The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial

Nat Commun. 2024 Aug 27;15(1):7388. doi: 10.1038/s41467-024-51442-2.

Abstract

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Aniline Compounds
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma* / drug therapy
  • Multiple Myeloma* / pathology
  • Neoplasm Recurrence, Local / drug therapy
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor, Transforming Growth Factor-beta Type I* / antagonists & inhibitors
  • Receptor, Transforming Growth Factor-beta Type I* / metabolism
  • Thalidomide* / administration & dosage
  • Thalidomide* / analogs & derivatives
  • Thalidomide* / therapeutic use
  • Transforming Growth Factor beta / metabolism
  • Triazoles

Substances

  • pomalidomide
  • Thalidomide
  • Receptor, Transforming Growth Factor-beta Type I
  • vactosertib
  • Transforming Growth Factor beta
  • TGFBR1 protein, human
  • Protein Kinase Inhibitors
  • Aniline Compounds
  • Triazoles

Associated data

  • ClinicalTrials.gov/NCT03143985