1719O - Multisarc: A randomized precision medicine study in advanced soft-tissue sarcomas

Background

Next-generation sequencing exome (NGS) has retrospectively shown potential in identifying driver mutations in Soft-tissue sarcomas (STS). However, the effectiveness of this approach in prospective studies remains under-explored.

Methods

MULTISARC, is a phase II/III randomized trial across 17 French Sarcoma Group sites, included patients (pts) with advanced STS. Pts were randomized 1:1 to an experimental “NGS” arm (exome and RNA sequencing), or a standard “No NGS” arm. Molecular profiling data were analyzed by a national molecular tumor board. Pts with actionable alterations were offered phase II trials for targeted therapies as second-line or maintenance treatments. The primary goal was to evaluate the feasibility of NGS in a large cohort and, secondarily, to determine if NGS-guided therapy could improve Pts outcomes. Secondary objectives included survival rates, efficacy and safety profiles of targeted therapies.

Results

Between 10/2019 and 10/2023, 439 Pts were enrolled (median age 62.0 years, range 18-88). Main histological subtypes were leiomyosarcoma (23.9%), liposarcoma (23.0%), and undifferentiated pleiomorphic sarcoma (15.3%). In the NGS arm, 314 alterations were identified across 62 genes, with a median of 2 alterations per Pts. The most frequently altered genes were TP53, MDM2, FRS2, CDK4, ATRX, RB1, CDKN2A, DDR2, NF1, PTEN, MYC, ATM, PIK3CA, HMGA2, RICTOR, VEGFA, FGFR1, BRCA1, KRAS, BRCA2. 47 gene fusions were identified, with the most common being SS12::SSX1 and NAB2::STAT6. Notably, 14% of cases exhibited a transcriptomic tertiary lymphoid structure signature. 47% of pts in NGS arm had at least one targetable alteration, and 36% of these received targeted investigational agents based on NGS. Among these, 26 pts participated in the durvalumab-olaparib trial, with the primary endpoint being 6-month non-progression. Of these, 8 pts (32%) were progression-free indicating the study objective was met.

Conclusions

MULTISARC trial demonstrates the feasibility of high-throughput molecular profiling in advanced STS, identifying actionable alterations that lead to clinical benefits. This trial represents a milestone in the evolution of personalized medicine for STS pts, highlighting the potential of tailored therapeutic approaches.

Clinical trial identification

NCT03784014.

Editorial acknowledgement

Legal entity responsible for the study

Institut Bergonié.

Funding

Inserm Source Type: Government Agency.

Disclosure

B. Verret: Financial Interests, Institutional, Invited Speaker: Lilly, Pfizer, Pierre Fabre, Seagen, Daiichi Sankyo, Gilead, Novartis, MSD, AstraZeneca; Financial Interests, Institutional, Advisory Board: Lilly, Daiichi Sankyo, Gilead, Novartis, Owkins, AstraZeneca, MSD, Boehringer Ingelheim. S. Watson: Financial Interests, Personal, Invited Speaker: Deciphera, AstraZeneca; Financial Interests, Personal, Advisory Board: Deciphera, Boehringer Ingelheim. N. Penel: Financial Interests, Institutional, Research Grant, Research grant for clinical trials in sarcoma filed: Bayer HealthCare. 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. M. Brahmi: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen, PharmaMar, Deciphera. N. Isambert: Financial Interests, Personal, Advisory Board: Novartis, Transgene, Pfizer, GSK; Financial Interests, Personal, Invited Speaker: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Novartis, Roche, Daiichi Sankyo, MSD, Deciphera, Anaveon, Dizal Pharmaceutical, Exelisis, Iteos Therapeutics, Amgen, Janssen, Pyramid Biosciences. 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. I. Soubeyran: Financial Interests, Institutional, Invited Speaker, congress; meeting: AstraZeneca; Financial Interests, Institutional, Funding, research funding: AstraZeneca. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have declared no conflicts of interest.