Abstract CT185: First in human dose-escalation trial with the c-MET targeting antibody-drug conjugate BYON3521
Authors: Kotecki N. , van Herpen C.M.L. , Curigliano C. , Hendriks M. , Vermaas T C. , Corrigan L. , Belli C. , Jungels C. , Desar I.M.E. , Koper N.P. , Schellens J.H.M. , Banerji U. 
Published: April 2023

Abstract
Background: BYON3521 is a novel c-MET targeting antibody-drug conjugate (ADC) with a cleavable linker-duocarmycin (vc-seco-DUBA) payload that causes irreversible alkylation of DNA in tumor cells. BYON3521 has demonstrated potent and selective killing of c-MET expressing tumor cells in preclinical models, even at low c-MET expression levels. In addition, in vitro studies showed that the active toxin can passively permeate the cell membrane and kill neighboring, c-MET negative cells as a bystander effect.
Methods: Patients with previously treated progressive locally advanced or metastatic solid tumors, c-MET positive membrane staining by immunohistochemistry and/or MET-amplified by dual in situ hybridization and/or known activating MET-mutation (excluding exon14m), ECOG performance status 0-1 and adequate organ function are eligible for the dose-escalation part of this first-in-human trial (ClinicalTrials.gov identifier: NCT05323045). An adaptive approach using the Continual Reassessment Method of Neuenschwander (N-CRM model) is used to evaluate the safety of BYON3521 and to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE). BYON3521 is administered intravenously every three weeks until tumor progression or unacceptable toxicity.
Results: Up to 01 January 2023, 8 patients (1F, 7M, median age 61 yrs) were enrolled. Tumor types were: 4 colorectal cancer, 1 NSCLC, 1 renal cell carcinoma, 1 esophageal cancer and 1 pancreatic cancer. One patient received 0.8 mg/kg, three patients each 1.6 and 3.2 mg/kg and one patient received 4.8 mg/kg. So far, no grade 3 or 4 related adverse events and no dose-limiting toxicities (DLTs) occurred. Most commonly observed related AEs were decreased appetite/weight, fatigue, abdominal pain, back pain, vomiting and chills. Typical ADC associated AEs as keratitis and pneumonitis have not been observed so far. Stable disease was the best response observed in 2 patients at a dose of 3.2 mg/kg. Human PK was in line with predicted preclinical in vivo PK.
Conclusions: To date, BYON3521 is well-tolerated with no DLTs at the investigated dose levels. Patient enrollment is ongoing and updated safety, efficacy and pharmacokinetic data will be presented. After the dose-escalation phase the trial will continue with expanded cohorts of patients with specific c-MET expressing cancer types.
Citation Format: N. Kotecki, C.M.L. van Herpen, C. Curigliano, M. Hendriks, T C. Vermaas, L. Corrigan, C. Belli, C. Jungels, I.M.E. Desar, N.P. Koper, J.H.M. Schellens, U. Banerji. First in human dose-escalation trial with the c-MET targeting antibody-drug conjugate BYON3521 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT185.