Abstract 6880: Rinatabart sesutecan (PRO1184) in combination with standard-of-care therapy exerted potentiated antitumor activity in preclinical cancer models

Abstract Background: Rinatabart sesutecan (Rina-S) is an investigational antibody-drug conjugate composed of a human monoclonal antibody that selectively binds to folate receptor alpha (FRα), a novel protease-cleavable highly hydrophilic linker, and a topoisomerase 1 inhibitor, exatecan. Preclinical studies have demonstrated potent antitumor activity of Rina-S monotherapy in a broad range of tumors. In the phase 1/2 GEN1184-01 study (NCT05579366), treatment with Rina-S monotherapy resulted in antitumor activity in patients with heavily pretreated platinum-resistant ovarian cancer (PROC) and endometrial cancer (EC) across various FRα expression levels, with a manageable safety profile. Here we evaluate the combinability and antitumor activity of Rina-S with standard-of-care (SOC) therapies in preclinical cancer models. Methods: To evaluate the effect of Rina-S on immunogenic cell death (ICD), FRα-expressing cell lines (KB and 3LL-FRα cells) were treated with either Rina-S or exatecan for 24 to 72 hours and then assessed for markers of ICD, including extracellular ATP, HMGB1, and calreticulin. To assess the antitumor activity of Rina-S alone or in combination with SOC therapies, multiple in vivo studies were conducted in various mouse models. Xenograft mouse models inoculated with OC (OVCAR-8 cells) or EC (HEC-1-A cells) received either phosphate-buffered saline (PBS) alone or Rina-S alone, with or without carboplatin (OC), bevacizumab (OC), or olaparib (EC). Syngeneic mouse models of lung cancer or colorectal cancer received either PBS alone or Rina-S alone, with or without an anti-PD1 agent nofazinilmab (CS1003). Antitumor activity was assessed by measuring tumor volume over 30 days and the evaluation durations for lung cancer and colorectal cancer were 20 and 28 days, respectively. Results: In vitro incubation of FRα-expressing cells with Rina-S or exatecan resulted in upregulation of ICD overall, as measured by ATP, HMGB1, and calreticulin levels. In models of OC and EC, Rina-S combined with carboplatin, bevacizumab, or olaparib produced potentiated antitumor activity compared with single-agent treatment. Combination of Rina-S with an anti-PD1 agent in syngeneic models of lung and colorectal cancer showed a potentiated effect compared with single-agent treatment. Conclusions: These preclinical studies provide evidence for combination therapy with Rina-S and various SOC therapies and suggest that Rina-S may be investigated in different treatment settings in the clinic. A phase 1/2 study (NCT05579366) is currently ongoing to study the efficacy and safety of Rina-S in combination with carboplatin, bevacizumab, or pembrolizumab for the treatment of platinum-sensitive OC, PROC, and EC, respectively. Citation Format: Lei Wang, Wanwan Shen, Wenke Qi, Qilin Wu, Yang Xiao. Rinatabart sesutecan (PRO1184) in combination with standard-of-care therapy exerted potentiated antitumor activity in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6880.