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

Web Exclusives - Conference Highlights ASCO

Targeting HER2 with the antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) provides clinically meaningful benefits for patients with HER2-low metastatic breast cancer, according to results presented at the 2022 ASCO meeting.

In the randomized phase 3 clinical trial DESTINY-Breast04, trastuzumab deruxtecan 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, trastuzumab deruxtecan induced a 50% risk reduction for disease progression or death (hazard ratio, 0.50; P <.0001). The median PFS was 9.9 months with trastuzumab deruxtecan versus 5.1 months in the control arm, and the median OS was 23.4 months 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,” lead investigator Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, NY, said. “These findings have the potential to impact survival for approximately 50% of all patients diagnosed with metastatic breast cancer today,” Dr Modi added. Approximately 50% of patients with breast cancer have HER2-low expression.

HER2 status is currently defined in a binary model, in which HER2-positive breast cancer driven by the HER2 oncogene is treatable with 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,” she 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,” Dr Modi explained.

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 the 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.

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

The PFS and OS advantage with trastuzumab deruxtecan 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 0.48 (95% CI, 0.24-0.95) for OS, both favoring trastuzumab deruxtecan. The magnitude of benefit with trastuzumab deruxtecan was similar across all subgroups, including HER2 status and previous use of cyclin-dependent kinase 4 or 6 inhibitor.

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

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

Interstitial lung disease or pneumonitis was 12.1% in the trastuzumab deruxtecan 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 trastuzumab deruxtecan arm died from this adverse event.

“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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Last modified: September 30, 2022
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