Cancer Res Treat.  2023 Apr;55(2):626-635. 10.4143/crt.2022.1058.

Trastuzumab Combined with Irinotecan in Patients with HER2-Positive Metastatic Colorectal Cancer: A Phase II Single-Arm Study and Exploratory Biomarker Analysis

• Xu T
• Wang X
• Xin Y
• Wang Z
• Gong J
• Zhang X
• Li Y
• Ji C
• Sun Y
• Zhao F
• Huang D
• Bai Y
• Li J
• Shen L

• KMID: 2541249
• DOI: http://doi.org/10.4143/crt.2022.1058

Abstract

Purpose
The human epidermal growth factor receptor 2 (HER2) is an established therapeutic target for various kinds of solid tumors. HER2 amplification occurs in approximately 1% to 6% of colorectal cancer. In this study, we aimed to assess the efficacy and safety of trastuzumab in combination with chemotherapy in HER2-positive metastatic colorectal cancer (mCRC).
Materials and Methods
An open-label, phase II trial (Clinicaltrials.gov: NCT03185988) was designed to evaluate the antitumor activity of trastuzumab and chemotherapy in HER2-positive digestive cancers excluding gastric cancer in 2017. Patients from this trial with HER2-positive, KRAS/BRAF wild-type, unresectable mCRC were analyzed in this manuscript. Eligible patients were treated with trastuzumab (8 mg/kg loading dose and then 6 mg/kg every 3 weeks) and irinotecan (120 mg/m² days 1 and 8 every 3 weeks). The primary endpoint was the objective response rate.
Results
Twenty-one HER2-positive mCRC patients were enrolled in this study. Seven patients (33.3%) achieved an objective res-ponse, and 11 patients (52.4%) had stable disease as their best response. The median progression-free survival (PFS) was 4.3 months (95% confidence interval, 2.7 to 5.9). Four of the 21 patients (19.0%) had grade 3 adverse events, including leukopenia, neutropenia, urinary tract infection, and diarrhea. No treatment-related death was reported. Exploratory analyses revealed that high tumor tissue HER2 copy number was associated with better therapeutic response and PFS. Alterations in the mitogen-activated protein kinase pathway, HER2 gene, phosphoinositide 3-kinase/AKT pathway, and cell cycle control genes were potential drivers of trastuzumab resistance in mCRC.
Conclusion
Trastuzumab combined with chemotherapy is a potentially effective and well-tolerated therapeutic regimen in mCRC with a high HER2 copy number.

Keyword

HER2 positivity; Metastatic colorectal cancer; Trastuzumab; Resistance

Figure

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  Fig. 1 Best change from baseline in target lesion size by each patient. FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2. a)Progression of non-target lesions or ccurence of new lesions, b)HER2 2+FISH positive.

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  Fig. 2 Progression-free survival (A) and overall survival (B) in patients with human epidermal growth factor receptor 2–positive metastatic colorectal cancer treated with trastuzumab and chemotherapy. CI, confidence interval; mOS, median overall survival; mPFS, median progression-free survival.

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  Fig. 3 Molecular alterations in trastuzumab resistance-related genes at baseline and acquired mutations after trastuzumab treatment. (A) Pretreatment tissue. (B) Baseline circulating tumor DNA (ctDNA). (C) ctDNA at progression, the acquired mutations were marked with a black block. Asterisks indicate no available samples for analysis in this patient. Best OR, best of response; PD, progression disease; PR, partial response; SD, stable disease; SV, structural variation.

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  Fig. 4 Genetic characteristics associated with trastuzumab resistance. (A) Progression-free survival by human epidermal growth factor receptor 2 (HER2) gene copy number variation; HER2 amplification copy number ranking the top two-thirds were defined as high copy number variation (CNV), and the others were defined as low CNV (high ERBB2 CNV > 26; low ERBB2 CNV ≤ 26). (B) HER2 expression of patient No. 15 before treatment and after progression on trastuzumab treatment. (C) Progression-free survival of circulating tumor DNA mitogen-activated protein kinase (MAPK) pathway wild-type (WT; n=15) and mutant (MUT; n=3, 2 with KRAS amplification and one with BRAF amplification) HER2-positive metastatic colorectal cancer. (D) Multiple acquired mutations in HER2 gene in patient No. 16 after exposure to trastuzumab.

Reference

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