A second-generation antibody–drug conjugate to treat HER2-positive breast cancer

Breast cancers overexpressing the human epidermal growth factor receptor 2 (HER2, also known as ERBB2) protein were historically associated with a poor prognosis. 1 Slamon DJ Clark GM Wong SG Levin WJ Ullrich A McGuire WL Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235: 177-182 Crossref PubMed Scopus (10333) Google Scholar However, their dependence on HER2 led to the development of targeted monoclonal antibodies that transformed their natural history through impressive improvements of survival outcomes in patients with advanced disease and improvements in cure rates in localised tumours. 2 Swain SM Shastry M Hamilton E Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2022; (published online Nov 7)http://doi.org/10.1038/s41573-022-00579-0 Crossref PubMed Scopus (70) Google Scholar At the advanced stage, de-novo metastatic disease is therefore currently prominent, and patients who relapse after adequate treatment at earlier stages might have hard-to-treat tumours. 3 Grinda T Antoine A Jacot W et al. Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008–2017 ESME cohort. ESMO Open. 2021; 6: 100114 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar For the past decade, the recommended sequence of therapy for HER2-positive metastatic breast cancer has been front-line trastuzumab, pertuzumab, and taxanes combination followed by second-line trastuzumab emtansine. 4 Verma S Miles D Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367: 1783-1791 Crossref PubMed Scopus (2798) Google Scholar , 5 Swain SM Miles D Kim S-B et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020; 21: 519-530 Summary Full Text Full Text PDF PubMed Scopus (394) Google Scholar In 2021, findings from the DESTINY-Breast03 randomised phase 3 trial led to the approval of trastuzumab deruxtecan, a next-generation antibody–drug conjugate targeting HER2, for patients with pretreated HER2-positive metastatic breast cancer, based on a major improvement in progression-free survival over trastuzumab emtansine. 6 Cortés J Kim S-B Chung W-P et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022; 386: 1143-1154 Crossref PubMed Scopus (338) Google Scholar In The Lancet, Sara A Hurvitz and colleagues 7 Hurvitz SA Hegg R Chung W-P et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022; (published online Dec 7)http://doi.org/10.1016/S0140-6736(22)02420-5 Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar report a preplanned overall survival and updated safety analyses of the DESTINY-Breast03 trial, after a median follow-up of 28·4 months (IQR 22·1–32·9) with trastuzumab deruxtecan and 26·5 months (14·5–31·3) with trastuzumab emtansine. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trialTrastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. Full-Text PDF Open Access