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The European Medicines Agency has validated the marketing authorization application for trastuzumab duocarmazine for the treatment of patients with HER2-positive unresectable, locally advanced or metastatic breast cancer.
The European Medicines Agency (EMA) has validated the marketing authorization application (MAA) for vic-trastuzumab duocarmazine (SYD985) for the treatment of patients with HER2-positive unresectable, locally advanced or metastatic breast cancer.1
The MAA is based on data from the phase 3 TULIP trial (NCT03262935), where the anti-HER2 antibody-drug conjugate (ADC) demonstrated a significant improvement in progression-free survival (PFS) vs physician’s choice of therapy in patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer, meeting the primary end point of the trial.2
Per central review, trastuzumab duocarmazine achieved a median PFS of 7.0 months (95% CI, 5.4-7.2) compared with 4.9 months (95% CI, 4.0-5.5) for physician’s choice of therapy (HR, 0.64; 95% CI, 0.49-0.84; P = .002). The investigator-assessed median PFS was 6.9 months (95% CI, 6.0-7.2) for trastuzumab duocarmazine vs 4.6 months (95% CI, 4.0-5.6) for physician’s choice of therapy (HR, 0.60; 95% CI, 0.47-0.77; P < .001).
“The MAA validation is an important step forward in our mission to make hope real for patients," Marco Timmers, PhD, chief executive officer of Byondis, stated in a press release. “About 1 in 5 breast cancers are HER2-positive, often resulting in a more aggressive disease. There is a dire need to provide an alternative treatment option to these patients.”
The investigational next-generation, HER2-directed ADC received fast track designation from the FDA in January 2018 based on phase 1 data (NCT02277717) in heavily pretreated patients with HER2-positive metastatic breast cancer.3 Previously in July 2022, the FDA accepted for review a biologics license application for trastuzumab duocarmazine for the treatment of patients with HER2-positive unresectable, locally advanced or metastatic breast cancer, based on data from TULIP.4
The multi-center, open-label TULIP trial enrolled patients who had received at least 2 prior therapies or ado-trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting. Once enrolled, investigators randomly assigned patients to 1.2 mg/kg of intravenous trastuzumab duocarmazine (n = 291) every 21 days or physician’s choice of treatment (n = 146) until disease progression or unacceptable toxicity.
Physician’s choice of treatment included lapatinib (Tykerb) plus capecitabine (Xeloda), trastuzumab (Herceptin) plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin.
Along with the primary end point of centrally assessed PFS, secondary end points included investigator-assessed PFS, overall survival (OS), overall response rate (ORR), and health-related quality of life.
The median patient age was 57 years (range, 24-86). Most patients were White (69.4% vs 65.1% in the experimental and control arms, respectively) and had received prior treatment with trastuzumab (89.3% vs 86.3%), T-DM1 (87.6% vs 87.7%), and pertuzumab (Perjeta; 60.8% vs 57.5%). The median number of prior therapies was 4 (range, 1-16) and 5 (range, 1-14), respectively.
Additional data showed trastuzumab duocarmazine produced a median OS of 20.4 months (95% CI, 18.0-23.7) compared with 16.3 months (95% CI, 13.4-22.8) with physician’s choice of treatment (HR, 0.83; 95% CI, 0.62-1.09; P = .153).
The ORR was 27.8% vs 29.5% for trastuzumab duocarmazine and physician’s choice, respectively. Clinical benefit rates were 38.5% and 32.2%, respectively.
Investigators observed grade 3 or higher treatment-related adverse effects (TRAEs) in 52.8% of patients in the trastuzumab duocarmazine arm vs 48.2% in the physician’s choice arm. The most common grade 3 or higher TRAEs with the ADC were keratitis (12.2%), conjunctivitis (5.6%), and neutropenia (4.9%). The most common grade 3 or higher TRAEs with physician’s choice included neutropenia (18.2%), palmar-plantar erythrodysesthesia syndrome (3.6%), and diarrhea (2.2%).
Interstitial lung disease (ILD) and pneumonitis of any grade occurred in 7.6% of patients in the trastuzumab duocarmazine arm, including grade 3 or higher in 2.4% of patients. There was no incidence of ILD/pneumonitis in the control arm. ILD/pneumonitis led to treatment discontinuation in 5.2% of patients who received trastuzumab duocarmazine and dose modifications in 2.1%.
Notably, investigators reported no deaths in the control arm compared with 6 in the experimental arm. Four of those deaths were attributed to treatment-related: 1 incidence each of respiratory failure and pneumonia and 2 cases of pneumonitis. Two deaths were due to acute respiratory failure (n = 1) and COVID-19 pneumonia (n = 1) unrelated to the study treatment.