Anti-PD-1/TGF-βRII bispecific antibody fusion protein LBL-015 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose-escalation study.

2592 Background: LBL-015 is a bispecific fusion protein which consists of fully anti PD-1 monoclonal antibody and TGF-βRII ectodomain, designed to block PD-1/PD-L1 and TGFβ signal pathway, reversing immune suppression and promoting anti-tumor immunity. Here we report the preliminary safety and efficacy of LBL-015 in patients with advanced solid tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-015 in patients with advanced solid tumors that progressed after standard therapy. The dose escalation phase consists of 6 dose cohorts of LBL-015 at 0.3, 1.2, 4, 6, 10, and 20 mg/kg (iv Q2W), using an accelerated titration design (first dose) followed by a 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of December 05, 2023, 25 patients Demography: 11 (44%) male, median age 59 years (range:24, 72), 23 (92%) ECOG score of 1 received LBL-015 treatment. Tumor types included 7 (28%) colorectal cancer, 6 (24%) renal carcinoma (RCC), 2 (8%) gastric carcinoma, 2 (8%) nasopharyngeal carcinoma and 8 (32%) other tumors. 15 (60%) previously received anti-PD(L)-1 treatment. During the study, 2 DLTs (respiratory failure at grade 5 and pulmonary infection at grade 3, respectively) were observed at the dose of 10 and 20 mg/kg, and the MTD was not reached. 25 patients (100%) experienced TEAEs of any grade and 11 patients (44%) at grade ≥3. The most common grade TEAEs (≥20%) were grade 1-2 and included anaemia, AST increased, γ–GT increased, gingival bleeding, pyrexia, LDH increased, proteinuria, ALT increased, weight decreased, asthenia, bilirubin conjugated increased, decreased appetite, hypoalbuminaemia, asthenia. Treatment interruption and permanent discontinuation of LBL-015 due to TEAEs occurred in 3 (12%) and 2 (8%) patients, respectively. Six patients (24%) experienced SAEs. Out of the 20 patients who underwent at least one efficacy evaluation per RECIST, 1 patient with RCC achieved PR at first image assessment which remained partial response for more than 28 weeks, and 4 patients achieved SD. The ORR and DCR were 5%, and 25%, respectively. Conclusions: LBL-015 has demonstrated good safety profiles in patients with advanced solid tumors. The encouraging preliminary efficacy signals indicated additional studies with a focus on TGFβ signaling pathway deregulated or activated tumors such as RCC, pancreatic cancer, etc. should be further explored. Clinical trial information: NCT05107011 .