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The European Medicines Agency has validated a Type II Variation application for trastuzumab deruxtecan as monotherapy for adults with unresectable or metastatic HER2-low breast cancer.
The European Medicines Agency (EMA) has validated a Type II Variation application for fam-trastuzumab deruxtecan-nxki (Enhertu) as monotherapy for adults with unresectable or metastatic HER2-low breast cancer. Daiichi-Sankyo announced the move in a press release June 22, 2022.1
Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). A Type II variation represents a major change to a drugs marketing authorization that may have a significant impact on the quality, safety or efficacy of a medicine, but does not involve a change to the active substance, strength, or method of administration. Such a change requires a formal approval.2 The CHMP typically releases an opinion, or requests more information on a Type II application, 60 days after initiating the evaluation.3
The HER2-directed antibody drug conjugate (ADC) would be available for patients who have received systemic therapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Those with hormone receptor (HR)–positive breast cancer must also have received or be ineligible for endocrine therapy.
The company based this application on findings from the phase 3 DESTINY-Breast04 trial (NCT03734029) presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.4,5
“The DESTINY-Breast04 data established patients with HER2-low disease as a targetable population, and these data are going to compel us to rethink subgroups within the HER2-negative category of breast cancer,” lead author Shanu Modi, MD a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a previous interview with OncLive®. “These findings are specific to the drug trastuzumab deruxtecan. This is our new standard of care for this population of patients. It is exciting that we’ve been able to now translate HER2-targeted therapy to a broader group of patients with HER2-expressing breast cancer.”
In the trial, 557 patients were randomly assigned to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy consisted of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).
Low expression of HER2 was defined as an immunohistochemistry score of 1+ or 2+ with a negative in situ hybridization test, representing approximately 65% of breast cancer diagnoses. Overall, 88.7% of patients were HR positive and 11.3% were negative.
In those with HR-positive, HER2-low disease, trastuzumab deruxtecan induced a median progression-free survival (PFS) of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; P = .003).
The median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan across the entire study population compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this group was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the ADC (HR, 0.64; 95% CI, 0.49-0.84; P = .001).
In patients with HR-negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the HR-negative cohort was 18.2 months (95% CI, 13.6-not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).
In patients with HR-positive disease who received prior treatment with a CDK4/6 inhibitor, the median PFS was 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan compared with 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). For those with hormone receptor-positive disease who did not receive a CDK4/6 inhibitor, the median PFS was 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64).
In April 2022, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for this patient population based on findings from DESTINY-Breast04. The agency previously granted that designation to the ADC for the treatment of second-line HER2-positive metastatic breast cancer in 2021 and later-line HER2-positive metastatic breast cancer in 2017.6