DATO DXD TRIAL
DATO DXD PLUS

The most recent guidelines from the National Comprehensive Cancer Network (NCCN) recommend T-DXd for patients with HER2 IHC 1+ or 2+/ISH-negative metastatic breast cancer who have received prior chemotherapy. Now that T-DXd is approved for use in patients with HER2-low metastatic breast cancer, as of August 5 of this year, many patients can benefit from this agent. This includes patients with HR-positive disease, as well as many patients with HR-negative (ie, triple-negative) disease. PT Beyond the impressive improvements in outcomes observed in the trial, I believe it is important to stress that the HER2-low population that was enrolled in DESTINY-Breast04 reflects a very large population of patients in clinical practice-at least half of patients with metastatic breast cancer.

DATO DXD TRIAL

H&O Could you further discuss what made the results of this trial remarkable? Fortunately, a decrease in the left ventricular ejection fraction occurred in fewer than 5% of the patients in this study. Another adverse event of special concern is cardiotoxicity, so it is important to monitor the left ventricular ejection fraction in these patients. As a result, patients receiving T-DXd must have scans every 6 to 12 weeks to monitor their lung function. This is usually grade 1 or 2 when it occurs, but ILD led to 3 fatalities in this study. The most concerning adverse event with T-DXd remains interstitial lung disease (ILD).

In addition, hematologic toxicities such as neutropenia and anemia occurred with T-DXd, but less often than with traditional chemotherapy. Fatigue was also common with T-DXd in this trial. Fortunately, we are getting better at managing these side effects with prophylactic antiemetics. We did see a fair amount of nausea and vomiting, both of which are very important to address. One problem is that patients experience off-target side effects from the chemotherapy payload delivered by the ADC. The safety profile of T-DXd in this trial was similar to what we have seen with this agent in HER2-positive disease, for which it received approval in 2019. Results were similar in the HR-positive cohort, in which the median PFS was 10.1 months with T-DXd vs 5.4 months with traditional chemotherapy and OS was 23.9 months vs 17.5 months, respectively-a difference of 6.4 months. This was truly remarkable because we do not frequently see improvements in OS in this setting, particularly in a first analysis of study results-so these were very important findings. Overall survival (OS) was also significantly better in the T-DXd group vs the traditional chemotherapy group, at 23.4 vs 16.8 months, respectively-an absolute difference of 6.6 months. This difference represented improvement that was both statistically significant and clinically meaningful. The investigators found that for all patients, the median progression-free survival (PFS) was nearly doubled in the T-DXd group vs the traditional chemotherapy group, at 9.9 vs 5.1 months, respectively. Most patients (88.7%) had HR-positive disease the remaining 11.3% had HR-negative disease. IHC results were based on the most recent biopsy, a previous biopsy, or even the primary tumor.Ī total of 557 patients underwent randomization in a 2:1 ratio to T-DXd or traditional chemotherapy.

DATO DXD PLUS

They were also required to have HER2-low disease, which was defined as either a score of 1+ on immunohistochemistry (IHC) or an IHC score of 2+ plus negative results on in situ hybridization (ISH). Patients were eligible for the trial if they had received 1 or 2 lines of previous chemotherapy, as well as endocrine therapy if they had hormone receptor (HR)–positive disease. Dr Shanu Modi presented the results, which were simultaneously published in the New England Journal of Medicine, at the 2022 American Society of Clinical Oncology (ASCO) annual meeting. The choice of chemotherapy regimen was left to the treating physician and could include taxanes, eribulin, capecitabine, or gemcitabine. T-DXd is an anti-HER2 antibody-drug conjugate (ADC). PT DESTINY-Breast04 was a landmark phase 3 trial that compared trastuzumab deruxtecan, also known as T-DXd (Enhertu, Daiichi-Sankyo/AstraZeneca), with traditional chemotherapy for patients who had pretreated, human epidermal growth factor receptor 2 (HER2)–low metastatic breast cancer. H&O Could you describe the activity and safety results of the DESTINY-Breast04 trial?

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