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January 19, 2025 – The US Food and Drug Administration (FDA) has approved a novel therapy, datopotamab deruxtecan (Dato-DXd), for patients with unresectable or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This innovative treatment is specifically indicated for individuals who have undergone prior endocrine-based therapy and chemotherapy for their advanced disease.
Developed by Daiichi Sankyo in collaboration with AstraZeneca, this approval marks the first for Dato-DXd in the United States. The therapy is a Trop-2-directed antibody drug conjugate (ADC) combined with a topoisomerase inhibitor. Its approval is based on promising results from the TROPION-Breast01 trial, a large-scale, randomized, multicenter study involving 732 patients unsuitable for further endocrine therapy and who had received up to two lines of prior chemotherapy.
Significant Clinical Benefits
The trial demonstrated that Dato-DXd significantly improved progression-free survival (PFS) compared to standard chemotherapy options like eribulin, capecitabine, vinorelbine, or gemcitabine.
- Median PFS: 6.9 months for Dato-DXd vs. 4.9 months for chemotherapy (hazard ratio [HR], 0.63).
- Overall Response Rate (ORR): 36% for Dato-DXd compared to 23% for chemotherapy.
- Median Duration of Response: 6.7 months vs. 5.7 months, respectively.
While overall survival did not differ significantly (18.6 months for Dato-DXd vs. 18.3 months for chemotherapy), the lower toxicity profile of Dato-DXd provided a notable advantage. Patients receiving the ADC experienced fewer grade 3 or higher toxicities and required fewer dose reductions or interruptions than those on chemotherapy.
Adverse Reactions and Recommended Dose
Common side effects (≥20% of patients) included stomatitis, nausea, fatigue, hair loss, and various laboratory abnormalities. Despite these, the ADC was better tolerated overall. The recommended dose is 6 mg/kg, up to a maximum of 540 mg for patients ≥90 kg, administered via intravenous infusion every three weeks until disease progression or unacceptable toxicity.
Global Impact and Ongoing Development
Dato-DXd was first approved in Japan in December 2024 and is under priority review by the FDA for non-small cell lung cancer (NSCLC). A comprehensive global clinical development program is underway, with over 20 trials evaluating its efficacy and safety across multiple cancers, including NSCLC, triple-negative breast cancer (TNBC), and HR-positive, HER2-low or HER2-negative breast cancer.
Expert Insights
Speaking at the 2023 European Society of Medical Oncology Congress, Dr. Aditya Bardia, MD, MPH, highlighted the significant clinical benefits of Dato-DXd, particularly in reducing toxicities compared to standard chemotherapy.
The approval of Dato-DXd ushers in a new era of hope for patients battling HR+, HER2- breast cancer, offering improved treatment outcomes and a more manageable side-effect profile. This advancement underscores the potential of ADCs to revolutionize cancer care.
