FDA Approves New Treatment for HER2-positive Breast Cancer

The U.S. Food and Drug Administration (FDA) approved a new molecularly targeted therapeutic called fam-trastuzumab deruxtecan-nxki (Enhertu) for treating certain patients with breast cancer on Dec. 20, 2019. Specifically, it was approved for treating adults who have unresectable or metastatic HER2-positive breast cancer that has progressed despite treatment with two or more other HER2-targeted treatment regimens after the diagnosis of metastatic disease.

Treatment-resistant breast cancer cells. Image courtesy of the National Cancer Institute.

Just days before the FDA decision regarding fam-trastuzumab deruxtecan-nxki, Ian Krop, MD, PhD, debuted the data underpinning the approval during the San Antonio Breast Cancer Symposium (SABCS), which is hosted by UT Health San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine.

An estimated 268,600 women in the United States were newly diagnosed with breast cancer in 2019, according to statistics from the National Cancer Institute (NCI). About 15 percent of women diagnosed with breast cancer have tumors characterized by high levels of HER2. For most of these women, a HER2-targeted therapeutic forms a central part of their treatment regimen.

Krop explained the need for new HER2-targeted therapeutics in an AACR press release, saying: “Although HER-2 directed therapies such as trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1 (Kadcyla) have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs.”

Fam-trastuzumab deruxtecan-nxki is a type of molecularly targeted therapeutic known as an antibody-drug conjugate. It comprises a cytotoxic agent, deruxtecan, attached to the HER2-targeted antibody trastuzumab by a linker. When the antibody attaches to HER2 on the surface of breast cancer cells, the antibody-drug conjugate is internalized by the cells. This leads to deruxtecan being released from the linker and antibody. Once free, the deruxtecan is toxic to the breast cancer cells, which ultimately die.

The approval of fam-trastuzumab deruxtecan-nxki was based on results from the phase II DESTINY-Breast01 clinical trial, which were published in the New England Journal of Medicine at the same time that Krop presented them at SABCS. The results showed that just over 60 percent of the 184 patients enrolled on the trial who received the recommended dose of fam-trastuzumab deruxtecan-nxki had partial or complete tumor shrinkage and that the median time before disease progression was 16.4 months.

Ian Krop, MD, PhD. Photo by Sam Ogden.

“Both of these measures of efficacy are substantially higher than that seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” Krop said in the AACR press release. The women included in this analysis had received a median of six previous treatments. Krop added in an Associated Press article about the study that, “to see anything hold such serious cancers at bay for more than a year is exciting.”

The new treatment was not without serious side effects, however, with 57 percent of patients having treatment-emergent adverse events of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue. In addition, 25 patients had interstitial lung disease, four of whom died as a result of the side effect. Thus, the FDA approved fam-trastuzumab deruxtecan-nxki with a boxed warning for interstitial lung disease.

Krop explained in the AACR press release that because of this potential toxicity, close monitoring for signs and symptoms of interstitial lung disease is recommended for early detection. If the side effect is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests, and if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended, he said.

In the Associated Press article, Jennifer Litton, MD, a breast cancer expert not involved in the study, said, “It’s worth the risk because the drug’s benefit is so great.”

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