A novel antibody-drug conjugate known as trastuzumab deruxtecan had a manageable safety profile and promising activity in an expansion cohort of a phase I study of patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine. The agent could eventually present a new option in this setting.
“Although continuation of HER2-targeted therapies is recommended, no standard of care has been established for HER2-targeted therapy in patients with metastatic HER2-positive breast cancer whose disease has progressed on or after trastuzumab emtansine,” wrote study authors led by Kenji Tamura, MD, of the National Cancer Center Hospital in Tokyo. “Thus, a substantial need remains unmet in this patient population.”
Trastuzumab deruxtecan combines the monoclonal antibody with a potent topoisomerase I inhibitor. The new study was an open-label phase I trial with a dose-escalation and then a dose-expansion cohort. A total of 115 patients were treated with at least one dose of trastuzumab deruxtecan at the recommended expansion dose of 5.6 mg/kg (49 patients) or 6.4 mg/kg (66 patients). All patients had been previously treated with trastuzumab emtansine. The results were published in Lancet Oncology.
All patients had at least one treatment-emergent adverse event of any grade; 19% had one or more serious event, and 50% had an event of grade 3 or worse. Eleven percent of the cohort had a drug-related treatment-emergent adverse event that led to treatment discontinuation; these included interstitial lung disease or pneumonitis in nine patients. Thirty percent of the cohort required a treatment interruption due to a treatment-emergent adverse event, including pneumonitis and organizing pneumonia.
There were three deaths due to treatment-emergent adverse events, including one from progressive disease and two from pneumonitis; the two pneumonitis deaths were considered drug-related.
The most common grade 3 or worse treatment-emergent adverse events included anemia (17%) and decreased neutrophil count (14%), platelet count (8%), and white blood cell count (9%). There was one case of febrile neutropenia.
Response was evaluable in 111 of the 115 patients. Of those, 66 patients (59.5%) achieved a confirmed objective response, and 104 patients (93.7%) achieved disease control with a median follow-up of 9.9 months. The median time to response was 1.6 months; responders had a median duration of response of 20.7 months. The median overall survival was not yet reached, and the median progression-free survival was 22.1 months.
The authors noted that trastuzumab deruxtecan is now being studied in several phase II and III trials in HER2-positive breast cancer, as well as other malignancies including gastric cancer. “The results reported here suggest trastuzumab deruxtecan might offer an additional therapeutic option for advanced HER2-positive breast cancer,” they concluded.
In an accompanying editorial, Gaia Giannone and Filippo Montemurro, MD, both of the Candiolo Cancer Institute in Italy, wrote that “these findings appear even more interesting considering that all patients had to have trastuzumab emtansine-resistant disease by protocol and most of them had also progressed on pertuzumab.”
They added that if confirmed in larger studies, the results suggest that the therapy should be studied in settings beyond those where patients were resistant to currently approved targeted treatments. “Several hints point to antibody-drug conjugates being active regardless of cancer cell dependence on aberrant HER2 signaling,” they wrote, adding that alterations in various genes including PIK3CA and AKT are markers of resistance to trastuzumab, pertuzumab, and lapatinib, but not to trastuzumab emtansine. This and other issues will require substantial further study to determine best treatments, they concluded.