Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)

Cancer Res Treat. 2024 Oct;56(4):1136-1145. doi: 10.4143/crt.2023.1324. Epub 2024 Apr 29.

Abstract

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC).

Materials and methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity.

Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D.

Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Keywords: Chemotherapy; Epidermal growth factor receptor; HER2; Stomach neoplasms; Varlitinib.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Paclitaxel* / administration & dosage
  • Paclitaxel* / adverse effects
  • Paclitaxel* / therapeutic use
  • Receptor, ErbB-2* / genetics
  • Receptor, ErbB-2* / metabolism
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / mortality
  • Stomach Neoplasms* / pathology
  • Treatment Outcome

Substances

  • ErbB Receptors
  • Paclitaxel
  • Receptor, ErbB-2
  • EGFR protein, human
  • ERBB2 protein, human