reported treatment-emergent adverse events. 40.0% (phase 1) and 62.5% (phase 2) patients experienced grade ≥3 treatment-related adverse events, respectively. The overall ORR was 26.8% and the median progression-free survival (PFS) was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at ≥450 mg once daily. HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients. Nevertheless, cardiotoxicity is a notable concern that warrants careful attention.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Oncogene Proteins, Fusion* / genetics
  • Protein Kinase Inhibitors* / administration & dosage
  • Protein Kinase Inhibitors* / adverse effects
  • Protein Kinase Inhibitors* / pharmacokinetics
  • Proto-Oncogene Proteins c-ret* / genetics

Substances

  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors

Associated data

  • ClinicalTrials.gov/NCT03994484
  • ClinicalTrials.gov/NCT05117658