Trastuzumab Then and Now: A look at …

Trastuzumab was the first approved monoclonal antibody to target the oncogene HER2 protein…

Trastuzumab was the first approved monoclonal antibody to target the oncogene HER2 protein, and its development was a life-changing therapy for women with HER2+ breast cancer. The significance of the role trastuzumab has played in treatment of breast cancer was recognized in 2019 when the Lasker-DeBakey Clinical Medical Research Award was given to the Herceptin team for paradigm-shifting invention of trastuzumab.[1]

The development of this drug began in 1987 when Slamon et al.[2] reported HER2 to be amplified in 30% of invasive breast cancers and established a significant clinical correlation between HER2 amplification/overexpression and poor clinical outcome. Trastuzumab has had significant impact on HER2+ breast cancer in both the adjuvant setting as well as the metastasis breast cancer (MBC) setting since it was first approved in 1998.. Today eighty-five percent of HER2+ early stage breast cancer patients are now expected to survive for at least ten years, a spectacular improvement in the outcome of these patients[3] this benefit was observed in patients with both hormone receptor-positive and negative disease.[4] Trastuzumab was approved for use in HER2+ gastric cancer in 2011[5] and recently a study conducted at Yale cancer center found that combining trastuzumab with chemo significantly improved survival rates for women with a rare uterine serous carcinoma, an aggressive type of endometrial cancer.[6]

Treatment challenges

In surveying a number of HER2+ (MBC) Phase III trials[7] when trastuzumab is give along with a taxane the ORR is 65% and OS up to 15-20 months is 82%. Despite the success of treatment with trastuzumab in metastatic disease the known heteregenicy of HER2 expression in tumors has meant that there has been varying success in treatment with some patients. Because there are now several drug protocols that can successfully target systemic disease in HER2+ MBC, the risk for developing brain metastases is higher in patients with more aggressive subtypes of breast cancer, including HER2-positive disease. To address this issue several small molecule drugs targeting the intracellular HER2 pathway were developed. Lapatinib, neratinib and the recently approved tucatinib have both showed promise in treat brain metastasis in HER2+ disease in combination with trastuzumab and sometimes capecitabine.[8]

There are also HER2+ metastatic cancer patients that develop resistance to trastuzumab plus chemotherapy. The development of trastuzumab-antibody drug conjugates (ADC) is one approach, which has tried to solve this issue. In 2013, the FDA approved Ado-trastuzumab emtansine (T-DM1) for metastatic HER2+ BC, becoming the first ADC approved for HER2+ mBC patients.[9] The success of T-DM1 has led to the development second-generation trastuzumab-ADCs. One such drug, trastuzumab-deruxtecan, has been approved for use in patients has received two or more prior anti-HER2-based regimens in the metastatic breast setting. A third trastuzumab ADC, Trastuzumab Duocarmazine is late stage trials.[10] The latter two trastuzumab-ADCs compounds deliver a higher level of the attached chemotherapy molecule. This and the fact the chemotherapy molecules used in these new trastuzumab-ADCs can cross the cell membrane for greater cytotoxic effect to neighboring cells within the tumor microenvironment[11] makes these newer drugs more potent than TDM-1.

Increasing access to trastuzumab

Clearly trastuzumab and trastuzumab-based drugs have been very important in treating HER2+ breast and gastric cancers. In the last 3 years advances have been made that will increase worldwide patient access to these life saving drug. The first means of making these life saving trastuzumab drugs more available can come from moving for a formulation that is administered IV and instead given by subcutaneous inject[12] this new delivery method has been shown to save both time, that of doctors and patients. It is also though to be more cost effective, an impressive time saving of 19 hours and 16 minutes and a cost saving of an estimated 19.2 million euro for UK’s National Health Service (NHS).[13] . The first subcutaneous trastuzumab was approved in February 2019.

A second important step in achieve increased accessibly comes from introduction of high quality biosimilar trastuzumab. All FDA-approved biological products, including biosimilar products, undergo a rigorous evaluation so that patients can be assured of the efficacy, safety, and quality of these products. All FDA-approved biological products, products and biosimilar undergo a rigorous evaluation so that patients can be assured of the efficacy, safety, and quality of these products. There are currently twenty-eight FDA approved biosimilars five of which are trastuzumab[14]. All of the currently approved biosimilar trastuzumab are IV delivery creating an opportunity a subcutaneous biosimilar of trastuzumab.

[1] http://www.laskerfoundation.org/new-noteworthy/articles/announcing-2019-lasker-award-winners/

[2] Science. 1987;235:177–182

[3] .J. Clin. Oncol. 2014;32:3744–52.

[4] https://www.esmo.org/career-development/young-oncologists-corner/journal-club/A-decade-after-completion-of-the-HERA-trial-where-are-we-in-the-adjuvant-treatment-of-patients-with-HER2-positive-early-breast-cancer

[5] Clin. Invest, (2011) 1(1) 9-12

[6] [6] https://www.cancer.gov/news-events/cancer-currents-blog/2020/endometrial-cancer-usc-her2-trastuzumab

[7] N Engl J Med. 366(2):109-19, 2012; J Clin Oncol. 33(14): 1574-83, 2015, J Clin Oncol. 33(14):1574-83, 2015; N Engl J Med. 344(11):783-92, 2001; JAMA. 317(1):37-47, 2017.

[8] https://www.breastcancer.org/research-news/tucatinib-improves-survival-in-her2-pos-mbc; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191090/

[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191090/

[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191090/

[11] N Engl J Med. 2020;382:610–621

[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788333/

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788333/

[14] https://www.fda.gov/drugs/biosimilars/biosimilar-product-information

Keywords

biosimilarstrastuzumabmonoclonal antibodybreast cancerHER2+trastuzumab ADCantibody drug conjugates

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