Novel MPS1 Inhibitor Shows Early Signs of Activity in Third-line HCC

Maria Reig, MD, PhD

A novel MPS1 inhibitor, NMS-01940153E (S81694), has demonstrated clinical activity in patients with relapsed or refractory unresectable hepatocellular carcinoma (HCC), according to the phase 1 results of a phase 1/2 trial (MPSA-153-001). The data were presented at the 2022 European Organisation for Research and Treatment–National Cancer Institute–American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics.¹

Maria Reig, MD, PhD, head of the Hepatic Oncology Unit at the Hospital Clínic de Barcelona, Spain, explained that the MPS1 kinase regulates the spindle assembly checkpoint, and when it is inhibited, it leads to cancer death because of excess mitotic instability. There is a high unmet need for new therapies with novel mechanisms in the third-line setting and high expression of MPS1 has been found in HCC compared with normal tissue (P = .003), and MPS1 was found to be an independent prognostic factor for overall survival in HCC (HR, 1.92; 95% CI, 1.01-3.68).²

Reig presented new preclinical data showing that NMS-01940153E is highly active specifically in HCC cell lines. Compared with traditional therapies for HCC, including regorafenib (Stivarga), lenvatinib (Lenvima), sorafenib (Nexavar), and doxorubicin, NMS-01940153E demonstrated high sensitivity and a low half maximal inhibitory concentration (< 0.05 M) across 7 HCC cell lines.¹

In data from a first-in-human study (ISRCTN35641359) of the MPS1 inhibitor in patients with advanced solid tumors, among 35 evaluable patients, 2 patients showed a response and 13 had stable disease. Both patients with HCC in the study had stable disease lasting 6 months, and 1 had a transient reduction in liver target lesion size of 27% after having received 3 prior systemic therapies.³

The MPSA-153-001 trial is a dose-finding and dose-expansion study in patients with unresectable HCC who were previously treated with systemic therapy. In phase 1, patients were enrolled if they had failed standard treatment options to determine the maximum tolerated dose and recommended phase 2 dose for the agent. In the ongoing phase 2 portion of the trial, up to 40 patients who were being treated in the third line or beyond were included.

Patients received NMS-01940153E intravenously at either 100 mg/m² (n = 6) or 135 mg/m² (n = 6) on days 1, 8, and 5 of each cycle. Treatment continued until disease progression or treatment intolerance.

Twelve evaluable patients have been studied to date in the phase 1 portion who have a median age of 64 years (range, 28-76) and 91.7% are male. Half the patients have locally advanced disease and the other half have metastatic disease. The most common metastatic site was the lung, for 33.3%, followed by the lymph nodes, for 25%. Patients had an ECOG performance status of 0 (50%) or 1 (50%), and all had Child-Pugh class A disease and an albumin-bilirubin grade of 1 (83.3%) or 2 (16.7%). The median number of prior lines of therapy was 2 (range, 1-3), with the most common prior therapies including sorafenib (75%), cabozantinib (Cabometyx; 33.3%), regorafenib (25%), and lenvatinib (25%).

As of the data cutoff, 2 patients achieved a partial response, 1 in each dose group, and 3 had stable disease. Of the 2 responders, the duration of response was 2.6 months for 1 patient and 9.3 months for the other. Two patients, 1 in each group, are receiving ongoing treatment. Among 7 patients evaluable for α-fetoprotein, 3 experienced a decrease in levels of at least 20%.

Reig noted that 1 patient who experienced a partial response and a duration of response of 9.3 months had a reduction in lesion size of 44% from baseline. The patient was still alive at 12.3 months from study entry.

“This is something completely unexpected in our field, and that’s why we believe that in spite of the small sample of this trial, we have a sign of activity,” she said.

The most common adverse events (AEs) reported were neutropenia in 50% of patients, platelet count decrease in 25%, and chromaturia in 25%. In the 100-mg/m² dose group, only 2 grade 3 events of neutropenia and 1 grade 4 event of sepsis were observed. AEs were more common in the 135-mg/m2 dose group, with 5 grade 3 events (neutropenia, platelet count decrease, asthenia, and systemic hypertensive crisis) and 2 grade 4 events (neutropenia), which were considered dose-limiting toxicities.

One discontinuation was due to an AE (grade 3 asthenia and platelet count decrease) in the 135-mg/m² group. One patient in the 100-mg/m² group had a treatment interruption in the first cycle due to an infusion reaction. As a result, the maximum tolerated dose was determined to be 100 mg/m² per week.

_REFERENCES:

_{1. Reig M, Damian S, Roberti D, et al. NMS-01940153E, an MPS1 inhibitor with anti-tumor activity in relapsed or refractory unresectable hepatocellular carcinoma. Paper presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 26-28, 2022; Barcelona, Spain. Abstract 3LBA.}

_{2. Jiang H, Yuan F, Zhao Z, et al. Expression and clinical significance of MPS-1 in hepatocellular carcinoma. Int J Gen Med. 2021;14:9145-9152. doi:10.2147/IJGM.S334378}

_{3. Schöff ski P, Awada A, de la Bigne AM, et al. First-in-man, firstin- class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered intravenously in adult patients with advanced, metastatic solid tumours. Eur J Cancer. 2022;169:135-145. doi:10.1016/j.ejca.2022.04.001}