Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study
Dong-Hoe Koo1, Minkyu Jung2, Yeul Hong Kim3
1Divison of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
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.
Insights
Varlitinib plus paclitaxel showed manageable toxicity and modest antitumor effects in advanced gastric cancer patients with EGFR/HER2 co-expression. This combination offers a potential second-line treatment option for this patient group.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Advanced gastric cancer (AGC) remains a significant health challenge with limited second-line treatment options.
- Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) overexpression are observed in a subset of AGC patients.
- Targeted therapies are being investigated to improve outcomes in AGC.
Purpose of the Study:
- To evaluate the safety and efficacy of a combination therapy with varlitinib and paclitaxel.
- To assess varlitinib and paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer.
- To determine the recommended phase II dose (RP2D) for this combination therapy.
Main Methods:
- A phase Ib/II study design was employed.
- Patients with EGFR and HER2 overexpression (≥ 1+ by immunohistochemistry) were enrolled.
- Varlitinib and paclitaxel were administered every 4 weeks, with dose escalation in phase Ib to determine RP2D.
Main Results:
- The RP2D was varlitinib (300 mg twice daily) combined with paclitaxel.
- Median progression-free survival was 3.3 months and median overall survival was 7.9 months in 27 patients.
- Objective response rate was 31% in patients with measurable disease; higher response and survival were noted in patients with strong HER2 expression.
Conclusions:
- The combination of varlitinib and paclitaxel demonstrated manageable toxicity and modest antitumor activity.
- This regimen represents a potential therapeutic option for patients with EGFR/HER2 co-expressing AGC progressing after first-line chemotherapy.
- Further investigation may be warranted, particularly in subgroups with strong HER2 expression.
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