A randomised, multicenter phase-III study comparing doxorubicin (dox) alone versus dox with trabectedin (trab) followed by trab in non-progressive patients (pts) as firstline therapy, in pts with metastatic or unresectable leiomyosarcoma (LMS): Final results of the LMS-04 study

Background: In the LMS‐04 study primary analysis (NCT02997358), the combination of dox + trab demonstrated a significant progression‐free survival (PFS) benefit (12·2 months versus 6·2 months], adjusted hazard ratio (HR) 0·41 [95% CI 0·29–0·58]; p<0·0001) in 1st‐line treatment of patients with advanced LMS (Pautier; Lancet Oncol 2022). Herein, we report the updated PFS (uPFS) and final results of overall survival (OS) analyses (planned when all pts had at least 3 years of follow‐up). Methods: Pts received either dox alone 75 mg/m2 (arm A) or dox 60 mg/m2 followed by trab 1.1 mg/m2 as a 3‐hour infusion (arm B), repeated every 3 weeks for up to 6 cycles (cy) followed in arm B by trab in non‐progressive pts up to 17 cy. Surgery for residual disease was permitted. Randomisation was stratified by tumour location (uterine versus soft tissue) and disease (locally advanced versus metastatic). The analysis of PFS and OS was adjusted for stratification factors. Results: Overall, 150 pts with LMS (67 with uterine LMS and 83 with soft‐tissue LMS), and mostly with metastatic disease (90%), were enrolled. The median duration of follow‐up was 54.9 months [95% CI = 51.25‐60.48] with 107 deaths (60 in arm A and 47 in arm B). Median uPFS was significantly longer with dox + trab versus dox alone (12.19 mo [95% CI = 10.09‐15.57] versus 6.21 mo [95% CI = 4.07‐7.06] with adjusted HR: 0.37 [95%CI = 0.26‐0.53] and p<0.0001). Median OS was also significantly longer with the association (33.08 [95% CI = 26.22‐47.54] versus 23.78 months with dox alone [95% CI = 18.86‐30.68], adjusted HR=0.65 [95% CI = 0.44‐0.95] p=0.0253). No new safety signal was observed. Conclusions: dox + trab combination can be considered as first ‐line treatment for metastatic/advanced uterine and soft‐tissue LMS. Clinical trial identification: NCT02997358. Legal entity responsible for the study: Gustave Roussy Cancer Campus. Funding: PharmaMar. Disclosure: P. Pautier: Financial Interests, Personal, Advisory Board, 2015, 2022 : PharmaMar; Financial Interests, Institutional, Advisory Board, 2020 : Roche, Clovis; Financial Interests, Institutional, Advisory Board, 2021 : AstraZeneca; Financial Interests, Personal, Advisory Board, 2019‐2020: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, 2018‐2019: Roche; Financial Interests, Institutional, Advisory Board, 2022 : MSD; Financial Interests, Personal and Institutional, Research Grant: PharmaMar; Financial Interests, Research Grant: Onxeo. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. S. Piperno‐Neumann: Financial Interests, Personal, Advisory Board: Immunocore, Pierre Fabre, Atlanthera. P. Boudou Rouquette: Financial Interests, Personal, Invited Speaker, speaker Journée du Centre Hépato‐Biliaire (2022) : Ipsen; Other, Other, travel fees for ESMO sarcoma congress (2023) travel fees for GSF GETO congress (2022): PharmaMar; Other, Travel fees for ASCO congress (2021): Pfizer. I.L. Ray‐Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, adaptimmun, Eisai, Sutro, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Financial Interests, Principal Investigator: PAOLA1; Financial Interests, Other, President: GINECO. 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. All other authors have declared no conflicts of interest.