The CHMP recommended EU approval of T-DXd plus pertuzumab as first-line therapy for HER2-positive metastatic breast cancer,
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval in the European Union (EU) of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or ISH+) breast cancer.¹
The recommendation is based on results from the phase 3 DESTINY-Breast09 trial (NCT04784715), which showed that T-DXd plus pertuzumab reduced the risk of disease progression or death by 44% vs a taxane, trastuzumab, and pertuzumab (THP; HR, 0.56; 95% CI, 0.44-0.71; P < .00001) in patients who had not received prior chemotherapy or HER2-targeted therapy, or who had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before an advanced or metastatic diagnosis (n = 383). If approved by the European Commission, the combination would become the first new first-line treatment option for this population in the EU in more than a decade.
Median progression-free survival (PFS) by blinded independent central review (BICR) was 40.7 months (95% CI, 36.5-not estimable [NE]) with T-DXd plus pertuzumab vs 26.9 months (95% CI, 21.8-NE) with THP. The PFS benefit was consistent across prespecified stratification factors, including hormone receptor status, de novo or recurrent disease, and PIK3CA mutation status.¹
"[T-DXd] in combination with pertuzumab improved progression-free survival by more than one year compared with the current first-line standard of care, representing a meaningful advantage early in the treatment of patients with metastatic HER2-positive disease," John Tsai, MD, said.
DESTINY-Breast09 was a global, multicenter, randomized, open-label phase 3 trial evaluating T-DXd at 5.4 mg/kg, either alone or in combination with pertuzumab vs THP as first-line treatment in patients with HER2-positive metastatic breast cancer.¹
Patients (n = 1157) across sites in Africa, Asia, Europe, North America, and South America were randomly assigned 1:1:1 to T-DXd monotherapy with a pertuzumab-matching placebo, T-DXd plus pertuzumab, or THP, with random assignment stratified by prior treatment setting (de novo metastatic disease vs progression from early-stage disease), hormone receptor status, and PIK3CA mutation status.
The primary end point was PFS by BICR in both the T-DXd monotherapy and combination arms vs THP. Secondary end points include investigator-assessed PFS, overall survival, objective response rate (ORR), duration of response (DOR), pharmacokinetics, and safety.
Confirmed ORR was 85.1% (95% CI, 81.2%-88.5%) with T-DXd plus pertuzumab vs 78.6% (95% CI, 74.1%-82.5%) with THP.¹ Complete responses occurred in 58 patients (15.1%) in the combination arm vs 33 patients (8.5%) with THP, while partial response rates were similar between arms at 268 (70.0%) and 271 (70.0%), respectively.¹ Median DOR exceeded 3 years at 39.2 months with Enhertu plus pertuzumab compared with 26.4 months with THP.¹
The safety profile of T-DXd plus pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual agent, with no new safety signals identified.¹ Among patients treated with the combination (n = 381), the most common grade 3 or higher treatment-related adverse events were neutropenia (23.9%), hypokalemia (10.2%), and anemia (8.4%).
Interstitial lung disease (ILD) or pneumonitis, as determined by an independent adjudication committee, occurred in 12.1% of patients treated with T-DXd plus pertuzumab; most cases were low grade (grade 1, 4.5%; grade 2, 7.1%). Two grade 5 events of ILD or pneumonitis (0.5%) were reported in the combination arm.
“HER2-positive metastatic breast cancer is an aggressive subtype, so starting patients on an effective HER2-targeted treatment early and continuing it for as long as they benefit can have a meaningful impact on long-term outcomes,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Hematology R&D at AstraZeneca, added in the news release. “DESTINY-Breast09 sets a new benchmark with a median progression-free survival of more than three years, underscoring the potential of [T-DXd] plus pertuzumab to redefine first-line treatment for patients with HER2-positive metastatic breast cancer.”
