FDA Approves Datopotamab Deruxtecan for Unresectable or Metastatic HR+/HER2-Negative Breast Cancer

The FDA has approved datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) for adult patients with unresectable or metastatic, hormone receptor–positive, HER2-negative breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

The regulatory decision was supported by data from the phase 3 TROPION-Breast01 trial (NCT05104866), which showed that patients treated with Dato-DXd (n = 365) experienced a median progression-free survival (PFS) of 6.9 months (95% CI, 5.7-7.4) vs 4.9 months (95% CI, 4.2-5.5) for those given chemotherapy (n = 367; HR, 0.63; 95% CI, 0.52-0.76; 2-sided P < .0001).1,2

The median overall survival was 18.6 months (95% CI, 17.3-20.1) in the Dato-DXd arm compared with 18.3 months (95% CI, 17.3-20.5) in the chemotherapy arm (HR, 1.01; 95% CI, 0.83-1.22). The 2-sided P value was not statistically significant.1

TROPION-Breast01 was a multicenter, open-label, randomized trial that enrolled patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who experienced disease progression, were deemed unsuitable for further endocrine therapy, and had received 1 to 2 lines of prior chemotherapy for unresectable or metastatic disease.1,2 An ECOG performance status of 0 or 1 was also required.2

Patients were excluded if they had a history of interstitial lung disease (ILD)/pneumonitis requiring steroids; ongoing ILD/pneumonitis; clinically active brain metastases; or clinically significant corneal disease.1

Patients were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg once every 3 weeks or investigator's choice of chemotherapy until disease progression or unacceptable toxicity.2

Stratification factors included lines of chemotherapy in the unresectable/metastatic setting (1 vs 2), geographic location (US/Canada/Europe vs rest of the world), and previous treatment with a CDK4/6 inhibitor (yes vs no).

PFS per blinded independent central review and OS served as the trial's primary end points. Secondary end points included overall response rate (ORR), investigator-assessed PFS, and safety.

Additional data showed that patients treated with Dato-DXd experienced a confirmed ORR of 36% (95% CI, 31%-42%) vs 23% (95% CI, 19%-28%) for those given chemotherapy.1 The median durations of response were 6.7 months (95% CI, 5.6-9.8) and 5.7 months (95% CI, 4.9-6.8), respectively.

The most common adverse effects (AEs) reported in at least 20% of patients included stomatitis, nausea, fatigue, decreased leukocyte counts, decreased calcium levels, alopecia, decreased lymphocyte counts, decreased hemoglobin levels, constipation, decreased neutrophil counts, dry eye, vomiting, increased ALT levels, keratitis, increased AST levels, and increased alkaline phosphatase.

Regarding AEs of special interest, oral mucositis/stomatitis led to treatment discontinuation in 1 patient treated with Dato-DXd.2 Most ocular AEs were dry eye, and 1 patient discontinued Dato-DXd due to an ocular AE. Adjudicated drug-related ILD occurred at any grade in 3% of patients in the experimental arm, including 1% of patients who experienced grade 3 or higher adjudicated drug-related ILD.

The recommended dose of Dato-DXd is 6 mg/kg—with a maximum of 540 mg for patients weighing at least 90 kg—given once every 3 weeks until disease progression or unacceptable toxicity.1

Along with approving the indication for Dato-DXd in breast cancer, in January 2024, the FDA granted priority review to the biologics license application (BLA) seeking the approval of the agent for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer who have received prior systemic therapies, including an EGFR-directed therapy.3 The Prescription Drug User Fee Act action date for the BLA is July 12, 2025.

References

1. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast
2. Bardia A, Jhaveri K, Im S, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015
3. Datopotamab deruxtecan granted priority review in the U.S. for patients with previously treated advanced EGFR-mutated non–small cell lung cancer. News release. Daiichi-Sankyo. January 13, 2025. Accessed January 17, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202501/20250113_E1.pdf