A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.

Abstract

TPS3175 Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.

A GLOBAL CONGRESS DIGEST ON SOLID TUMORS. Report from the ASCO Hybrid Congress , 3rd – 7th June 2022

“…The antitumor activity of ICIs in recurrent or metastatic NPC was only seen in a subset of patients [13]. In an attempt to expand the clinical benefit of ICIs to more patients, ICIs were combined to agents that block immunosuppressive pathways, like TGF-β, and investigated in advanced solid tumors [27,28]. The purpose of the NCT04282070 study was to evaluate the efficacy and safety of SHR-1701 -a bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of the TGF-β receptor II -in patients with recurrent or metastatic NPC.…”

“…The LEAP-014 trial (NCT04949256) is a randomized, 2-part, open-label, phase III study that aims to investigate the effi- cacy and safety of upfront lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic ESCC [28]. The primary endpoint in part-1 of the study (Figure 3) is safety per NCI CTCAE v5.0 and tolerability (dose-limiting toxicity, DLT), whereas the dual primary endpoint in part-2 consists of OS and PFS by BICR per RECIST v1.1; the secondary endpoints include ORR by BICR per RE-CIST v1.1, DoR, and HRQoL.…”

“…Moreover, a phase 3 study will investigate the combination of bemarituzumab plus mFOLFOX6 versus mFOLFOX6 in patients with FGFR2b overexpressing advanced gastric or GEJ cancer [28]. The FORTITUDE-101 study (NCT05052801) is currently enrolling patients according to the following inclusion criteria: adults, histologically confirmed G/GEJ adenocarcinoma, FGFR2b overexpression as determined by centrally performed IHC testing, unresectable, locally advanced, or metastatic disease, evaluable disease per RECIST v1.1 and no contraindication to receive mFOLFOX6 chemotherapy.…”

“…Previously published preclinical studies have demonstrated that monotherapy with BI 765049 induced a dose-dependent anti-tumor ac-tivity in humanized in vivo CRC models, as well as an infiltration of T-cells [27]. BI 765049 is currently under clinical investigation in a Phase 1 trial as monotherapy or in combination with the PD-1 inhibitor ezabenlimab in patients with CRC or other B7-H6 positive tumors in several indications (non-small cell lung cancer [NSCLC], as well as head and neck squamous cell-[HNSCC], hepatocellular-, pancreatic-, gastric-or colorectal [CRC] carcinoma) [28].…”