On December 20, 2019, the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki was granted accelerated approval in the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.1,2
Supporting Efficacy Data
Accelerated approval was based on response rate and duration in the multicenter phase II DESTINY-Breast01 trial (ClinicalTrials.gov identifier NCT03248492).3 In the trial, 184 women with HER2-positive unresectable or metastatic breast cancer who had received two or more prior anti-HER2 therapies received fam-trastuzumab deruxtecan-nxki at 5.4 mg/kg via intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.
Fam-trastuzumab deruxtecan has a boxed warning for interstitial lung disease and embryofetal toxicity.
The median age of study patients was 55 years (range, 28–96 years, 76% < 65 years); 55% were white and 38% were Asian; an Eastern Cooperative Oncology Group performance status was 0 in 55% and 1 in 44%; 92% had visceral disease, 29% bone metastases, and 13% had brain metastases; and 53% had hormone receptor–positive disease. The median number of prior regimens in the locally advanced/metastatic setting was five (range, 2–17); all patients had received trastuzumab and ado-trastuzumab emtansine and 66% had received prior pertuzumab.
The confirmed objective response rate on independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1, was 60.3% (95% confidence interval [CI] = 52.9%–67.4%), with a 4.3% complete response rate. The median response duration was 14.8 months (95% CI = 13.8–16.9 months).
How It Works
Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody and topoisomerase inhibitor ADC. It is composed of three components: a humanized anti-HER2 IgG1 monoclonal antibody covalently linked to a topoisomerase inhibitor via a tetrapeptide-based cleavable linker. Deruxtecan is composed of a protease-cleavable maleimide tetrapeptide linker and the topoisomerase inhibitor DXd, which is an exatecan derivative.
Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.
How It Is Used
Fam-trastuzumab deruxtecan must not be substituted for or with trastuzumab or ado-trastuzumab emtansine.
The recommended dosage of fam-trastuzumab deruxtecan is 5.4 mg/kg via intravenous infusion once every 3 weeks until disease progression or unacceptable toxicity. The first infusion should be given over 90 minutes; subsequent infusions can be given over 30 minutes if prior infusions are well tolerated. Infusion should be slowed or interrupted if infusion-related symptoms develop. Treatment should be permanently discontinued in the case of severe infusion reactions.
Management of adverse reactions may require temporary treatment interruption, dose reduction, or treatment discontinuation. The dose can be reduced to 4.4 mg/kg and then to 3.2 mg/kg; treatment should be discontinued if further dose reduction is required. The dose should not be re-escalated after any dose reduction. Product labeling provides specific instructions for dose modification for and management of interstitial lung disease/pneumonitis, neutropenia, febrile neutropenia, and left-ventricular dysfunction.
Safety data are from 234 patients with unresectable or metastatic HER2-positive breast cancer who received fam-trastuzumab deruxtecan-nxki at 5.4 mg/kg in the DESTINY-Breast01 trial and study DS8201-A-J101 (NCT02564900). The median duration of treatment was 7 months.
The most common adverse events of any grade (≥ 20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%). The most common grade 3 or 4 adverse events included neutropenia (16%), anemia (7%), nausea (7%), fatigue (6%), and leukopenia (6%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (16%), decreased hemoglobin (7%), and decreased white blood cell count (7%).
Serious adverse events occurred in 20% of patients, with those occurring in more than 1% consisting of interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Adverse events led to dose interruptions in 33% of patients and to dose reductions in 18% (most commonly due to fatigue, nausea, and neutropenia). Adverse events led to permanent treatment discontinuation in 9% of patients, most commonly due to interstitial lung disease (6%). Fatal adverse events occurred in 4.3% of patients, including interstitial lung disease in 2.6% and acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock in one patient each.
Fam-trastuzumab deruxtecan has a boxed warning for interstitial lung disease and embryofetal toxicity. Interstitial lung disease and pneumonitis, including fatal cases, have been reported. Patients should be monitored and promptly evaluated for signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Treatment should be permanently discontinued in all patients with grade ≥ 2 interstitial lung disease/pneumonitis. Patients should be advised of the risk and to immediately report symptoms. Exposure to fam-trastuzu-mab deruxtecan during pregnancy can cause embryofetal harm. Patients must be advised of these risks and the need for effective contraception while receiving fam-trastuzumab deruxtecan.
Fam-trastuzumab deruxtecan also carries warnings/precautions for neutropenia and left-ventricular dysfunction. Complete blood cell counts should be monitored prior to initiation of treatment, prior to each dose, and as clinically indicated. Left-ventricular ejection fraction should be assessed prior to treatment and at regular intervals during treatment as clinically indicated. Treatment should be permanently discontinued in patients with symptomatic congestive heart failure. ■
1. U.S. Food and Drug Administration: FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer. Accessed January 13, 2020.
2. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use, Daiichi Sankyo Co, Ltd., December 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf. Accessed January 13, 2020.