Initial safety and efficacy results from a first-in-human, phase 1/2 study of SAR445877, an anti-PD-1/IL-15 fusion protein, for patients with advanced solid tumors.

2572 Background: SAR445877 is a fusion protein of an PD-1 antibody combined with a detuned IL-15, designed to selectively expand and activate CD8+ T and NK cells expressing both PD-1 and IL-2/15Rβγ. Preclinical studies demonstrated the efficacy of SAR445877 in neoplastic models. Here, we present initial safety and efficacy observations from a first-in-human, dose escalation of SAR445877 monotherapy in patients (pts) with advanced solid tumors. Methods: This open-label, multicenter, Phase 1/2 study in adult pts with any type of measurable, advanced unresectable or metastatic solid tumors (NCT05584670) comprised two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, SAR445877 was administered intravenously at two dosing schedules (Q2W and QW). Pts with advanced solid tumors that do not typically respond or were resistant/refractory to immune checkpoint inhibitors (ICI), and with at least 1 measurable lesion per RECIST 1.1, were eligible. Tumor biopsy was performed at baseline and on treatment. The primary objective for Part 1 was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity. Results: Thirty-two pts (Q2W) and 17 pts (QW), respectively, were enrolled. Median lines of prior therapy were 3 for both schedules. The Q2W schedule was tested at 6 dose levels (DLs) and QW schedule at 3 DLs. Median exposure to SAR445877 was around 9 weeks (Q2W range: 2–55 weeks; QW range: 1–46 weeks). All pts reported at least one treatment-emergent adverse event (TEAE). Treatment-related AEs (TRAEs) were reported in 47 pts (Grade ≥3: 12 pts [Q2W]; Grade ≥3: 5 pts [QW]). Most common TRAE was cytokine release syndrome (CRS), which was mainly Grade 1 or 2. Six pts discontinued treatment due to any TEAEs. DLTs occurred in 4 pts in the Q2W cohort (n = 1 each metabolic acidosis, pneumonia, hyperbilirubinemia, and GI hemorrhage) and in 2 pts in the QW cohort (both CRS). Serious TEAEs were reported in 23 pts (Q2W) and 7 pts (QW). All toxicities were manageable/reversible, and no TEAEs leading to death were observed. Confirmed partial response was reported in 5 pts (Q2W) and in 2 pts (QW) bearing melanoma, CRC, SCC of the scalp, penile cancer, adnexal carcinoma, urothelial carcinoma, and myxofibrosarcoma, with benefits lasting > 1 year. Five of the 7 pts had progressed on prior immunotherapy. Stable disease ≥ 6 months was observed in 3 pts (Q2W) and 3 pts (QW). Antidrug antibodies (ADAs), detected in 23 pts (Q2W) and 13 pts (QW), did not correlate with clinical benefit or toxicity. A trend of dose dependent increase of cytokine (IFNγ, TNFα, IL-6, IL-8, IL-10) and chemokine (CCL2, CXCL10, MIP1α, MIP1ß) release were detected at both dosing schedules. Conclusions: SAR445877 monotherapy demonstrated a tolerable safety profile and promising antitumor activity in pts with advanced solid tumors unresponsive or resistant to ICI. Clinical trial information: NCT05584670 .