Abstract 509: The MPS1/TTK inhibitor, NMS-01940153, synergizes with tisotumab vedotin in colorectal cancer

Abstract

Abstract Background: MPS1 kinase plays a crucial role in maintaining genomic integrity by controlling the spindle assembly checkpoint (SAC). MPS1 is highly expressed in tumors of different origins and overexpression is associated with poor prognosis. By inhibiting MPS1, cancer cells are forced to enter anaphase before chromosomes are aligned, leading to mitotic catastrophe and apoptosis. NMS-01940153 (NMS-153) is a potent and selective MPS1 inhibitor, with antitumor activity in vitro and in vivo. NMS-153, under investigation in a clinical trial, shows early signs of clinical activity, an acceptable safety profile, with manageable and reversible neutropenia as the main adverse effect (EudraCT 2020-001002-26; Reig et al, Eur J Cancer 174S1, 2022). Microtubule targeting agents (MTAs), such as taxanes and vinca alkaloids, cause mitotic arrest and activate the SAC. Concomitant SAC disruption by MPS1 inhibition synergizes with MTAs, but the combination is limited by neutropenia in the clinic. Purpose and Methods: The goal is to show synergism between NMS-153 and MTA and to find a strategy to overcome the limiting neutropenia of this combination. For this, Tisotumab vedotin (TV), an anti-Tissue Factor (TF) with Monomethyl auristatine E (MMAE) payload, was used. TF is aberrantly expressed in a variety of tumors compared to normal tissue counterpart. In colorectal cancer (CRC), TF is overexpressed in patients with distinct molecular features including BRAF mutation, a colon cancer population that hardly responds to chemotherapy or BRAF inhibitors. At therapeutic doses, TV induces low rate of grade ≥3 neutropenia. The combination of NMS-153 and TV is expected to synergize and have an acceptable safety profile. LS411N CRC model expressing TF and harboring a BRAFV600E mutation was selected for testing NMS-153 and TV in combination. In vivo, NMS-153 was tested at 13 or 20 mpk every 4 days for 7 doses. TV was tested at 1 or 4 mpk weekly for 2 doses. The 2 therapeutic doses of both agents were tested in combination. Results: In vitro, synergism of NMS-153 with TV in LS411N cells was observed. In vivo, NMS-153 and TV as single agents were efficacious in LS411N xenograft with TGIs up to 53% and 89%, respectively. The median survival time (MST) for the vehicle group was 35.5 days. NMS 153 and TV single agents prolonged survival with MSTs up to 53 and 73.3 days, respectively. When combined, a dose-dependent therapeutic benefit was observed, with an MST of >137 days, and 6 out of 10 mice profiting of long-term tumor regressions at the highest doses tested. The combination benefit was statistically significantly different from single agents and more than additive. Treatments were well tolerated. Conclusions: The combination of NMS-153 with TV is synergistic in the LS411N CRC model. These data strongly suggest the potential for clinical efficacy of NMS-153 with TV and the combinability of NMS-153 with TV and other MMAE-based ADCs in different tumor contexts. Citation Format: Gemma Texido, Fabio Gasparri, Antonella Ciavolella, Laura Gianellini, Anders E. Pedersen, Alberto Ocaña, Riccardo Colombo, Domenico Roberti, Lisa Mahnke, Claudia Perrera. The MPS1/TTK inhibitor, NMS-01940153, synergizes with tisotumab vedotin in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 509.