First-in-human phase I/II trial evaluating BNT142, a first-in-class mRNA encoded, bispecific antibody targeting Claudin 6 (CLDN6) and CD3, in patients (pts) with CLDN6-positive advanced solid tumors.

Abstract

2501 Background: CLDN6 is an oncofetal cell surface protein silenced in normal adult tissues but aberrantly activated in testicular, ovarian, non-small cell lung (NSCLC) and other cancers. The investigational therapeutic BNT142 is a novel lipid nanoparticle (LNP)-encapsulated mRNA encoding the anti-CLDN6/CD3 bispecific antibody RiboMab02.1. After intravenous administration, BNT142 RNA-LNPs are taken up by liver cells and are translated into RiboMab02.1. The first results of the dose escalation part of the BNT142-01 trial testing 7 dose levels (DL) are presented here. Methods: BNT142-01 (NCT05262530) is a Phase I/II, open-label, multi-center trial to evaluate weekly BNT142 treatment with premedication (antipyretics, antihistamines, fluids) at the investigators’ discretion in pts with CLDN6+ (≥10% of cells with at least weak membrane positivity) advanced solid tumors. Primary objectives include safety, tolerability and identifying the recommended Phase 2 dose (RP2D), secondary and exploratory objectives include pharmacokinetics, pharmacodynamics and preliminary efficacy (RECIST 1.1). Results: As of 02 Dec 2024, 65 pts (median age 57 years [range 18 – 79]; 75% female; 60% ECOG 1; 44 ovarian, 10 testicular, 5 NSCLC, 6 rare cancers) received ≥1 dose (median 7, range 1 – 38) of BNT142. Of 65 pts, 46 (71%) had ≥4 prior lines of systemic therapy. Mostly mild to moderate treatment-related adverse events (TRAEs) occurred in 41 (63%) pts, including 15 (23%) pts with ≥G3 TRAEs. Most common (≥10%) TRAEs were cytokine release syndrome (CRS) in 14 (22%) pts (1 pt [2%] ≥G3), aspartate or alanine aminotransferase (AST, ALT) increased in 12 (19%) pts (8 pts [12%] ≥G3), and pyrexia, chills or fatigue in 8 (12%) pts (0/0/2 pts [0%/0%/3%] ≥G3, respectively). TRAEs leading to dose reduction, treatment interruption or discontinuation occurred in 1 (2%), 12 (19%) or 2 pts (3%), respectively (mostly G3; most common related terms AST or ALT increased and infusion related reaction). Two (3%) pts had a dose limiting toxicity (G4 ALT increased [DL5], leading to dose reduction, and G5 CRS [DL6]). BNT142 led to transient, dose-dependent increases in inflammatory cytokines. Translated RiboMab02.1 was detected in serum in a dose-dependent manner, peaking 24 – 72 h post-dose. Across all DLs, the disease control rate (DCR) was 58% with a tendency of higher efficacy in the higher DLs. In ovarian cancer, there were 7 RECIST 1.1 partial responses (PRs) and the DCR was 75%. Conclusions: BNT142 demonstrated a manageable safety profile and promising anti-tumor activity at the higher DLs, with 7 RECIST 1.1 PRs in CLDN6+ ovarian cancer, a tumor usually refractory to immunotherapy. We provide the first clinical proof-of-concept for an mRNA encoded bispecific antibody. Dose optimization is ongoing. Clinical trial information: NCT05262530 .