Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment

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Abstract

HER2-targeted immunotherapy consists of monoclonal antibodies (e.g. trastuzumab, pertuzumab), bispecific antibodies (e.g. MM-111, ertumaxomab) and activated T cells armed with anti-HER2 bispecific antibody (HER2Bi-aATC). Trastuzumab is a classic drug for the treatment of HER2 positive metastatic breast cancer. The combined application of pertuzumab, trastuzumab and paclitaxel has been suggested as a standard therapy for HER2 positive advanced breast cancer. The resistance to anti-HER2 antibody has resulted in disease progression. HER2-directed bispecific antibody may be a promising therapeutic approach for these patients. Ertumaxomab enhanced the interaction of immune effector cells and tumor cells. MM-111 simultaneously binds to HER2 and HER3 and blocks downstream signaling. Besides, HER2Bi-aATC is also an alternative therapeutic approach for HER2 positive cancers. In this review, we summarized the recent advancement of HER2-targeted monoclonal antibodies (trastuzumab, pertuzumab and T-DM1) and bispecific antibodies (MM-111, ertumaxomab and HER2Bi-aATC), especially focus on clinical trial results.

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Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

A Schneeweiss, S. Chia, T Hickish … (2013)

Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

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Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.

Véronique Diéras, David Miles, Sunil Verma … (2017)

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial.

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Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.

Kimberly Blackwell, Harold J Burstein, Anna Storniolo … (2010)

Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.

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Author and article information

Contributors

Shengnan Yu: 1334870996@qq.com

Qian Liu: 521095072@qq.com

Xinwei Han: hanxinwei2006@163.com

Shuang Qin: 617150988@qq.com

Weiheng Zhao: zhaoweiheng319420@163.com

Anping Li: li_anping@yahoo.com

Kongming Wu: kmwu@tjh.tjmu.edu.cn

Journal

Journal ID (nlm-ta): Exp Hematol Oncol

Journal ID (iso-abbrev): Exp Hematol Oncol

Title: Experimental Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 2162-3619

Publication date (Electronic): 28 November 2017

Publication date PMC-release: 28 November 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: 31

Affiliations

[1 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Oncology, Tongji Hospital of Tongji Medical College, , Huazhong University of Science and Technology, ; 1095 Jiefang Avenue, Wuhan, 430030 China

[2 ]GRID grid.412633.1, Department of Interventional Radiology, , First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 China

Article

Publisher ID: 91

DOI: 10.1186/s40164-017-0091-4

PMC ID: 5704598

PubMed ID: 29209558

SO-VID: 8d701070-bf77-4e0d-81ad-a8c563dd2f71

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 October 2017

Date accepted : 20 November 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81572608

Award Recipient : Kongming Wu

Funded by: Wuhan Science and Technology Bureau

Award ID: 2017060201010170

Award Recipient : Kongming Wu

Funded by: National High Technology Research and Development Program of China

Award ID: 2015AA020301

Award Recipient : Kongming Wu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: her2,trastuzumab,pertuzumab,t-dm1,bispecific antibody,ertumaxomab,mm-111,her2bi-aatcs

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: her2, trastuzumab, pertuzumab, t-dm1, bispecific antibody, ertumaxomab, mm-111, her2bi-aatcs

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Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment

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Abstract

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Karger: Oncology

Most cited references 84

Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.

Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.

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Cited by 56

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