LBA80 - Siremadlin (S) and ribociclib (R) in patients (pt) with advanced well-differentiated/dedifferentiated liposarcomas (WD/DD LPS) and other molecularly selected cancers: Final analysis of the MEGAMOST “Ribociclib/HDM201” basket study

Background

MEGAMOST was designed to evaluate the clinical benefit of molecular driven treatment (ttt) matched to molecular alteration in advanced solid tumors. We present the results of the “R (CDK4/6 inhibitor) and S (p53-MDM2 inhibitor)” cohort.

Methods

This phase II trial, with a sequential Bayesian design, aim to assess the efficacy and safety R + S in pt with advanced solid tumors harboring amplification (amp) of CDK6 and/or CDK4, and/or CDKN2A homozygous deletion, and/or amp of CCND1 and/or CCND3, and with no deletion/losses more than single copy of RB1 by copy number and P53 wild-type (including WD/DD-LPS). Primary endpoint was progression free rate after 3 months (mo) (3M-PFR). Secondary endpoints were Objective response rate after 3 mo (3M-ORR), best overall response, Progression Free Survival (PFS), Overall survival (OS), % of long-term responders (> 6 mo) and safety profile.

Results

Amongst 50 pt included, 49 were evaluable (median age 63 years (y) [27-79]; 42.9% female) including 17 WD/DD-LPS (15 DD and 2 WD) and 32 other histotypes. All LPS harbored MDM2/CDK4 amp whereas molecular alterations were heterogeneous for the other. The median number of prior lines was 2 [0-5]. Grade ≥3 related adverse events (AE) were reported in 21 pt (42%), mainly anemia (8%) and nausea (6%). The median duration of exposure was 2.8 months (mo) [0.7; 32.4]. 20 pt are in success, the 3M-PFR (bayesian estimation) is 41.2% [95% CI: 28.2; 54.8], predictive probability that the estimated 3M-PFR is ≥ 40% (efficacy boundary) is 56% and 3M-ORR was 0 with 2 late partial responses (both LPS pt). Median PFS was 2.8 mo [95%CI: 2.4; 5.1] and median OS was 10.7 mo [95%CI: 7.6; 13.8]. At the time of analysis, one pt was considered as long term responder (21 mo). In LPS group, 3M-PFR was 78.9% [95% CI: 58.6; 93.6], median-PFS was 8.3 mo [95%CI: 5.2; 19.5], PFS-rate at 6 mo was 52.9% [95%CI: 27.6-73] and median-OS was 23.0 mo [95%CI: 10.9; NE].

Conclusions

S + R demonstrated a manageable safety profile with encouraging efficacy in patients with advanced MDM2-CDK4 amp LPS while the results in others cancers characterized by different molecular alterations were modest.

Clinical trial identification

NCT04116541.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Novartis.

Disclosure

M. Brahmi: Financial Interests, Advisory Board: Bayer, Boehringer; Financial Interests, Invited Speaker: Deciphera. O. Tredan: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Pierre Fabre Oncologie, Seagen, Daiichi Sankyo, Gilead, Eisai, Stemline-Menarini, Veracyte, Exact Sciences. C.A. Gomez-Roca: Financial Interests, Personal, Invited Speaker: BMS, Roche / Genentech, Pierre Fabre; Financial Interests, Personal, Other, IDMC member: PharmaMar; Financial Interests, Personal, Advisory Board: Macomics, Ellipses Pharma, PSAD; Financial Interests, Institutional, Research Grant: Roche / Genentech, Amgen; Financial Interests, Institutional, Coordinating PI: Amunix, Kazia Therapeutics, IDEAYA; Non-Financial Interests, Member of Board of Directors: FITC (Société française d'Immuno-Thérapies du Cancer); Non-Financial Interests, Officer: ESMO Membership Committee, ESMO - MCBS Extended Working Group; Non-Financial Interests, Officer, Young Investigators Committee at imCORE: inFLAME; Non-Financial Interests, Member of Board of Directors, Network of Early Phase Units: OncoDistinct; Non-Financial Interests, Leadership Role: FITC (Société française d'Immuno-Thérapies du Cancer). A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. E.B. Saada: Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Invited Speaker: Merck Serono, MSD; Financial Interests, Coordinating PI: Novartis; Financial Interests, Institutional, Coordinating PI: Roche. P. Cassier: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: Roche, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Other, Advisor: Ose Immunotherapeutics; Financial Interests, Institutional, Local PI: AbbVie, Blueprint, Boehringer Ingelheim, Bristol Meyer Squibbb, Exelixis, GSK, Incyte, Janssen, Loxo/Eli Lilly, Novartis, Roche, Taiho, Toray Industries; Financial Interests, Institutional, Coordinating PI: Amgen, Transgene; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca, GSK. D. Perol: Financial Interests, Personal, Invited Speaker: Astrazenena, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli-Lilly, Gilead, Ipsen, Pfizer, Novartis, Merck Sharp and Dohme, Roche, Takeda; Financial Interests, Personal, Advisory Board: Brenus Pharma; Other, travel expenses (ESMO annual meeting Madrid 2023): Novartis; Other, travel expenses (ESMO annual meeting Paris 2022): Roche. J. Blay: Financial Interests, Institutional, Invited Speaker: MSD, MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022: Innate Pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE Pharma. A. Dufresne: Non-Financial Interests, Project Lead, Translational research project: GSK, Adaptimmune; Non-Financial Interests, Project Lead, Translational research program: Bayer. All other authors have declared no conflicts of interest.