HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease

In this international, multicenter, single-arm, multicohort, optimal Simon's design phase II clinical trial, patients will be treated with HER3-DXd, which is a new antibody-drug conjugate (ADC) that targets specifically the HER3 protein (which is expressed in the surface of tumor cells) and that is attached to deruxtecan. Male or female patients ≥ 18 years of age with MBC or aNSCLC with untreated or progressing BM after local treatment, or solid tumor patients with treatment-naive LMD or patients with recurrence of LMD after radiotherapy, and no need for immediate local treatment. All patients except for patients with LMD (cohort 3) must have received one prior line of systemic therapy in the advanced setting. Note I: prior systemic treatments for breast cancer (BC) eligible patients would be defined as follows: * triple negative breast cancer (TNBC) patients must have received at least one line of prior systemic therapy for advanced disease. * luminal BC patients must have received at least one line of endocrine therapy (ET) and one line of chemotherapy (CT) in the advanced setting. * HER2-positive (HER2\[+\]) BC patients must have progressed on at least two previous treatments with HER2-targeted therapies in the advanced setting. Note II: prior systemic treatments for NSCLC eligible patients would be defined as follows: * Patients without and with epidermal growth factor receptor (EGFR) (and other) activating driver alterations are allowed. * Patients with activating driver alterations must have received at least one prior line of an approved genotype directed therapy. * Patients with EGFR T790M mutation following first-line treatment with erlotinib, gefitinib, afatinib, or dacomitinib must have received second-line osimertinib, and have documentation of radiological disease progression on treatment. After confirmed eligibility, patients will be assigned to one of three study cohorts as follows: * Cohort 1 (N=20): 10 patients in the stage I and 10 patients in the stage II. MBC with untreated or progressing BM after local treatment. * Cohort 2 (N=20): 10 patients in the stage I and 10 patients in the stage II. aNSCLC with untreated or progressing BM after local treatment. * Cohort 3 (N=20): 10 patients in the stage I and 10 patients in the stage II. Advanced solid tumor with treatment-naive LMD or LMD progressing after radiotherapy. Upon meeting all selection criteria, patients enrolled in the study will receive patritumab deruxtecan (HER3-DXd), which will be dosed at 5.6 mg/kg body weight as an intravenous (IV) infusion administered on day 1 (D1) of each 21-day cycle. Patients will receive treatment disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. Patients discontinuing the study treatment period prematurely, will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected, until end of study (EoS) or study termination, whichever occurs first.