On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo).1 The agent is now indicated for treating adults with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2–based regimens in the setting of metastasis.2 Fam-trastuzumab deruxtecan-nxki is a humanized immunoglobulin G1 HER2-directed antibody and topoisomerase inhibitor conjugate attached to a cleavable linker.1 These mechanisms of action enable the drug to target HER2 changes that promote cancer proliferation as well as link to a topoisomerase inhibitor, a chemical compound toxic to cancer cells.
The approval of fam-trastuzumab deruxtecan-nxki stemmed from results of the phase 2 DESTINY-Breast01 trial (NCT03248492) of fam-trastuzumab deruxtecan-nxki monotherapy in patients with HER2-positive metastatic breast cancer.3 The trial enrolled 184 women with HER2-positive, unresectable and/or metastatic breast cancer who had received 2 or more prior anti-HER2 therapies in the metastatic setting (median, 6 therapies; range, 2-27). Patients received fam-trastuzumab deruxtecan-nxki every 3 weeks. The primary end point of overall response rate (complete and partial responses), verified by independent central review, included 60.9% (95% CI, 53.4-68.0) of patients, with a median duration of response of 14.8 months (95% CI, 13.8-16.9). Within this population, there was a 6% complete response rate (n = 8) and a 54.9% partial response rate (n = 103).
Fam-trastuzumab deruxtecan-nxki has a black box warning for interstitial lung disease (ILD) and pneumonitis, including reports of fatal cases. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. The drug should be permanently discontinued in patients with grade 2 or higher ILD/pneumonitis. An additional black box warning concerns embryo-fetal toxicity. Advise female patients of reproductive potential to avoid breastfeeding and to use effective contraception during treatment and for at least 7 months following the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose.3 Fam-trastuzumab deruxtecan-nxki s not interchangeable with the following HER2 products: ado-trastuzumab emtansine, conventional trastuzumab, and trastuzumab/ hyaluronidase. Dosing and treatment schedules vary in nature. In certain patients, hypersensitivity reactions (typically delayed) have been reported following exposure to products containing polysorbate 80.1
The most common adverse reactions (≥20%) are nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. There are no clinically meaningful drug interactions to report at this time.2 Fam-trastuzumab deruxtecan-nxki may increase patient risk of developing left ventricular dysfunction as decreased left ventricular ejection fraction has been observed with anti-HER2 treatments.1
Dosage and Cost
Dosage is 5.4-mg/kg intravenous infusion once every 3 weeks (21-day cycle) until there is disease progression or unacceptable toxicity.2 For delayed or missed doses, administer as soon as possible (do not wait for the next planned cycle). Adjust the administration schedule to maintain an interval of 3 weeks between doses. No dose adjustments are recommended for mild to moderate renal or hepatic impairment. No data are available in severe renal or hepatic impairment.
The cost per 100-mg single-use vial is $2755.1
1. Enhertu. Lexi-Drugs. Lexicomp. Wolters Kluwer. Accessed March 5, 2020.
2. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2019. Accessed April 7, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2019/761139s000lbl.pdf
3. Modi S, Saura C, Yamashita T, et al; DESTI- NY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510