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The European Commission has approved fam-trastuzumab deruxtecan-nxki for use as a single agent in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least 1 anti–HER2-based regimen.
The European Commission has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for use as a single agent in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least 1 anti–HER2-based regimen.1
The regulatory decision is supported by findings from the phase 3 DESTINY-Breast03 trial, in which trastuzumab deruxtecan significantly improved progression-free survival (PFS) vs trastuzumab emtansine (T-DM1; Kadcyla), with a median PFS that was not yet reached (95% CI, 18.5–not estimable [NE]) per blinded independent central review (BICR) vs 6.8 months (95% CI, 5.6-8.2) with trastuzumab emtansine), translating to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.22-0.37; P < .001).2
“This approval is an important milestone for patients and clinicians in Europe, since previously treated patients with HER2-positive metastatic breast cancer typically experience disease progression in less than 1 year with historical standard-of-care treatment,” Javier Cortés, MD, PhD, head of International Breast Cancer Center in Barcelona, Spain, stated in a press release. “In the DESTINY-Breast03 trial, the time to progression was extended well beyond 1 year for patients receiving [trastuzumab deruxtecan], illustrating the potential for this medicine to set a new benchmark in the treatment of HER2-positive metastatic breast cancer.”
The multicenter, open-label, randomized, active-controlled trial enrolled patients with HER2-positive, unresectable or metastatic breast cancer that had progressed during or following treatment with trastuzumab (Herceptin) and a taxane in the context of advanced or metastatic disease or who had progressed within 6 months following neoadjuvant or adjuvant treatment involving trastuzumab or a taxane. Those with clinically stable, previously treated brain metastases were permitted.
Patients could not have previously received a HER2-targeted antibody-drug conjugate in the context of metastatic disease, nor could they have a history of noninfectious interstitial lung disease (ILD) for which they were given glucocorticoids. Those with suspected ILD that could not be ruled out via imaging, were also excluded.
Study participants were randomized 1:1 to receive intravenous (IV) trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) or IV trastuzumab emtansine at 3.6 mg/kg every 3 weeks (n = 263).
PFS per BICR served as the primary end point of the trial. A key secondary end point was overall survival (OS). Other secondary end points comprised overall response, PFS per investigator assessment, and safety.
Demographic and baseline disease characteristics were observed to be comparable between the treatment arms, and to be mostly representative of the overall HER2-positive breast cancer population.
The median number of prior lines of therapy received in the investigative and control arms were 1 (range, 0-16) and 2 (range, 0-14), respectively. In the trastuzumab deruxtecan arm, 49.8% of patients previously received 1 line of therapy, 21.5% received 2 prior lines, 13.4% received 3 prior lines, 5.7% received 4 prior lines, and 8.8% received 5 or more prior lines; in the trastuzumab emtansine arm, these rates were 46.8%, 24.7%, 13.3%, 7.2%, and 6.8%, respectively.
Moreover, in the investigative arm, 99.6% previously received trastuzumab, 62.1% received prior pertuzumab (Perjeta), 99.6% previously received a taxane, 16.1% received a prior anti-HER2 antibody, 41.8% received hormone therapy, and 99.6% received another systemic treatment; these rates were 99.6%, 60.1%, 99.6%, 14.4%, 42.6%, and 99.6%, respectively, in the control arm.
Additional data published in the New England Journal of Medicine showed that the percentage of patients who were alive without disease progression at 12 months in the trastuzumab deruxtecan arm was 75.8% (95% CI, 69.8%-80.7%) per BICR vs 34.1% (95% CI, 27.7%-40.5%) with trastuzumab emtansine.
Per investigator assessment, the median PFS in the investigative arm was 25.1 months (95% CI, 22.1-NE) vs 7.2 months (95% CI, 6.8-8.3) in the control arm (HR, 0.26; 95% CI, 0.20-0.35; P < .001). Subgroup analyses also demonstrated an improvement in PFS with trastuzumab deruxtecan over trastuzumab emtansine across all subsets analyzed.
There was a higher percentage of patients alive at 12 months in the investigative arm vs the control arm, at 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%), respectively, although the difference between the arms did not reach the prespecified cutoff for statistical significance (HR, 0.55; 95% CI, 0.36-0.86; P = .007).
Trastuzumab deruxtecan elicited an overall response rate (ORR) of 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%) with trastuzumab emtansine. Among those who responded to treatment in the investigative and control arms, 16.1% and 8.7% of patients, respectively, achieved a complete response; disease progression was the best overall response in 1.1% and 17.5% of patients, respectively.
The median duration of treatment with trastuzumab deruxtecan was 14.3 months (range, 0.7-29.8) vs 6.9 months (range, 0.7-25.1) with trastuzumab emtansine. At the start of treatment, 99.6% of those in the investigative arm experienced adverse effects (AEs) vs 95.4% of those in the control arm; serious AEs occurred in 19.1% and 18.0% of patients, respectively. Grade 3 or higher effects were experienced by 52.1% of those in the investigative arm vs 48.3% in the control arm. More patients who received trastuzumab deruxtecan discontinued treatment due to AEs vs trastuzumab emtansine, at 13.6% vs 7.3%, respectively.
The most frequently experienced AEs that were associated with study treatment in the trastuzumab deruxtecan arm were nausea (72.8%), fatigue (44.7%), and vomiting (44.0%); these rates were lower than what was observed in the trastuzumab emtansine arm (27.6%, 29.5%, and 5.7%, respectively).
The most common grade 3 or higher treatment-related AEs reported in the investigative arm included neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), and nausea (6.6%).