Abstract 2699: FF-10850, a dihydrosphingomyelin (DHSM)-based novel liposomal topotecan, achieved favorable efficacy and safety in combination with platinum, PARP and immune checkpoint inhibitors
Authors: Okada Ken , Kimura Toshifumi , Kasagi Noriyuki , Mori Mikinaga , Shimoyama Susumu 
Published: April 2023

Abstract
Introduction: Topotecan is approved as a monotherapy for ovarian and small cell lung cancers. Although topotecan is also approved in combination with cisplatin for cervical cancer, reductions of dose and administration frequency are required due to safety issues. Similar observations have been reported in combination with other anti-cancer agents. We previously reported on a dihydrosphingomyelin (DHSM)-based novel liposomal topotecan, FF-10850 which has been in a Phase I clinical study for solid tumors including ovarian cancer and Merkel cell carcinoma (NCT04047251). FF-10850 demonstrated superior efficacy and safety to non-liposomal topotecan via preferential tumor accumulation and efficient payload release mediated by both tumor-associated macrophages and ammonia produced by glutaminolysis in the tumor microenvironment. In the present study, we examined if FF-10850 could enhance efficacy in combination with platinum, PARP, and immune checkpoint inhibitors in mice models, leveraging its preferential accumulation in the tumor microenvironment.
Methods: FF-10850 in combination with carboplatin or olaparib were evaluated in a platinum-sensitive A2780 and a BRCA2-deficient Capan-1 xenograft model, respectively. A CT26 syngeneic model was used for evaluation of FF-10850 in combination with anti-PD-1 antibody. To confirm establishment of tumor-specific immunity with the FF-10850 and anti-PD-1 antibody combination, re-inoculation of CT26 cells and subsequent inoculation of 4T1 cells was performed in mice that achieved durable complete regressions with the prior combination treatment.
Results: FF-10850 in combination with carboplatin or olaparib significantly improved efficacy compared to each monotherapy without increased body weight loss. Olaparib also attenuated tumor regrowth in a maintenance setting after the completion of FF-10850 monotherapy. Although only 1 or 0 of 8 mice showed complete regression with FF-10850 or anti-PD-1 antibody monotherapy, 6 of 8 mice achieved durable complete regressions with the combination treatment. Furthermore, these mice successfully rejected re-inoculated CT26 cells without subsequent rejection of irrelevant 4T1 cells.
Conclusion: FF-10850 demonstrated favorable efficacy and safety in combination with carboplatin, olaparib or anti-PD-1 antibody, likely related to preferential tumor drug exposure. The combination of FF-10850 with anti-PD-1 antibody efficiently established tumor-specific immunity and long-lasting tumor suppression. Collectively, these observations strongly support further investigations of FF-10850 and improved efficacy in combination with various anti-cancer agents.
Citation Format: Ken Okada, Toshifumi Kimura, Noriyuki Kasagi, Mikinaga Mori, Susumu Shimoyama. FF-10850, a dihydrosphingomyelin (DHSM)-based novel liposomal topotecan, achieved favorable efficacy and safety in combination with platinum, PARP and immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2699.