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Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis

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Abstract

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8–72.7%; 95% CI, 18–32%) and 36.0% (range, 8.3–63.0%; 95% CI, 31–42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16–5.62), 12.78 (95% CI, 10.24–15.32), and 8.12 (95% CI, 6.48–9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.

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Funding

This work was supported by Central Government Guiding Local Scientific and Technological Development Funds for Qinghai Province in China.

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  1. Yonghui Zheng, Guoshuang Shen and Chengrong Zhang have contributed equally and Co-first authors

Authors and Affiliations

  1. Breast Disease Diagnosis and Treatment Center of Affiliated Hospital, Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China

    Yonghui Zheng, Guoshuang Shen, Chengrong Zhang, Xingfa Huo, Yuanfang Xin, Qianqian Fang, Yumei Guan, Fuxing Zhao, Dengfeng Ren, Zhen Liu, Miaozhou Wang & Jiuda Zhao

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Contributions

YZ, GS and CZ contributed equally to this work. YZ, GS and CZ participated in the studies search, data extraction and completed the draft. YZ, XH, YX, QF, YG, FZ and DR contributed to statistical analysis modify the article. All authors critically revised successive drafts of the paper and approved the final version. Concept and design: YZ, GS, CZ and JZ. Acquisition, analysis, or interpretation of data: YZ, XH, YX, QF, YG, ZL and MW. Drafting of the manuscript: YZ, GS, CZ and JZ. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: YZ, XH, YX, QF, YG, FZ, DR, ZL and MW. Obtained funding: All authors. Administrative, technical, or material support: All authors. Supervision: All authors.

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Correspondence to Jiuda Zhao.

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Zheng, Y., Shen, G., Zhang, C. et al. Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis. Clin Exp Med 23, 3205–3216 (2023). https://doi.org/10.1007/s10238-023-01072-7

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