TUXEDO-3: Evaluating HER3-DXd in Patients With NSCLC and Brain Metastases

Thorsten Füreder, MD, of the Medical University of Vienna, joined Lung Cancers Today to share insights from the non-small cell lung cancer (NSCLC) cohort of the phase 2 TUXEDO-3 trial, which was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

The trial is evaluating patritumab deruxtecan (HER3-DXd) in patients with active brain metastases from NSCLC, as well as metastatic breast (mBC) cancer and leptomeningeal disease (LMD). This research stems from a previous finding showing that HER3 is overexpressed in brain metastasis tissue from patients with NSCLC.

“About 50% of the patients show HER3 high expression and only 27% of the patients are HER3-negative,” Dr. Füreder said. “From a clinical perspective, brain metastases are a challenge when we treat our patients. Unfortunately, those patient populations are quite often excluded from clinical trials, so that is why we wanted to particularly focus on this patient cohort. TUXEDO-3 was designed to treat those patients with patritumab deruxtecan.”

The international, single-arm trial enrolled patients from multiple centers and included patients who were at least 18 years old with histologically documented disease, an Eastern Cooperative Oncology Group performance status of 0-2, a left ventricular ejection fraction of at least 50%, at least one prior line of systemic treatment, and newly diagnosed or progressing brain metastases with at least one brain lesion of at least 10 mm per MRI.

“We intentionally avoided the terminology ‘symptomatic’ or ‘asymptomatic’ brain metastasis because this is a quite vague terminology and does not necessarily reflect the tumor biology,” Dr. Füreder explained.

Patients received HER3-DXd 5.6 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was the intracranial overall response rate (IC-ORR) per local investigator according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM).

The NSCLC cohort showed a “very striking response rate,” Dr. Füreder said, with 6 out of 20 patients in the cohort showing an intracranial response.

“Most notably, all of the patients were EGFR wild-type and only one patient had a KRAS G12C mutation. Other patients who did not have activated driver mutations responded to our therapy, which is remarkable since patritumab deruxtecan (HER3-DXd) is currently [being] developed with a strong focus on EGFR-mutated patients. This gives us some hints that patritumab deruxtecan is definitely active in EGFR wild-type patients as well.”

Dr. Füreder also shared insights on survival outcomes in patients with NSCLC brain metastases who were receiving patritumab deruxtecan, explaining that the median intracranial progression-free survival (PFS) was 4.8 months, with a median extracranial PFS of 8.1 months. The duration of response was 2.1 months for intracranial lesions and 7.8 months for extracranial lesions. The median overall survival was 6.7 months.

“From a safety perspective, there were no new safety signals in our patient cohort,” he said. “Patritumab deruxtecan was tolerated and the side effects were well manageable.”

Beyond safety and efficacy, the researchers also “looked a bit deeper into the quality of life,” Dr. Füreder said, noting that from “that perspective, the quality of life remained constant or even improved slightly,” he said.

Additionally, the researchers conducted exploratory analyses of HER3 expression in tumor tissue, but the analyses “did not reveal any association regarding response from that perspective,” Dr. Füreder said. He said that focusing on HER3 overexpression “might not be sufficient,” and that this research highlights the importance of identifying more effective biomarkers in this setting, he said.

“Perhaps we have to move to something like [what] has been developed for TROP2, perhaps some normalized membrane ratio supported by artificial intelligence,” he said.

Dr. Füreder also outlined the next steps and potential future directions with this line of research.

“Besides the biomarker question and identifying a population, it might be fascinating to combine this compound with other types of immunotherapy for EGFR, or even a targeted therapy to get the best out of two worlds into one setting,” he concluded.