FDA approves Enhertu for HER2-low breast cancer

The FDA approved fam-trastuzumab deruxtecan-nxki for treatment of certain patients with unresectable or metastatic HER2-low breast cancer.

The approval — the first for a targeted therapy to treat HER2-low breast cancer — applies to patients who received prior chemotherapy in the metastatic setting, or those whose disease progressed during or within 6 months of adjuvant chemotherapy.

Fam-trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.

The agent already had been approved in the United States for treatment of adults with metastatic HER2-positive breast cancer who received prior anti-HER2-based therapies, as well as adults with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma who received a prior trastuzumab-based regimen.

Approximately 85% of breast cancer cases among women previously had been classified as HER2-negative, meaning tumors do not overexpress the HER2 protein.

However, more than half of cases once considered HER2-negative now are classified as HER2-low. This newly defined subtype encompasses breast cancers in which some HER2 proteins are on the cell surface, but not enough to be classified as HER2-positive.

Until the expanded approval of fam-trastuzumab deruxtecan-nxki, patients with HER2-low disease received chemotherapy or endocrine therapy.

The FDA approved fam-trastuzumab deruxtecan-nxki for the new indication based on results of the randomized phase 3 DESTINY-Breast04 trial, which included 557 adults with unresectable or metastatic HER2-low breast cancer.

Researchers randomly assigned 373 patients to fam-trastuzumab deruxtecan-nxki via IV infusion every 3 weeks. The other 184 patients received physician’s choice of chemotherapy.

As Healio previously reported, patients assigned fam-trastuzumab deruxtecan-nxki achieved longer PFS and OS.

“[This] approval highlights the FDA’s commitment to be at the forefront of scientific advances, making targeted cancer treatment options available for more patients,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release. “Having therapies that are specially tailored to each patient’s cancer subtype is a priority to ensure access to safe and innovative treatments.”

The most common adverse events reported among patients treated with fam-trastuzumab deruxtecan-nxki included nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain and diarrhea. The prescribing information includes a boxed warning about risk for interstitial lung disease and embryo-fetal toxicity.