Milademetan Shows Promise for Patients With Advanced MDM2-Mutated Solid Tumors

The interim analysis of the phase 2 MANTRA-2 trial of milademetan, an MDM2 inhibitor, has demonstrated promising safety and activity in patients with advanced solid tumors. The trial will continue enrolling patients.

Preliminary data from the phase 2 MANTRA-2 trial (NCT05012397) of milademetan (RAIN-32) in patients with MDM2-amplified advanced solid tumors, showed promising activity and with a consistent safety profile to prior studies, according to Rain Therapeutics, Inc.1

Two patients exhibited an unconfirmed partial response (PR) at the time of their first scan. Out of the 10 evaluable patients, 2 more saw promising tumor regression activity. These data showed the monotherapy activity of milademetan in patients with MDM2-amplified solid tumors.

“In the first 10 evaluable patients, we have observed activity with 2 unconfirmed partial responses at their first scan and promising tumor regression activity in 2 patients following milademetan monotherapy. In addition, anti-tumor activity was observed in patients with genetic co-alterations, and in tumors with MDM2 copy number above 8. Hence, we plan to revise the protocol to include patients tested locally for MDM2 copy number of 8 and greater,” stated Richard Bryce, MD, MBChB, chief medical officer of Rain Therapeutics, Inc, in the press release. “We are encouraged by these preliminary data, and we look forward to continuing the trial and evaluating additional data as they become available in the coming months.”

Milademetan is an oral, small molecule inhibitor of the MDM2-p53 complex that reactivates p53 and is being developed by Rain Therapeutics Inc. for the treatment of MDM2-amplified advanced solid tumors.

Previously, milademetan received an orphan drug designation from the FDA for the treatment of patients with liposarcoma. In a phase 1 clinical trial, the agent showed antitumor activity in an MDM2-amplified subtype of liposarcoma and other solid tumors. This trial was also supported by a rationally designed dosing schedule to mitigate safety concerns and widen the potential therapeutic window of MDM2 inhibition.

Besides the evaluation of milademetan in the phase 2 MANTRA-2 trial, the phase 3 MANTRA trial (NCT04979442) recently completed enrollment of patients with liposarcoma. Further, the company aims to start a phase 1/2 clinical trial evaluating the safety, tolerability, and efficacy of milademetan in combination with atezolizumab (Tecentriq) in patients with loss of cyclin-dependent kinase inhibitor 2A and wildtype p53 advanced solid tumors (MANTRA-4) in 2023.

MANTRA-2 is a multicenter, single arm, open-label, phase 2, basket trial evaluating the safety and efficacy of milademetan monotherapy in patients with advanced or metastatic solid tumors who are refractory or intolerant to standard-of-care therapy, and must exhibit wild-type p53 and a prespecified minimum MDM2 gene copy number (CN).2

Further, patients enrolled on the trial must be aged 18 years and older with a measurable tumor lesion(s), have an ECOG performance of 0-1, adequate bone marrow, renal, and hepatic function, and have resolved from any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy.

Approximately 65 patients are anticipated to be enrolled and administered oral milademetan 260 mg once daily on days 1 to 3 and days 15 to 17 of each 28-day cycle. As of the latest data cutoff on October 26, 2022, 17 patients have been enrolled.

Investigators are evaluating the primary end point of objective response rate as measured by RECIST criteria and the secondary endpoints of duration of response, disease control rate progression-free survival by investigator assessment, overall survival, and growth modulation index.

At the data cutoff date of October 26, 2022, 17 patients were enrolled and 15 were dosed with milademetan. Among these patients, 10 were efficacy-evaluable with CN ≥8 by central testing, there were various tumor histologies enrolled amongst the evaluable patients, and most had co-alterations in oncogenes or tumor suppressors, including KRAS, EGFR, and PIK3CA amongst others.

The observed anti-tumor effect of milademetan was assessed in patients who were heavily pretreated, refractory, and had a median of 4 prior therapies.

There were 2 unconfirmed PRs observed with tumor regression of 34% in pancreatic cancer and 30% in lung cancer, respectively. The patient with pancreatic cancer is pending response confirmation and ongoing treatment.

Two patients exhibited promising activity with tumor regression of 29% (biliary tract) and 27% (breast cancer) and are continuing with the investigational therapy.

Overall, the safety profile of milademetan remains consistent with what was demonstrated in a phase 1 trial of the agent. However, 1 patient on the study with lung cancer died due to COVID-19.

“We are encouraged by the preliminary observations from the MANTRA-2 trial,” said Avanish Vellanki, co-founder and chief executive officer of Rain Therapeutics Inc, in the press release. “Treatment with milademetan led to tumor regression in patients previously treated with a multitude of therapies across a range of cancers. We look forward to expanding this dataset as the trial continues to enroll.”

A protocol amendment of the study planned to adjust MDM2 CN threshold to CN ≥ 8 from CN ≥ 12. The MANTRA-2 trial will continue to enroll patients across the United States, including in California, Florida, Massachusetts, Missouri, New York, North Carolina, Tennessee, and Texas.

Rain Therapeutics provides interim analysis of phase 2 basket trials of milademetan for MDM2-amplified advanced solid tumors (MANTRA-2). News release. Rain Therapeutics. November 4, 2022. Accessed November 7, 2022.
Milademetan in advanced/metastatic solid tumors. Updated August 17, 2022. Accessed November 7, 2022.