The Lynx Group

Trastuzumab Deruxtecan Is a New Standard of Care for Patients with HER2-Low Metastatic Breast Cancer

August 2022, Vol 13, No 4 Online Only

Targeting HER2 with the antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) provided clinically meaningful benefits for patients with HER2-low metastatic breast cancer, according to findings presented at the 2022 American Society of Clinical Oncology Annual Meeting.

In the randomized phase 3 clinical trial DESTINY-Breast04, T-DXd prolonged progression-free survival (PFS) and overall survival (OS) compared with physicians’ choice of standard single-agent chemotherapy, in patients with HER2-low unresectable and/or metastatic breast cancer. At a median follow-up of 18.4 months, the drug induced a 50% risk reduction for disease progression or death (hazard ratio, 0.50; P <.0001). The median PFS was 9.9 months in the T-DXd arm versus 5.1 months in the control arm, and the median OS was 23.4 versus 16.8 months, respectively.

“The strong efficacy of T-DXd [trastuzumab deruxtecan] in this HER2-low patient population supports the need to now reclassify HER2-low as a new therapeutically targetable category of metastatic breast cancer,” said lead investigator Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, NY. “With these results, we have expanded the benefits of HER2-targeted therapy to a new population of patients with breast cancer and have established T-DXd as the new standard of care for patients with HER2-low metastatic breast cancer. These findings have the potential to impact survival for approximately 50% of all patients diagnosed with metastatic breast cancer today,” she added.

HER2 status is currently defined in a binary model, in which HER2-positive breast cancer driven by the HER2 oncogene is treatable with currently available targeted therapies, Dr Modi said. Within the HER2-negative population, tumors with low levels of HER2 expression are classified as HER2-low.

“This low level of HER2 may be targetable by third-generation antibody–drug conjugates,” Dr Modi said. “Historically, we have treated HER2-low breast cancer as HER2-negative breast cancer, where therapy is guided by hormone receptor [HR] status. Ultimately, all patients with HER2-low metastatic breast cancer, both hormone-positive and -negative, have limited options in the late-line setting and are typically treated with palliative single-agent chemotherapy. This offers only modest benefits,” she explained.

Study Details

DESTINY-Breast04 was an open-label, multicenter study of 557 patients with centrally confirmed HER2-low metastatic breast cancer who had received 1 or 2 lines of chemotherapy in the metastatic setting. All patients had received a median of 3 lines of systemic therapy, including 1 line of chemotherapy and 2 lines of endocrine therapy. Approximately 80% of patients in each arm had received targeted therapy.

Patients were randomized in a 2:1 ratio to T-DXd 5.4 mg/kg or to single-agent chemotherapy. The primary end point of the trial was PFS. At the data cutoff of January 11, 2022, 58 (15.6%) patients in the T-DXd arm and 3 (1.7%) in the chemotherapy arm remained on treatment. The rates of progressive disease were 59.3% versus 75.6%, respectively.

The PFS and OS advantage with T-DXd was similar in the patients with HR-positive disease and in the overall cohort. In the HR-negative cohort, the hazard ratio for PFS was 0.46 (95% confidence interval [CI], 0.24-0.89), and the hazard ratio for OS was 0.48 (95% CI, 0.24-0.95), both favoring T-DXd. The magnitude of benefit with T-DXd was similar across all subgroups, including HER2 status and previous use of cyclin-dependent kinase 4 or 6.

The objective response rates across the HR-positive and HR-negative subgroups were 53% and 50%, respectively, with T-DXd versus 16% and 17%, respectively, with chemotherapy.

Safety Profile

The overall safety profiles of T-DXd and chemotherapy were similar in terms of treatment-emergent adverse events. The similar rates occurred although the patients in the T-DXd arm received therapy for nearly 5 months longer than those who received chemotherapy.

Interstitial lung disease or pneumonitis was 12.1% in the T-DXd arm and 0.6% in the chemotherapy arm. It was reported a median of 129 days after treatment initiation. Most cases (10%) were grade 1 or 2, but 3 patients in the T-DXd arm died from this side effect.

“With this new class of anticancer agents, we must also rethink novel, more accurate, and sensitive ways of assessing HER2 status,” said discussant Patricia LoRusso, PhD, DO, FASCO, Associate Cancer Center Director, Yale University, New Haven, CT. She noted that the standard of care for patients with HER2-low breast cancer should “absolutely change” based on the results of this study.

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