In the phase II TUXEDO-3 trial—reported in two articles in The Lancet Oncology—Fuereder et al and Bartsch et al found that the topoisomerase-1 HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) was active in cohorts of patients with active brain metastases from advanced non–small cell lung cancer (NSCLC) and from breast cancer, respectively.
Study Details
In the study, 20 patients with NSCLC and 21 patients with breast cancer from sites in Austria and Spain received HER3-DXd at 5.6 mg/kg once every 3 weeks. In both cohorts, the threshold to meet the primary endpoint was intracranial response in at least 15% of patients.
Key Findings
In the NSCLC cohort, 13 patients had brain metastases progressing after local therapy and 7 had untreated brain metastases; 5 had activating driver mutations. The primary endpoint was met, with intracranial objective response occurring in six patients (30.0%, 95% confidence interval [CI] = 11.9%–54.3%). Among the six responders, two had nonsquamous NSCLC, two had untreated brain metastases, and four had progressing brain metastases, with one patient having an activating driver mutation (KRAS G12C).
In the breast cancer cohort, five patients had luminal disease, nine had HER2-positive disease, and seven had triple-negative disease. The primary endpoint was met, with intracranial objective response observed in five patients (23.8%, 95% CI = 8.2%–47.1%). Responses were observed irrespective of breast cancer subtype.
In the NSCLC cohort, treatment-related adverse events of any grade occurred in 80% of patients, most commonly nausea (35%), diarrhea (30%), and asthenia (30%); the most common grade 3 or 4 events were neutropenia (15%) and febrile neutropenia (10%). No treatment-related deaths were reported. In the breast cancer cohort, treatment-related adverse events of any grade occurred in 81% of patients, with grade 3 or 4 events observed in 24%. Treatment-related serious adverse events occurred in 5% of patients. No treatment-related deaths were reported.
The investigators in both cohorts concluded: “HER3-DXd showed promising clinical activity in patients with [advanced NSCLC or metastatic breast cancer] and active brain metastases, and could offer a novel therapeutic option in [these settings].”
Matthias Preusser, MD, of the Division of Oncology, Medical University of Vienna, is the corresponding author for both The Lancet Oncology articles.
Disclosure: The study was funded by Daiichi-Sankyo and Merck Sharp & Dohme. For full disclosures of all study authors, visit thelancet.com.
