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

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

• Koo DH
• Jung M
• Kim YH
• Jeung HC
• Zang DY
• Bae WK
• Kim H
• Kim HS
• Lee Ck
• Kwon WS
• Chung HC
• Rha SY

• KMID: 2560248
• DOI: http://doi.org/10.4143/crt.2023.1324

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.

Keyword

Chemotherapy; Stomach neoplasms; Epidermal growth factor receptor; HER2; Varlitinib

Figure

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  Fig. 1. Progression-free survival and overall survival in all patients (A). Progression-free survival and overall survival according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression (B). Progression-free survival according to the circulating tumor DNA (ctDNA) analysis (C). CI, confidence interval.

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  Fig. 2. Waterfall plot of the best percentage change in target lesion size from baseline for individual patients with measurable disease (A). Swimmer plot showing patients’ treatment duration and response (B). Waterfall plot (C) and Swimmer plot (D) according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression. CR, complete response; F/U, follow-up; PD, disease progression; PR, partial response; SD, stable disease.

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  Fig. 3. Genomic alteration landscape in circulating tumor DNA analysis according to the progression-free survival (PFS), overall survival (OS), and epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) immunohistochemical expression (n=15). IHC, immunohistochemistry; PD, disease progression.

Reference

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