First-in-human study (FIH) of FS222, a next-generation tetravalent PD-L1/CD137 bispecific antibody: Safety, pharmacodynamics (PD), and antitumor activity in patients (pts) with advanced solid tumors including PD-1 refractory melanoma.
Authors: Garralda Elena , Oberoi Arjun , de Velasco Guillermo , Victoria Iván , Pesantez David , Eguren Santamaría Inaki , Moreno Victor , Boni Valentina , Cervantes Andres , Gambardella Valentina , Ciuleanu Tudor-Eliade , Bergamino Sirvén Milana , Rodriguez-Abreu Delvys , Alonso Guzman , Gales Laurentia Minea , Jones Daniel , Patki Abhay , Melero Ignacio 
Published: June 2024

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Background: Most pts receiving immune checkpoint inhibitors do not respond to treatment or relapse. FS222 is a novel affinity optimized, tetravalent bispecific PD-L1/CD137 antibody. FS222’s structure allows for potent, PD-L1-dependent, CD137 activation across a wide range of dose levels, and is designed to provide selective CD137 agonism in the tumor. We present data from the ongoing, FIH, open-label, phase I trial of FS222 in advanced solid tumors. Methods: Pts with pretreated advanced solid tumors received increasing doses of FS222 in an accelerated dose titration and 3+3 design intravenously every 3 or 4 weeks (Q4W) until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary and exploratory endpoints included pharmacokinetics, PD and antitumor activity (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Results: As of data cut off (DCO) on 05Dec2023, a total of 104 pts had been treated across a range of doses and schedules in the FIH study (NCT04740424). We report interim results from the Q4W cohorts (N=90). Patients had a median age of 61 years (31-88 years) and had received a median of 2 (1-7) regimens of prior treatments. The median duration of exposure to FS222 was 82.5 days (24 – 529 days). The most common treatment-related AEs (TRAEs; >20% of pts) were increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), pyrexia, thrombocytopenia, asthenia, and neutropenia. The most common TRAEs grade ≥3 (≥10% of pts) were increased AST (13.3%) and ALT (11.1%). The most common treatment related serious AEs (≥3 pts) were febrile neutropenia (5 pts, 5.6%); and pyrexia, cytokine release syndrome, increased ALT, increased AST (all in 3 pts, 3.3%). On-target FS222 pharmacology was confirmed by the presence of dose-dependent target engagement, significant peripheral CD8+ T cell modulation and increased tumor CD3+ CD8+ T cells at multiple dose levels. At the DCO, 20 (22.2%) pts remained on treatment. Objective responses (CR, PR) were observed in pts with melanoma, NSCLC, ovarian cancer, TNBC, liposarcoma and colon cancer, for an ORR of 15.7% with evidence of further enrichment by dose. In post-PD-1 treated metastatic/advanced cutaneous melanoma the ORR was 60% (9/15, all PRs - 7 confirmed) and the disease control rate was 86.7% (13/15). Conclusions: The novel PD-L1/CD137 bispecific antibody FS222 demonstrated PD activity across a broad range of doses. The safety profile was acceptable and manageable. Encouraging anti-tumor activity was observed, including in patients with PD-1 refractory cutaneous melanoma. Next steps include further dose optimization and further evaluation of FS222 in patients with melanoma and other tumor types. Clinical trial information: NCT04740424 .