Trastuzumab Deruxtecan Promising in Patients with HER2-Positive Breast Cancer and Brain Metastases

February 2022, Vol 13, No 1 Online Only

Second-line therapy with trastuzumab deruxtecan (Enhertu; T-DXd) extended progression-free survival (PFS) and improved objective response rate (ORR) versus trastuzumab emtansine (Kadcyla; T-DM1) in women with HER2-positive metastatic breast cancer, including those with stable brain metastasis at baseline, according to a subgroup analysis of a phase 3 clinical trial. These findings were presented at the 2021 San Antonio Breast Cancer Symposium by the study’s lead investigator, Sara Hurvitz, MD, Director, Breast Cancer Clinical Research Program, University of California Los Angeles Jonsson Comprehensive Cancer Center.

“T-DXd demonstrated a consistent efficacy benefit over T-DM1 across patient subgroups and in patients with and without brain metastases. T-DXd is associated with substantial intracranial response and a reduction in central nervous system disease. These data do support T-DXd as a standard for second-line treatment of HER2-positive breast cancer with brain metastasis for patients who have progressed on currently available therapies,” Dr Hurvitz said.

The DESTINY-Breast03 Trial

The randomized, multicenter, open-label, phase 3 DESTINY-Breast03 trial randomized 524 women with HER2-positive metastatic breast cancer whose disease progressed on first-line therapy with trastuzumab (Herceptin) and taxane chemotherapy to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg every 3 weeks. Patients with clinically stable previously treated brain metastases were eligible as long as there were at least 2 weeks between the end of radiotherapy and enrollment. The primary end point of the trial was PFS by independent central review.

Baseline characteristics were well-balanced between the 2 arms. Median age was 54 years. Approximately 50% of patients were treated with 0 to 1 previous lines of therapy in the metastatic setting, and 50% were treated with ≥2 previous treatment regimens. In the T-DXd arm, 99.6% of patients had received previous trastuzumab therapy and 62.1% had received previous pertuzumab (Perjeta) therapy; these rates were 99.6% versus 60.1%, respectively, in the T-DM1 arm. At baseline, 16.5% of patients in the T-DXd group and 14.8% of those in the T-DM1 group had brain metastases.

Findings from the primary analysis of the trial, which were presented at the 2021 European Society for Medical Oncology annual meeting, showed that treatment with T-DXd prolonged PFS by 72% compared with T-DM1. The median PFS duration was not reached in the T-DXd arm and was 6.8 months in the T-DM1 arm, with estimated 12-month rates of 75.8% and 34.1%, respectively.

Dr Hurvitz called these primary results “phenomenal and practice-changing,” according to a news release from the University of California Los Angeles at the time of the presentation.

Although median overall survival was not evaluable in either arm, the estimated 12-month overall survival rates were 94.1% for T-DXd versus 85.9% for T-DM1. The confirmed ORRs were 79.7% and 34.2%, respectively. Nearly twice as many complete responses occurred in the T-DXd arm compared with the T-DM1 arm (16.1% vs 8.7%, respectively).

Updated Findings

Updated results from a subgroup analysis demonstrated that the PFS and ORR data also favored T-DXd across patient subgroups regardless of hormone receptor status, previous pertuzumab treatment, visceral disease, previous lines of therapy, and brain metastases. Dr Hurvitz also noted that T-DXd appeared to be surprisingly effective in patients who had stable brain metastases when they joined the study.

Among patients with brain metastases, the confirmed ORR was 67.4% (95% confidence interval [CI], 51.5%-80.9%) with T-DXd versus 20.5% (95% CI, 9.3%-36.5%) with T-DM1. Among patients without brain metastases, the confirmed ORR was 82.1% (95% CI, 76.4%-87.0%) versus 36.6% (95% CI, 30.3%-43.3%), respectively.

Regarding intracranial responses, the complete response rate was 27.8% with T-DXd versus 2.8% with T-DM1. The intracranial partial response rates were 36.1% versus 30.6%, respectively. T-DXd also led to a lower rate of intracranial progressive disease versus T-DM1, at 2.8% versus 22.2%, respectively.

Safety Profile

Treatment with T-DXd was associated with a manageable safety profile, with a similar rate of all adverse events (AEs) and grade ≥3 AEs compared with T-DM1. The most common grade ≥3 AEs in the T-DXd arm were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%), anemia (5.8%), and fatigue (5.1%). Drug-related interstitial lung disease was more common in the T-DXd arm than in the T-DM1 arm (10.5% vs 1.9%, respectively). However, most of these events were grade 1 or 2 in severity, with only 2 grade 3 cases in the T-DXd arm and no grade 4 or 5 cases in either arm.

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