LBA89 - 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.

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. Table: LBA89

Study findings

Clinical trial identification

RAIN-3201; NCT04979442.

Editorial acknowledgement

Editorial assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd). This work was funded by the study sponsor (Rain Oncology Inc.).

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, Daiichi, 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. R. Sanfilippo: Financial Interests, Personal, Other, Personal Fees: PharmaMar, Rain Oncology, and Boehringer Ingelheim; Financial Interests, Institutional, Other, Institutional fees: Advenchen Laboratories, Amgen, Bayer, Epizyme, Eli Lilly, Daiichi, GSK (GSK), Karyopharm, Novartis, Rain Therapeutics, Pfizer, SpringWorks Therapeutics, and PharmaMar. S.M. Schuetze: Financial Interests, Personal, Other, DSMC member: BioAtla; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Local PI: Tracon, Adaptimmune, Boehringer-Ingelheim, Shanghai Pharmaceuticals, Rain Therapeutics. A. Sebio: 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. R.M. Alvarez: Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Advisory Board: Boehringer, novartis, Roche; Financial Interests, Personal, Other, conference registration: MSD Oncology; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Personal and Institutional, Coordinating PI: Janssen Oncology, Rain Therapeutics, Boehringer, Cebiotex, Novartis. N. Bui: Financial Interests, Personal, Advisory Role: Rain Oncology Inc., Springworks Therapeutics. A.J. Wagner: Financial Interests, Personal, Advisory Board: Aadi Bioscience, Boerhinger-Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera, Eli Lilly, Epizyme, Mundipharma, BioAlta, Servier, Inhibrx; Financial Interests, Institutional, Coordinating PI: Aadi Bioscience; Financial Interests, Institutional, Local PI: Cogent Biosciences, Daiichi Sankyo, Deciphera, Eli Lilly, Foghorn Therapeutics, Karyopharm, Plexxikon, Rain Therapeutics, Boehringer Ingelheim; Non-Financial Interests, Member of Board of Directors: Sarcoma Alliance for Research Through Collaboration (SARC). S.P. Chawla: Financial Interests, Personal, Stocks/Shares, Own stocks.: Cellestia pharma; Financial Interests, Personal, Stocks/Shares, Stocks: Adi Biopharma; Financial Interests, Personal, Ownership Interest, Owner and stocks: Counterpoint; Financial Interests, Institutional, Local PI, Clinical research: Amgen; Financial Interests, Institutional, Local PI, Research: Adi bio, NK Gene, BMS, Rain Therapeutic, Shasqui, Monopar, Ayala, Boeinger; Financial Interests, Personal, Local PI, Research: Rain Therapeutic, Molleculin. T.W. Chen: Financial Interests, Personal, Invited Speaker: Eisai, Novartis, Roche, Pfizer, Daiichi Sankyo, Eli Lilly, TTY, AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, TTY, Eisai, Novartis, Blueprint; Financial Interests, Institutional, Research Grant, IIT study: Eisai; Financial Interests, Institutional, Research Grant, Preclinical: AstraZeneca. D. Pink: Financial Interests, Institutional, Invited Speaker: Blueprint, PharmaMar; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, PharmaMar, Roche; Financial Interests, Institutional, Coordinating PI: BMS, EUSA-Pharma, Lilly, PharmaMar, Roche; Financial Interests, Institutional, Other, scientific lead of a trial with funding from Novartis: Novartis. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. I.Z. Kiladze: Financial Interests, Personal and Institutional, Invited Speaker: MSD, AstraZeneca, Servier; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca. 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, Institutional, Principal Investigator: Rain Onc, Thesius, PTC Pharma. R. Bryce: Financial Interests, Personal, Full or part-time Employment: Rain Oncology; Financial Interests, Personal, Stocks or ownership: Rain Oncology. F. Xu: Financial Interests, Personal, Full or part-time Employment: Rain Oncology Inc.; Financial Interests, Personal, Stocks or ownership: Rain Oncology Inc.. R.C. Doebele: Financial Interests, Personal, Full or part-time Employment: Rain Oncology; Financial Interests, Personal, Stocks or ownership: Rain Oncology. G. Schwartz: Financial Interests, Personal, Stocks or ownership: Bionaut, GenCirq; 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, Research Grant, (Laboratory Support): Astex. All other authors have declared no conflicts of interest.