Lung cancer with HER2 mutation
Being diagnosed with lung cancer is a major challenge in life, but now carries improved prospects for length and quality of life. As with previous articles in our library, knowing your cancer biomarker profile is key to determine personalized medicines that can effectively treat lung cancer. One such marker is HER2 (also known as ERBB2), a biomarker (gene) extensively studied in breast cancer with transformative results, which has now been successfully used to target lung cancer.
HER2 proteins are an essential part of our cell surfaces, and responsible for normal cell growth and therefore mutations in the HER2 gene can lead to cancer cell growth and spread. HER2 gene mutations occurs in approximately 3% of lung cancers and more commonly in younger, female, never smokers with lung adenocarcinomas. Current US (NCCN) guidelines recommended routine testing for HER2 to help guide precision lung cancer treatment.
HER2 gene mutations can be assessed by analyzing tumor tissue acquired from a needle biopsy, surgery or liquid biopsies (blood-based test for tiny fragments of circulating tumor DNA can also detect gene alterations such as HER2 mutation).
For patients with HER2-mutant lung cancer, HER2-targeted precision medicine options fall under two broad categories: tyrosine kinase inhibitors given by mouth daily and antibody–drug conjugates given by intravenous injection every few weeks.
HER2 tyrosine kinase inhibitors work by binding to HER2 receptors to shut down cancer cell growth signals, and these drugs include afatinib, dacomitinib, neratinib, poziotinib, mobocertinib and pyrotinib. These drugs have so far shown modest efficacy, and new tyrosine kinase inhibitors or combination treatments are currently being evaluated in clinical trials.
HER2 antibody–drug conjugates act as biological guided missiles that target abnormal HER2 receptors on the cancer cell surface. The antibody–drug conjugates allow the active drug to enter into cancer cells, killing it from within whilst keeping normal cells safe. A particularly promising HER2 antibody–drug conjugate is called trastuzumab deruxtecan (Enhertu) demonstrated substantial tumor shrinkage of 55% and disease control with reduction in tumor size in 92% of patients with HER2-mutant lung cancers with an average (median) duration of response of 9 months [1]. Following these impressive clinical trial results, trastuzumab deruxtecan became the first HER2-targeted drug to receive accelerated approval in 2022 by the United States Food and Drug Administration (FDA) for patients with previously treated, metastatic non-small cell lung cancer with HER2 mutation.
Trastuzumab deruxtecan is currently under evaluation in international clinical trial for patients with newly diagnosed metastatic HER2-mutant lung cancers (DESTINY-Lung04; NCT05048797) and other novel HER2 antibody-drug conjugates are also in clinical trial development.
29 March 2023
This article was jointly co-authored by Dr. Si-Yang Liu, MD, Visiting Investigator, Memorial Sloan Kettering Cancer Center, New York, USA; Attending Thoracic Surgeon, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Chinese Thoracic Oncology Group, Guangzhou, China.
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References
[1] Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières J, Nagasaka M, Bazhenova L, Saltos AN, Felip E, Pacheco JM, Pérol M, Paz-Ares L, Saxena K, Shiga R, Cheng Y, Acharyya S, Vitazka P, Shahidi J, Planchard D, Jänne PA; DESTINY-Lung01 Trial Investigators. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251. doi: 10.1056/NEJMoa2112431. Epub 2021 Sep 18. PMID: 34534430; PMCID: PMC9066448.
Dr Bob T. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press.
Dr Bob T. Li is supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health.
*Dr Bob Li and Dr Si-Yang Liu's contributions to this article are in a personal capacity