Abstract CT046: Clinical and translational study of the TGF-β monoclonal antibody SAR439459 in combination with the PD-1 inhibitor cemiplimab for patients (pts) with advanced solid tumors: Results from the phase 1b TACTIC trial
Authors: Carlos Torrado, Katarzyna Tomczak, Ecaterina E. Dumbrava, Baohua Sun, Natalie Ngoi, Claudio Arrechedera, Edwin R. Parra, Jordi Rodon Anhert, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Siqing Fu, Aung Naing, Paula R. Pohlmann, David S. Hong, Funda Meric-Bernstam, Pavlos Msaouel, Cara L. Haymaker, Timothy A. Yap
Journal: Cancer Research (2025)

Abstract Background: Transforming growth factor-beta 1 (TGFβ1) plays a crucial role in tumor progression and immunosuppression in cancer. SAR439459 is a second-generation monoclonal antibody that targets all TGFβ isoforms. A first-in-human study (NCT03192345) established the SAR439459 dose at 15 mg/kg every three weeks as the initial recommended phase 2 dose. Methods: TACTIC (NCT04729725) is a phase Ib dose-expansion trial to evaluate the combination of SAR439459 (anti-TGF-β) and cemiplimab (anti-PD1) in pts with advanced solid tumors. Pts were mandated to have been treated with PD-1 or PD-L1 inhibitors (PD-1/L1i) as their most recent therapy. The primary objective of the trial was to assess efficacy; secondary objectives included toxicity; and translational studies included multiplex immunofluorescence (mIF) (n=2) and single-cell RNA-sequencing (5’GEX) of tumor (n=1) and blood (n=3). Results: Three pts were enrolled: advanced clear cell renal cell carcinoma (ccRCC), high-grade pancreatic neuroendocrine carcinoma (NEC), and castration-resistant prostate cancer (CRPC) (n=1 each). The ccRCC pt achieved a confirmed RECISTv1.1 partial response (PR), with -55% reduction in target lesions, progression-free survival (PFS) of 12 mths, and overall survival (OS) of 26 mths. The other two pts had RECISTv1.1 progressive disease (PD) Hemorrhagic adverse events occurred in all pts. Two grade 3 treatment-related adverse events were reported: rash and retroperitoneal hemorrhage. Two pts (ccRCC and CRPC pts) developed skin squamous cell carcinomas, attributed to SAR439459 and were treated with resection. Single-cell sequencing revealed higher Treg activation as well as CD8+ T cell (LAG3, TIGIT) and CD4+ T cell (TIGIT, PDCD1, CTLA4) exhaustion profiles in the blood samples collected at C2D1 (post SAR439459, pre-cemiplimab) of both pts who had PD versus the pt with the PR. LAG3 and TIGIT were also present in CD8+ T cells from on-treatment biopsies collected from one of the pts with PD. A unique on-treatment CD4+ T cell signature associated with NK-kB activation in response to TNF was found in the circulation of the pt with PR. Within the tumor microenvironment, longitudinal mIF analysis of one of the pts with PD demonstrated reductions in TGF-β, pSMAD3 and immune infiltrate by C2D1. Conclusions: In this phase 1b study, SAR439459 and cemiplimab demonstrated a deep and durable RECISTv1.1 PR in a post-PD-1/L1i treated pt with advanced ccRCC. While translational data are limited, these findings support the association of systemic immune activation with response to therapy. Despite this, based on data from another study (NCT03192345), all investigations of SAR439459 were discontinued due to lack of sufficient antitumor activity and the associated bleeding risk. Citation Format: Carlos Torrado, Katarzyna Tomczak, Ecaterina E. Dumbrava, Baohua Sun, Natalie Ngoi, Claudio Arrechedera, Edwin R. Parra, Jordi Rodon Anhert, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Siqing Fu, Aung Naing, Paula R. Pohlmann, David S. Hong, Funda Meric-Bernstam, Pavlos Msaouel, Cara L. Haymaker, Timothy A. Yap. Clinical and translational study of the TGF-β monoclonal antibody SAR439459 in combination with the PD-1 inhibitor cemiplimab for patients (pts) with advanced solid tumors: Results from the phase 1b TACTIC trial [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 CT046.