Abstract CT078: Results of a phase 1 first-in-human study of PRS-344/S095012, a PD-L1x4-1BB antibody-Anticalin fusion protein (Mabcalin), in patients with previously treated advanced solid tumors

Abstract Background: Activation of the 4-1BB co-receptor can enhance anti-tumor immune responses but has historically resulted in excessive toxicity. PRS-344/S0905012 is a “2+2” tetravalent, bispecific antibody-Anticalin fusion protein (Mabcalin), designed to activate 4-1BB in a PD-L1-dependent manner. In preclinical studies PRS-344/S095012 showed superior anti-tumor efficacy compared to monospecific anti-PD-L1 or 4-1BB antibodies. Methods: We tested PRS-344/S095012 in a phase 1, first-in-human study (NCT05159388) in patients (≥18 years) with previously treated advanced solid tumors without further available standard therapy. Primary objectives were to determine safety, tolerability, maximum tolerated/administered dose and recommended phase 2 dose. Secondary endpoints included characterization of PK, immunogenicity and preliminary anti-tumor activity. One cohort of patients received pretreatment with the anti-CD20 mAB obinutuzumab (OBI) to prevent the development of anti-drug antibodies (ADAs). Results: As of November 18, 2024, n=45 patients had received PRS-344/S095012 at dose levels of 12mg (n=4), 36mg (n=21, with 12 patients pretreated with OBI), 60 mg (n=14) and 80 mg (n=6) IV Q2W. The most frequent treatment-related adverse events were infusion-related reactions (31%), cytokine release syndrome (24%), fatigue (24%), hepatic (31%) and hematologic toxicities (33%). Eight of 35 DLT-evaluable patients experienced DLTs consisting mainly of: reversible grade3 (G3) and G4 neutropenia and thrombocytopenia at 36mg and 60mg; one case of G5 hemophagocytic lymphohistiocytosis (HLH) at 80mg; and G3 and G4 liver injury at 36 mg in the OBI-pretreated cohort. The 60mg dose level was identified as the MTD. An increase in peripheral blood PD markers indicated dose-dependent immune activation. PRS-344/S095012 was highly immunogenic, with 86% (24/28) of patients developing ADAs in the absence of OBI pretreatment. The emergence of ADAs coincided with marked decrease in drug exposure. OBI pretreatment effectively reduced ADA incidence (ADA positivity in 2/11 ADA-evaluable patients). However, OBI pretreatment was associated with severe hepatic toxicity in 4 of the 12 patients treated, leading to a stop in the enrollment to the study. Objective clinical responses occurred only in patients in the OBI cohort, with 1 confirmed partial response (PR) in a patient with melanoma and 1 unconfirmed PR in a patient with urothelial carcinoma. Conclusions: PRS-344/S095012 was associated with significant toxicity that was inconsistent with the aim of improving the therapeutic index of activating 4-1BB. While OBI pretreatment successfully mitigated ADA formation, the unexpected hepatic toxicity observed in this study warrants caution when considering OBI as an ADA mitigation strategy with other immune-stimulatory agents. Citation Format: Emiliano Calvo, Elena Garralda, Christiane Jungels, Timothy Price, Sara Wahlroos, Hans Prenen, Sylvie Rottey, John Powderly, Antony Tolcher, Michael Cooper, Matyas Ecsedi, Donal Landers, Agathe Lepissier, Najah Harouki Crochemore, Abbass Darwich, Peng He, Ariane Leconte, Ibtissam Marchiq, Aitana Calvo. Results of a phase 1 first-in-human study of PRS-344/S095012, a PD-L1x4-1BB antibody-Anticalin fusion protein (Mabcalin), in patients with previously treated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT078.