Milademetan Fails to Meet PFS End Point in Dedifferentiated Liposarcoma

Treatment with milademetan (RAIN-32) did not lead to a statistically significant improvement in progression-free survival (PFS) compared with trabectedin (Yondelis) in patients with dedifferentiated liposarcoma (DDLPS), failing to reach the primary end point of the phase 3 MANTRA trial (NCT04979442).¹

Topline data showed that milademetan elicited a median PFS of 3.6 months per blinded independent central review (BICR) vs 2.2 months for trabectedin (HR, 0.89; 95% CI, 0.61-1.29; P = .53).

“We are very disappointed in the outcome of the MANTRA trial, as the results did not closely mirror prior clinical results in patients with DDLPS,” Avanish Vellanki, co-founder and chief executive officer of Rain Oncology, stated in a news release. “We are truly saddened we will not likely be able to offer patients new treatment options for this challenging disease. However, the quality and robustness of the global MANTRA trial reflects an unambiguous data set.

“Rain’s mission remains to advance science, and therefore we will further evaluate the totality of the MANTRA data to support the scientific and medical community in the hope we can aid others in finding new strategies for patients with DDLPS. Based on the MANTRA topline results, we will also re-evaluate the path forward for milademetan. We continue to believe that reactivating p53 is an important avenue to pursue as part of a treatment strategy across cancer. I would like to extend our sincerest gratitude to the patients and clinicians who participated in the trial as well as our dedicated team.”

The randomized, multicenter, open-label, registrational MANTRA trial evaluated the safety and efficacy of milademetan—an oral, small molecule inhibitor of the MDM2-p53 complex that reactivates p53—compared with trabectedin, which is a current standard of care for patients with DDLPS.

The trial enrolled patients at least 18 years of age with histologically confirmed unresectable or metastatic DDLPS with or without a well-differentiated LPS component who had progressed on 1 or more prior systemic therapies, including at least one anthracycline-based therapy.2 Patients were also required to have at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate bone marrow and hepatic function.

Key exclusion criteria included prior treatment with any MDM2 inhibitor or trabectedin, history of other primary malignancies requiring systemic antineoplastic treatment within 2 years of enrollment, untreated brain metastases, or uncontrolled or significant cardiovascular disease.

The study included 175 patients who were randomly assigned in a 1:1 fashion to receive 260 mg of oral milademetan once per day on days 1 to 3 and days 15 to 17 of each 28-day cycle, or 1.5 mg/m2 of trabectedin as a 24-hour intravenous infusion once every 3 weeks.

Along with the primary end point of PFS per BICR, secondary end points included overall survival, investigator-assessed PFS, objective response rate, duration of response, disease control rate, safety, and patient-reported outcomes.

Regarding safety, most common treatment-emergent adverse effects (TEAEs) experienced by patients in the milademetan arm consisted of nausea, thrombocytopenia, anemia, vomiting and neutropenia.1 The most common grade 3/4 TEAEs in the experimental arm included thrombocytopenia (39.5%), neutropenia (25.5%), and anemia (18.6%). Serious TEAEs occurred in 36.0% and 48.1% of patients in the milademetan and trabectedin arms, respectively.

Additionally, 44.2% of patients in the milademetan arm required dose reductions compared with 29.1% of patients in the trabectedin arm. Rates of treatment discontinuations due to AEs were 11.6% and 19.0% for milademetan and trabectedin, respectively.

References

1. Rain Oncology announces topline results from phase 3 MANTRA trial of milademetan for the treatment of dedifferentiated liposarcoma. News release. Rain Oncology. May 22, 2023. Accessed May 22, 2023. https://www.rainoncology.com/news-press-releases/
2. Treatment of milademetan versus trabectedin in patient with dedifferentiated liposarcoma (MANTRA). ClinicalTrials.gov. Updated March 30, 2023. Accessed May 22, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04979442