On December 15, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test.
The FDA also approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for selecting patients for treatment with T-DXd in combination with pertuzumab.
DESTINY-Breast09
Efficacy was evaluated in DESTINY-Breast09 (ClinicalTrials.gov identifier NCT04784715), a randomized, three-arm, multicenter, global trial that enrolled 1,157 adults with HER2-positive advanced or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before the diagnosis of advanced or metastatic disease. A single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer.
Patients were randomly assigned 1:1:1 to receive T-DXd at 5.4 mg/kg plus pertuzumab (n = 383), THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab; n = 387), or an investigational therapy (n = 387) by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.
The major efficacy outcome measure was progression-free survival as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors version 1.1; additional efficacy outcome measures were overall survival and confirmed objective response rate assessed by BICR. Median progression-free survival was 40.7 months (95% confidence interval [CI] = 36.5 months to not estimable) in the T-DXd plus pertuzumab arm and 26.9 months (95% CI = 21.8 months to not evaluable) in the THP arm (hazard ratio = 0.56, 95% CI = 0.44–0.71, P < .0001). Confirmed objective response rate was 87% (95% CI = 83%–90%) and 81% (95% CI = 77%–85%) in the respective arms. At the time of the progression-free survival analysis, overall survival data were not mature, with 126 (16%) of patients who died across both study arms in the overall population.
The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.
The recommended T-DXd dose for cycle 1, day 1 is 5.4 mg/kg, followed by pertuzumab at 840 mg. For subsequent cycles, the recommended T-DXd dose is 5.4 mg/kg, followed by pertuzumab at 420 mg by intravenous infusion every 3 weeks.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This also review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review. T-DXd in combination with pertuzumab was granted Breakthrough Therapy designation.
