Background : MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUC_last data matched PK simulations based on non-human primate studies. C_max data at 10 µg/kg indicate that current in-pt exposure was between IC₅₀ values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922.