Trastuzumab deruxtecan is a HER2-targeted tyrosine kinase inhibitor (TKI), which Hamilton said is most commonly given in the third- or fourth-line setting. Although there is an ongoing debate among clinicians over whether to use trastuzumab deruxtecan or tucatinib first, Hamilton said she uses both depending on the patient.
The DESTINY Breast01 trial found a median duration of response of 14.8 months in heavily pre-treated patients who received trastuzumab deruxtecan, according to Hamilton’s presentation. Based on these findings, it received accelerated approval in December 2019 for HER2-positive breast cancer patients who have received at least 2 prior HER2-targeted therapies in the metastatic setting.
When implementing trastuzumab deruxtecan into practice, Hamilton said it is important to consider pre-mediating for nausea. Although this is not mandated, she said that most clinicians pre-medicate for nausea because it is the primary adverse effect.
Patients also frequently report fatigue and alopecia. Notably, clinicians should carefully monitor for interstitial lung disease (ILD) and should educate patients on its signs and symptoms, which can include cough, shortness of breath, and new breathing or respiratory problems. Detecting ILD as early as possible is essential, Hamilton said, so clinicians should ask patients about these symptoms at every opportunity.
Next, Hamilton discussed the 2020 approval of tucatinib for the treatment of HER2-positive breast cancer in combination with capecitabine and trastuzumab. Like trastuzumab deruxtecan, tucatinib is a TKI. However, Hamilton said it is notable because it is highly selective for HER2, making it a uniquely targeted treatment.
The HER2CLIMB trial found improvements in overall response rate from 23% to 41%, as well as improvements in overall survival from 17.4 months to 21.9 months. Tucatinib is typically used in the third or fourth line, although is it also approved for use in the second line. For this use, Hamilton said she would typically use tucatinib in patients with active brain metastases.
The most common adverse effect (AE) in the HER2CLIMB trial included diarrhea, hand-foot syndrome, nausea, and fatigue. When tucatinib is used in combination with capecitabine, diarrhea can increase compared to capecitabine alone. The majority of diarrhea is grade 1 or 2, so Hamilton said she typically does not start treatment for diarrhea prophylactically. If dose reductions are needed to manage diarrhea, she recommended reducing capecitabine before reducing tucatinib.
Finally, Hamilton outlined use of margetuximab for patients with HER2-driven metastatic breast cancer. In combination with chemotherapy in the SOPHIA trial, investigators found a progression-free survival improvement of 4.9 months to 5.8 months. Based on these findings, it was approved by the FDA in December 2020 for patients who have received at least 2 prior HER2 regimens for metastatic breast cancer.
Common AEs include fatigue, nausea, neutropenia, diarrhea, and anemia. Hamilton added that infusion-related reactions are a specific AE of special interest. In clinical trials, these reactions were typically grade 1 or 2 and occurred on day 1 of cycle 1. They can be treated by slowing the rate of infusion or stopping the infusion and can be pre-medicated similarly to other infusion-related events.
With these 3 recent approvals, Hamilton said patients with HER2-positive breast cancer have important, new treatment options as they reach later stages of the disease. Although trastuzumab deruxtecan has emerged as the new standard third-line option, Hamilton said tucatinib has impressive central nervous system activity, meaning it could be efficacious in patients with brain metastases. Finally, she said trastuzumab deruxtecan has an almost universal clinical benefit rate, especially in patients who have received multiple prior regimens.
REFERENCE
Hamilton E. FDA Approvals and Their Incorporation into Clinical Practice. Presented at: ASCO 2021 Annual Meeting. June 4, 2021. Accessed June 7, 2021.
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