Yuet, Amy

Abstract MT-5111 is a 55kD engineered toxin body 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 works by internalizing, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. This is a phase 1 study in adults with advanced HER2+ solid tumors. MT-5111 is dosed weekly IV over 30 min in every 21-day cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. The study has dose escalation (Part A) cohorts enrolling patients (pts) with any HER2+ cancer (CA) and expansion (Part B) cohorts for HER2+ breast cancer (BC), Gastric or Gastroesophageal junction adenocarcinoma (GEA), or other HER2+ solid CA. As of 30 June 2022, 42 total pts had enrolled (36 in Part A on 0.5-23 µg/kg/dose, 6 pts with BC in Part B1 on 10 µg/kg/dose). Median age 65 years, 28 (66.78%) pts were female, median of 4 prior systemic and 2 prior HER2-targeting treatment (tx). 17 pts with BC, 6 with biliary CA, 9 with GEA, and 10 with other solid CA have enrolled. Of the 17 BC pts, 15 received ≥ 10 µg/kg/dose. Tx emergent adverse events (TEAEs) have been reported in 40 (95%) pts, and tx-related AEs (TRAE) occurred in 23 (55%) pts. No pt experienced G4-G5 TRAE. G1 troponin elevations were noted in 5 pts without clinical signs of cardiotoxicity (1 pt 6.75 µg/kg, 2 pts 10 µg/kg, 1 pt 17 µg/kg, 1 pt 23 µg/kg). Reversible G1/G2 infusion-related reactions were reported in 2 pts. Tx-related G1-G3 rash was observed in 5 pts (4 pts ≥ 10 µg/kg/dose); maculopapular in 2 pts, acneiform in 1 pt and associated with pruritus in 3 pts. The G3 rash developed one wk after first dose of 23 µg/kg, was declared a DLT, improved with systemic steroid therapy and the pt continued tx at the same dose without recurrence. Best overall response per RECIST thus far is stable disease (SD) in 17 pts, non-CR/non-PD in 1 pt, and progressive disease (PD) in 14 pts. 1 pt had non-CR/non-PD for 30 wks (1 μg/kg, BC); 1 pt had SD for 24wks (10 μg/kg, pancreatic); 1 pt is on tx with SD through 8 cycles (10 μg/kg, BC). Of the 10 BC pts who received ≥ 10 μg/kg/dose, the best response was 5 SD. The mean serum concentration of MT-5111 has increased in a dose-proportional manner starting at 6.75µg/kg/dose (Table 1). The soluble HER2 (sHER2) levels at end of tx were higher compared to baseline in cohorts that received ≤ 4.5µg/kg/dose, but similar or lower in cohorts that received ≥ 6.75µg/kg/dose. Higher MT-5111 doses have been well tolerated and may saturate circulating sHER2, leading to more predictable serum concentrations and tumor penetration. The Cmax in humans at doses ≥6.75 µg/kg/dose is above the in vitro IC50 for high HER2+ cell lines (0.029nM) and at 17 µg/kg/dose, above the IC50 for moderate HER2+ cells (1.6nM). In conclusion, the dose proportionate increase in serum concentration with levels above the in vitro IC50 and the leveling off/reduction of sHER2 indicate exposure to MT-5111 is at clinically therapeutic levels. Skin toxicity at higher doses may indicate on-target effect as observed in other EGFR-targeted therapies where it is associated with clinical response and a better prognosis. sHER2 biomarker data is expected for all cohorts with PK correlation and 23µg/kg safety and efficacy data. PK profile of MT-5111, C1D1 values Citation Format: Meena Okera, Brian A. Van Tine, Joleen M. Hubbard, Minal Barve, Erika Hamilton, Monica M. Mita, Frances Valdes-Albini, Daniel Ahn, Admasu Mamuye, Joshua Pelham, Amy Yuet, Diana Yurewicz, Yanning Liu, Andres Machado Sandri, William J. Edenfield, Aki Morikawa, William Gradishar, Rajiv Kumar, Zev A. Wainberg. A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-11-01.

2583 Background: MT-5111 is a 55kD 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. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). 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 Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.