Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer

ESMO Open. 2024 Jun;9(6):103465. doi: 10.1016/j.esmoop.2024.103465. Epub 2024 Jun 3.

Abstract

Background: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.

Patients and methods: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.

Results: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.

Conclusions: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

Keywords: HER2; PIK3CA; ctDNA; metastatic breast cancer; taselisib.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology
  • Ado-Trastuzumab Emtansine / therapeutic use
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / pathology
  • Female
  • Fulvestrant / administration & dosage
  • Fulvestrant / pharmacology
  • Fulvestrant / therapeutic use
  • Humans
  • Imidazoles
  • Maximum Tolerated Dose*
  • Middle Aged
  • Oxazepines
  • Oxazoles / administration & dosage
  • Oxazoles / pharmacology
  • Oxazoles / therapeutic use
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Receptor, ErbB-2* / metabolism
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use
  • Uracil / administration & dosage
  • Uracil / analogs & derivatives
  • Uracil / pharmacology
  • Uracil / therapeutic use

Substances

  • Receptor, ErbB-2
  • 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
  • ERBB2 protein, human
  • Oxazoles
  • Quinazolines
  • pertuzumab
  • Paclitaxel
  • Uracil
  • Ado-Trastuzumab Emtansine
  • Fulvestrant
  • Trastuzumab
  • Imidazoles
  • Oxazepines
  • Antibodies, Monoclonal, Humanized