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

2005 Background: BM and LMD are common and severe complications of solid cancers with high morbidity, poor prognosis, and limited treatment options. Antibody drug conjugates (ADCs) have shown high intracranial overall response rates (IC-ORR) in HER2-positive mBC and EGFR -mutated NSCLC patients (pts). HER3-DXd, an ADC combining an anti-HER3 antibody with a topoisomerase (topo) I inhibitor, has shown promising results in mBC and aNSCLC pts. Since HER3 is highly expressed in aNSCLC and mBC CNS metastases, we hypothesized HER3-DXd may have clinical activity in BM from mBC and aNSCLC pts, and LMD from any solid tumor. Methods: TUXEDO-3 (NCT05865990) is an international, multicenter, multicohort, single-arm, phase II trial enrolling pts with BM from mBC (cohort 1), aNSCLC (cohort 2), and LMD from any solid tumor (cohort 3). Key inclusion criteria were: Pts ≥18 years old, histologically documented disease, ECOG PS 0-2, and left ventricular ejection fraction ≥50% in all cohorts; newly diagnosed/progressing BM with ≥1 brain lesions ≥10mm by MRI, and ≥1 line of prior systemic treatment, in cohorts 1 and 2; LMD per EANO-ESMO in cohort 3. Pts received HER3-DXd 5.6 mg/kg IV Q3W until disease progression, unacceptable toxicity or withdrawal for any reason. Primary endpoint was IC-ORR per local investigator according to RANO-BM in cohorts 1 and 2, and 3-month OS in cohort 3. Sample size was based on Simon’s two-stage design. Primary endpoint was met if ≥3 IC responses (H0: ≤5%; H1: ≥25%) in cohort 1 and 2; and if ≥3 pts with 3-month OS (H0: ≤5%; H1: ≥25%) in cohort 3. Overall sample size was 60 pts with a target population of 20 pts per cohort. Results: Between December 2023 and July 2024, 61 evaluable pts were enrolled from 8 Austrian and Spanish sites. Median age (min; max) was 57.0 (35.0; 75.0), 59.5 (37.0; 72.0) and 51.5 (40.0; 66.0) years in cohorts 1, 2 and 3, respectively. At data cut-off, median follow-up (min; max) was 4.4 (1.4; 10.1), 4.3 (0.2; 11.0) and 3.5 (0.8; 8.6) months in cohorts 1, 2 and 3, respectively. Primary endpoints were met in all three cohorts. In cohort 1, 5/21 (23.8%) pts had IC response irrespective of BC subtype; 2 (40.0%) responders had received previous topo I based ADCs. In cohort 2, 5/20 (25.0%) pts had IC response. In cohort 3, 11/20 (55.0%) pts achieved 3-month OS irrespective of the LMD type. No new signals of toxicity were observed and neurological symptoms, QoL and neurocognitive function remained stable or improved over the treatment period. Tumoral HER3 expression did not correlate with treatment response. Conclusions: TUXEDO-3 is the first trial evaluating efficacy and safety of HER3-DXd in pts with BM or LMD. HER3-DXd showed substantial CNS activity in parenchymal metastases and LMD, and may be a potential novel treatment for CNS disease in cancer pts. Clinical trial information: NCT05865990 .