76MO - Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas

Background

New treatments are needed for advanced dedifferentiated liposarcoma (DDLPS), which is characterized by MDM2 gene amplification. Milademetan is a selective, potent, small molecule inhibitor of the MDM2-p53 interaction that reactivates p53 to induce apoptosis of TP53 wild-type malignant cells. MANTRA (RAIN-3201; NCT04979442) is a global, randomized, multicenter, phase 3 study of milademetan vs. trabectedin in pretreated unresectable/metastatic DDLPS.

Methods

Eligible pts: ≥18y; unresectable/metastatic DDLPS±WD; ≥1 prior systemic therapies (≥1 anthracycline regimen); radiographic evidence of PD ≤6m. Pts were randomized (1:1) to milademetan (260 mg orally QD d1–3 & d15–17 q28d) or trabectedin (1.5 mg/m², 24-h iv infusion q3w) until PD or intolerability. Tumor response was evaluated at w8, 16, 24&32, then q12w. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints: OS; ORR; DCR; DOR; PFS by investigator; safety. Study sample size was estimated to support primary endpoint in favor of milademetan (HR 0.5, 94% power, type I error 0.05).

Results

Median age: 64y (range 20–82y); white (69.7%), male (56.6%). Median follow-up: 2.1m (range 0–13m). Median PFS by BICR was numerically but not significantly higher for milademetan. While immature, median OS was comparable in the two arms, as were ORR and DCR. Most common all grade and grade 3/4 TEAEs for milademetan (Table). No Grade 5 events occurred with milademetan vs. 5 with trabectedin. Dose reductions due to TEAEs were higher but discontinuation rates lower with milademetan. Table: 76MO

Study findings

^a Planned interim analysis.

Conclusions

While median PFS was longer for milademetan, the difference was not significant. TEAEs were consistent with previous reports and manageable by dose interruptions/modifications. Further evaluation of milademetan is warranted in populations that may benefit from MDM2 inhibition.

Clinical trial identification

NCT04979442.

Editorial acknowledgement

Editorial/writing assistance for the abstract was provided by Lee Miller, Miller Medical Communications.

Legal entity responsible for the study

Rain Oncology, Inc.

Funding

Rain Oncology, Inc.

Disclosure

R.L. Jones: Financial Interests, Personal, Advisory Board, I worked as a consultant.: Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Springworks, Tracon, Upto Date, Pharmamar, Astex, Immunicum, Karma Oncology, Merck, Mundipharma, Synox; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial.: MSD. A. Sebio Garcia: Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Expert Testimony: PharmaMar; Financial Interests, Personal, Training: Boston Scientific; Financial Interests, Personal, Advisory Role: PharmaMar, Boehringer Ingelheim. N. Bui: Financial Interests, Personal, Advisory Role, Paid Consulting: Rain Oncology Inc., Springworks Therapeutics. H.H.F. Loong: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly, Illumina, Bayer, Guardant Health; Financial Interests, Personal, Advisory Board: Novartis, Takeda. C. Yen: Financial Interests, Personal, Invited Speaker: Zai Lab, CStone; Financial Interests, Personal, Expert Testimony: Zai Lab; Financial Interests, Personal, Advisory Board: Zai Lab, CStone, TTY; Financial Interests, Institutional, Principal Investigator: Rain Oncology, Boehringer Ingelheim, Taiho, Cogent, Napo, Deciphera; Financial Interests, Institutional, Sponsor/Funding: Rain Oncology, Boehringer Ingelheim, Taiho, Cogent, Napo, Deciphera. S. Patel: Financial Interests, Personal, Invited Speaker: Deciphera, DSI, Rain, Bio Atla, Bayer; Financial Interests, Personal, Member of Board of Directors: Chordoma Foundation; Financial Interests, Personal, Principal Investigator: Rain Onc, Thesius, PTC Pharma. R.P. Bryce, F. Xu, B. Zhang, N.V. Shah, R.C. Doebele: Financial Interests, Personal, Full or part-time Employment: Rain Oncology Inc.; Financial Interests, Personal, Stocks/Shares: Rain Oncology Inc. G. Schwartz: Financial Interests, Personal, Advisory Board: Concarlo, Epizyme, OnCusp, Puretech Health, Aadi Subsidiary, Inc. Boehringer Ingelheim Pharmaceuticals, Kirilys Therapeutics, Sellas Life Sciences, Astex, Shanghai Pharma. Ipsen; Financial Interests, Personal, Stocks or ownership: Bionaut, GenCirq; Financial Interests, Institutional, Research Grant: Astex (Laboratory Support). All other authors have declared no conflicts of interest.