Oncology Overview: Fam-trastuzumab Deruxtecan-nxki (Enhertu) for HER2-Positive Breast Cancer, Gastric Adenocarcinoma

In December 2019, fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo) received accelerated approval for adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting.

In May 2022, the FDA granted regular approval with an updated indication for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.¹

In January 2021, the FDA approved fam-trastuzumab deruxtecan-nxki for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.²

Clinical Studies

DESTINY-Breast01 study results lead to fam-trastuzumab deruxtecan-nxki’s initial approval. The clinical trial enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer, who had received 2 or more prior anti-HER2 therapies in the metastatic setting.

These patients were heavily pretreated in the metastatic setting, receiving up to 17 therapies prior to receiving fam-trastuzumab deruxtecan-nxki every 3 weeks. Researchers measured tumor shrinkage by imaging every 6 weeks. The objective response rate (ORR) was 60.3% of patients with a median response duration of 14.8 months.^3,4

The clinical trial, DESTINY-Breast03, further measured efficacy by enrolling 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. Researchers randomized patients 1:1 to receive fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression occurred.

The ORR based on patients with measurable disease was 82.7% for those receiving fam-trastuzumab deruxtecan-nxki and 36.1% for those receiving ado-trastuzumab emtansine.^1,4

DESTINY-Gastric01 measured efficacy in 188 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least 2 prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy.

Researchers randomized patients 2:1 to receive fam-trastuzumab deruxtecan-nxki intravenously every 3 weeks or physician’s choice of irinotecan every 2 weeks or paclitaxel weekly. The fam-trastuzumab deruxtecan-nxki arm had a confirmed ORR of 40.5% compared with 11.3% for patients receiving irinotecan or paclitaxel.^2,4

Mechanism of Action^3,4

Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate. The humanized anti-HER2 IgG1 antibody trastuzumab is attached to the small molecule, deruxtecan (DXd), by a cleavable linker. Trastuzumab binds to HER2 on tumor cells and blocks growth. The tumor cell internalizes the antibody, and lysosomal enzymes cleave off DXd. DXd causes DNA damage during replication and apoptotic cell death as a topoisomerase I inhibitor.

Dosage and Administration⁴

Clinicians should not substitute fam-trastuzumab deruxtecan-nxki for or with trastuzumab or ado-trastuzumab emtansine. The patient should premedicate with antiemetic medications to prevent chemotherapy-induced nausea and vomiting. Managing adverse effects (AEs) may require temporary interruption, dose reduction, or discontinuation of fam-trastuzumab deruxtecan-nxki.

The recommended dosage is 5.4 mg/kg for breast cancer and 6.4 mg/kg for gastric cancer given by intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

AEs⁴

The most common AEs (incidence 20% or greater) were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, increased aspartate aminotransferase, fatigue, decreased lymphocyte count, vomiting, decreased platelet count, increased blood alkaline phosphatase, alopecia, constipation, hypokalemia, decreased appetite, and diarrhea.

Warnings and Precautions⁴

The prescribing information has a boxed warning for interstitial lung disease (ILD). ILD and pneumonitis, including fatal cases, have been reported with fam-trastuzumab deruxtecan-nxki. Clinicians should monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms.

Clinicians should counsel patients of the risk and to immediately report symptoms. Patients with grade 2 or higher ILD/pneumonitis should permanently discontinue treatment.

Patients can develop severe neutropenia, including febrile neutropenia when treated with fam-trastuzumab deruxtecan-nxki. Clinicians should monitor complete blood counts prior to treatment initiation, prior to each dose, and as clinically indicated. Neutropenia severity may influence dose interruption or reduction.

Patients treated with fam-trastuzumab deruxtecan-nxki may experience decreased left ventricular ejection fraction (LVEF). Clinicians should assess LVEF prior to treatment initiation and at regular intervals as clinically indicated.

Treatment should be interrupted if LVEF decreases and permanently discontinued if clinicians confirm LVEF of less than 40% or absolute decrease from baseline of greater than 20%. Patients with symptomatic congestive heart failure should permanently discontinue treatment.

Pregnancy and Lactation⁴

Pregnancy data are not available. The prescribing information has a boxed warning for embryo-fetal toxicity.

The topoisomerase inhibitor component of fam-trastuzumab deruxtecan-nxki, DXd, targets actively dividing cells and damages DNA, which can cause embryo-fetal harm when administered to a pregnant woman. Females of reproductive potential should verify pregnancy status prior to treatment initiation and use effective contraception during treatment and for at least 7 months following the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 4 months after the last dose.

No data are available regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, breastfeeding, or milk production. Mothers should not breastfeed during treatment and for 7 months after the last dose to avoid serious AEs in children.

About the Author

Wendy La, PharmD, is a clinical pharmacist at Elixir, a pharmacy benefits subsidiary of Rite Aid.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. U.S. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer. Accessed May 22, 2022.
2. FDA approves Enhertu for her2-positive gastric adenocarcinomas. U.S. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas. Accessed May 22, 2022.
3. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed May 22, 2022.
4. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed May 22, 2022.