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28 October 2022 15:00–16:30: PLENARY SESSION 7: Late Breaking and Proffered Papers| Volume 174, SUPPLEMENT 1, S2, October 01, 2022

NMS-01940153E, an MPS1 inhibitor with anti-tumor activity in relapsed or refractory unresectable Hepatocellular carcinoma

      Background: Monopolar Spindle 1 (MPS1) kinase is overexpressed in several tumors, including hepatocellular carcinoma (HCC) where it correlates with tumor features and poor overall and disease-free survival. NMS-01940153E is a highly potent and selective inhibitor of MPS1 kinase with strong preclinical anti-tumor activity in different tumor types. It was previously tested in a FIH study, CL1-81694-001 (EudraCT 2014-002023-10), where activity in HCC patients was detected. The Sponsor, Nerviano Medical Sciences S.r.l., further explored preclinical activity and initiated a Phase 1-2 study, MPSA-153-001 (EudraCT 2020-001002-26), in patients with HCC undergone more than one systemic therapy.
      Materials and Methods: Preclinically, a panel of HCC cell lines was assessed for antiproliferation activity. In the phase 1, a 3+3 escalation design started at 100 mg/m2/wk, with planned dose-increment of 25-35%, to determine MTD and RP2D. Secondary objectives were safety, PK, and preliminary anti-tumor activity. NMS-01940153E was administered IV, on days 1, 8 and 15 every 4 wks.
      Results: Here we present results from the phase 1 part of the trial and supporting pre-clinical data. In HCC lines NMS-01940153E showed ∼2-Log higher anti-proliferative activity compared to sorafenib, lenvatinib, and regorafenib. Twelve HCC patients were evenly enrolled. Median age was 64 years, median number of prior systemic therapies was 2 (range 1-3). At the data cut-off date, 16-AUG-2022, 10 patients had discontinued treatment, 7 due to disease progression (PD). Two DLTs (neutropenia G4 with either sepsis G4 or urinary tract infection G2) occurred at 135 mg/m2/wk. Overall, most frequent (≥10%) any grade drug-related TEAE were neutropenia (50% in the overall population, 2 out of 6 patients at 100 mg/m2/wk, all G≥3), chromaturia and thrombocytopenia/platelet count decrease (25%, 1/6 and 0/6), anemia, asthenia, diarrhea, and injection site reaction (16.7%, 0/6, 1/6, 0/6 and 0/6).
      Out of 11 patients evaluable for efficacy, two (one for each dose level) had confirmed investigator-assessed PR with duration of 11.1 and 40.3 wks (2.5 and 9.3 months); both discontinued treatment due to PD at 6.5 and 11.1 months from treatment start, respectively. Two further patients, one for each dose level, had long-lasting SD, still on treatment at cycles 18 and 11. Three patients, two with PR and one with SD, showed AFP down-modulation. The PK profiles of parent and metabolite showed an increase in exposure with the dose with approximately 4-day half-life for the parent drug; the metabolite accounted for 3% of the parent drug exposure.
      Conclusion: NMS-01940153E showed preclinical and clinical activity in HCC with manageable safety features. This MPS1 inhibitor is currently under evaluation in the phase 2 part of the study in patients with unresectable HCC previously treated with standard-of-care systemic therapy.
      Conflict of interest:
      Corporate-sponsored Research:
      M. Reig: Bayer, Ipsen
      L. Rimassa: Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.
      N. Personeni: Basilea, Merck Serono, Servier
      Other Substantive Relationships:
      M. Reig: consulting fees and/or travel support: AstraZeneca, Bayer, BMS, Eli Lilly, Geneos, Ipsen, Merck, Roche, Universal DX Lecture fees: AstraZeneca, Bayer, BMS, Eli Lilly, Gilead, Roche
      L.Rimassa: consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi travel expenses from Astra Zeneca
      N. Personeni: consulting fees from Amgen, Merck Serono, Servier lectures fees from AbbVie, Gilead, Lilly, Sanofi travel expenses from Amgen, ArQule