The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo, Inc.) for treatment of patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer. The approval is specific to individuals who have had prior treatment with an anti–HER2-based regimen in the metastatic, neoadjuvant, or adjuvant setting and have developed disease recurrence within six months of completing therapy.
"Although HER2-targeted therapies have improved disease outcomes, they are not curative for locally advanced or metastatic disease, and most patients will have disease progression," wrote Javier Cortés, MD, PhD, Head of the International Breast Cancer Center (IBCC) in Barcelona, Spain, and colleagues, in their published results of the DESTINY-Breast03 trial (NCT03529110), on which the approval was based. "Trastuzumab deruxtecan is uniquely designed with a high drug-to-antibody ratio of approximately eight that remains stable, thereby delivering a potent cytotoxic payload that is internalized and selectively cleaved by lysosomal enzymes that are overexpressed in cancer cells—a process that may reduce systemic toxic effects."
The phase 3, open-label, active-controlled, multicenter trial enrolled 524 patients with HER2-positive metastatic or unresectable breast cancer. Upon enrollment, patients were stratified according to hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, and randomized in a 1:1 ratio to receive either trastuzumab deruxtecan or trastuzumab emtansine via intravenous infusion (IV) every three weeks until unacceptable toxicity or disease progression. The primary end point was progression-free survival with secondary end points of overall survival and overall response rate.
At a median follow-up of 16.2 months for the trastuzumab deruxtecan group and 15.3 months for the trastuzumab emtansine group, investigators observed a significant progression-free survival benefit for treatment with trastuzumab deruxtecan. At data cutoff, median progression-free survival was not reached in patients receiving trastuzumab deruxtecan, compared with 6.8 months in those receiving trastuzumab emtansine. Although overall survival data was immature, it was noted at the 12-month mark that 94.1% of patients were still alive in comparison to 85.9% of patients surviving in the trastuzumab emtansine group. The overall response rate saw significant improvement, with 79.7% of patients receiving trastuzumab deruxtecan experiencing a response compared with 34.2% of those receiving trastuzumab emtansine.
The most common adverse events experienced by >30% of patients who received fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse events experienced by >1% of patients were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. It should be noted, as well, that the prescribing information for trastuzumab deruxtecan includes a boxed warning advising the risk of interstitial lung disease and embryo-fetal toxicity.
"Treatment with trastuzumab deruxtecan was associated with adjudicated interstitial lung disease and pneumonitis, but the incidence of these events was numerically lower in this trial than in previous trials; careful monitoring is essential in its clinical use," concluded Dr. Cortés and colleagues in their report. "Trastuzumab deruxtecan is an effective new treatment for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane, as well as with pertuzumab when available."
The recommended dosage of fam-trastuzumab deruxtecan-nxki is 5.4 mg/kg once every three weeks, given IV, until disease progression or unacceptable toxicity.
For More Information:
Clinicaltrials.gov (2022). DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. NLM identifier: NCT03529110.
US Food and Drug Administration (2022). FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-n
Image Credit: Dr. Cecil Fox. Licensed under Public Domain