MPS1 Kinase Inhibitor Shows Clinical Activity in Primary Liver Cancer
The targeted drug NMS-01940153E, a monopolar spindle 1 (MPS1) kinase inhibitor, has shown signs of clinical activity in a Phase I study of patients with relapsed or refractory unresectable hepatocellular carcinoma (HCC). The study findings were reported at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
“We only treated 12 patients, but two of them achieved partial response. That means decreased tumor burden [of] at least 30 percent,” said first author Maria Reig, MD, PhD, Professor and Head of the Barcelona Clinic Liver Cancer Unit at the Hospital Clinic of Barcelona at Barcelona University in Spain. Two further study patients (one for each dose level) had long-lasting stable disease, one of whom showed alpha-fetoprotein down modulation.
“NMS-01940153E represents a new type of treatment working in a very different way from the current options for treating liver cancer,” Reig noted. It offered potential to help patients in the future. But she emphasized that the efficacy noted in this early study—primarily dose-finding and toxicity—needed to be confirmed.
The study reported that the experimental agent had shown orders of magnitude (two logs) higher anti-proliferative activity in HCC cell lines than sorafenib, lenvatinib, and regorafenib, which are kinase inhibitor drugs already being tried to treat HCC.
“Preclinical work demonstrated that NMS-01940153E was highly effective in preventing the proliferation of cancer cells, both on its own and in combination with other anti-cancer drugs. It seems more potent than other kinase inhibitors in liver cancer cells. And so we are testing it—as a single agent—in a Phase 1 clinical trial in liver cancer patients,” said Reig, who noted the current standard for systemic treatment—immunotherapy—generally failed in three-quarters of all patients.
After her talk in Barcelona, Reig said their investigational Mps1 kinase inhibitor had been shown to target cell division in what she described as one of the most lethal cancers. “The amazing thing is that it works in the cycle of mitosis,” she said. “The key thing, here, is that expression of MPS-1 was demonstrated in several cancers—[and] also in HCC. However, until now we did not have data in hepatocellular carcinoma cell lines. [The] pre-clinical data that was presented was focused on that. We identified a new mechanism of action related to mitosis. This was used in the past for other tumors, but not in HCC.”
When she was asked what was special about this particular kinase inhibitor that set it apart, she told Oncology Times it was the specific target that made the difference. “We are really, really interested in continuing with this research because [it] seems that it could act in an area that we have never seen before in HCC. Because patients [who] were failures for other treatments—sorafenib, lenvatinib, regorafenib—now have a good outcome with this component.”
Patients with HCC enrolled in the study had a median age of 64 years and a median number of two prior systemic therapies. By the cut-off date (in August 2022), 10 patients had discontinued treatment, seven due to disease progression and two because of dose-limiting toxicities. Drug-related adverse events included neutropenia, chromaturia, thrombocytopenia, anemia, asthenia, and diarrhea.
Reig said neutropenia was the most frequent adverse event, defining the maximum tolerated dose. So, it was key in the management of patients, she said. But it was manageable. “The important thing [is] neutropenia recovered to Grade 1 in 9 days without [any] need to use treatment.”
Reig said that, although their patients developed progression, many of them had good performance status and liver function. “For example, one of the patients lived 11 months after progression. So that means that after three failures, the fourth line of treatment [gave] the median survival (from the beginning of the study) [of] almost a year—something amazing.”
The investigators concluded that the MPS1 inhibitor had shown preclinical and clinical activity in HCC and that the safety of the agent was manageable. In the ongoing Phase II study, it was currently under evaluation in patients with unresectable HCC previously treated with standard-of-care systemic therapy.
“I’m interested, but I’m really cautious,” said Reig. “We are talking about a very early phase of development. The sign is here, but be cautious. Consider this drug only in the setting of a clinical trial.”
Peter M. Goodwin is a contributing writer.
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