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Rain Therapeutics' Milademetan Shows Clinical Activity in MDM2-Amplified Intimal Sarcoma

NEW YORK – In the first study of an MDM2 inhibitor in intimal sarcoma, Rain Therapeutics' milademetan reduced tumor size and helped control disease for patients with an MDM2 amplification, according to data presented on Tuesday at the European Society for Medical Oncology Congress.

The small study involving 11 patients suggested that MDM2 inhibitors could potentially treat this rare sarcoma, which has limited therapeutic options and no targeted drugs, according to investigator Yuki Kojima, a staff physician at the National Cancer Center Hospital in Tokyo.

Intimal sarcoma is typically treated by surgery, but for recurrent or metastatic disease, no standard chemotherapy has been established. These sarcomas tend to be aggressive, with patients living between five to 18 months after diagnosis depending on the location of their tumor in the arteries.

However, as the research conducted by Kojima's group showed, the presence of MDM2 amplifications in up to 70 percent of intimal sarcomas provide an opportunity for targeted treatment. Kojima further noted during a presentation at the ESMO Congress that MDM2 amplifications usually occur in intimal sarcomas by themselves, without the co-occurrence of other biomarkers, such as p53 mutations.

These molecular features in intimal sarcomas make them suitable for treatment with an MDM2 inhibitor like milademetan, which inhibits p53 transcription activity in MDM2-amplifed, p53 wild-type tumors, Kojima said.

Milademetan was initially developed by Daiichi Sankyo, but in 2020, Rain Therapeutics licensed the rights to develop the MDM2 inhibitor worldwide for all indications, starting with MDM2-amplified liposarcoma.

The data on milademetan-treated MDM2-amplified intimal sarcoma patients that Kojima reported on this week comes from a large, nationwide registry and basket trial for rare cancers in Japan called the MASTER KEY Project. Within that project, researchers are compiling a national database of genetic and clinical information on patients with rare cancers to identify and enroll participants into basket trials that are investigating the activity of targeted therapies.

The researchers conducted next-generation sequencing to identify MDM2 amplification and p53 wild-type status in patients and confirmed their MDM2 status using immunohistochemistry. Of 10 evaluable patients, two patients (20 percent) had a partial response to treatment with milademetan. Half of the patients, including the two responders, reached stable disease. Half of the patients also remained on treatment for more than five months as of the data cutoff on Jan. 7.

The median progression-free survival was 3.7 months, and median overall survival was 12.2 months. Milademetan also showed an acceptable safety profile in the trial, Kojima said.

Kojima and colleagues continue to analyze the data and are looking for biomarkers to further home in on responders and non-responders to milademetan. The trial will continue through November 2022.

Sebastian Bauer, a researcher at the West German Cancer Center at the University Hospital Essen, who was not involved with the study, noted that simply recruiting MDM2-amplified intimal sarcoma patients for this trial was a "big achievement," considering these tumors make up only about 0.1 percent of all sarcomas.

Bauer also advised exploring combination treatment strategies in this subset of patients to hinder resistance to MDM2 inhibition, which can happen through acquired p53 mutations. Other sarcoma studies have explored p53 inhibition alongside CDK4 inhibitors to overcome that resistance, Bauer said.

"It's certainly a proof of concept [for MDM2 inhibitors] for this ultra-rare sarcoma subtype," Bauer said in discussing the data from this trial at the ESMO Congress. "Two partial remissions certainly are a notable result, despite the small study size, and there's long-term disease control possible in a disease that usually would rapidly grow."