Patritumab deruxtecan (HER3-DXd) in active brain metastases from metastatic breast and non-small cell lung cancers, and leptomeningeal disease from advanced solid tumors: The TUXEDO-3 phase II trial.

TPS2091 Background: Brain metastases (BM) are a common and severe complication of cancer, resulting in increased morbidity and mortality. Highest incidence of BM is observed in advanced non–small cell lung cancer (aNSCLC) and metastatic breast cancer (mBC). Metastatic solid tumors with leptomeningeal disease (LMD) have a dismal outcome. Patients (pts) with BM and/or LMD have very limited treatment options. Antibody drug conjugates have shown high intracranial response rates and HER3 is highly expressed in CNS metastases of aNSCLC and mBC. Patritumab deruxtecan (HER3-DXd), an antibody drug conjugate combining an anti-HER3 antibody with a topoisomerase I inhibitor. It has demonstrated promising results in mBC and EGFR-mutated NSCLC, as shown in the HERTHENA-Lung 01 study, in which a CNS objective response rate (ORR) of 33.3% was achieved. We hypothesized that HER3-DXd may have clinical activity in active BM from mBC and aNSCLC, and in LMD from metastatic solid tumors. This study aims to evaluate the efficacy and safety of HER3-DXd in these pts. Methods: This is an international, multicenter, single-arm, three-cohort, phase II trial (NCT05865990). A total of 60 evaluable pts (20 per cohort) will be recruited from Austrian and Spanish hospitals and assigned to one of the following cohorts: (1) HER2+, HER2- and triple negative mBC with BM, (2) aNSCLC with BM, and (3) metastatic solid tumors with LMD. Key inclusion criteria are: age ≥18 years, ≥1 line of prior systemic treatment, histologically documented disease, ECOG 0-2, and left ventricular ejection fraction ≥50% (for all cohorts); newly diagnosed/progressing BM with ≥1 measurable brain lesion (≥10mm) by MRI (for cohorts 1 and 2); and LMD with CSF positive cytology and/or MRI (for cohort 3). Pts will receive 5.6 mg/kg of intravenous HER3-DXd on day 1 of every 21-day cycle until disease progression or unacceptable toxicity. Primary endpoints are intracranial ORR (IC-ORR) per local investigator in cohorts 1 and 2 according to RANO-BM, and 3-month OS in cohort 3. Secondary endpoints are OS, ORR, progression-free survival, time to response and duration, clinical benefit rate, safety, tolerability, quality of life evaluation and neurocognitive function evaluation by NANO scale in all cohorts. The sample size was based on Simon’s two-stage design. One-sided alternative hypotheses are IC-ORR ≥25% in cohorts 1 and 2, and 3-month OS ≥25% in cohort 3. Null hypotheses are IC-ORR and 3-month OS ≤5%. Type I error is 10% and power 88%. This is the first prospective clinical trial to evaluate the intra-/extracranial efficacy and safety of HER-DXd in pretreated mBC and aNSCLC with BM, and metastatic solid tumors with LMD. If positive, TUXEDO-3 could streamline the introduction of HER3-DXd as a new treatment paradigm for these pts, who currently have very limited therapeutic options. Clinical trial information: NCT05865990 .