[Recurrent or refractory Osteosarcoma and Ewing sarcoma-French guidelines from the FSG/NETSARC and GroupOs groups].

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Déclaration de liens d’intérêts les auteurs déclarent ne pas avoir de liens d’intérêts. 20. Nat Med. 2026 Jun;32(6):2227-2237. doi: 10.1038/s41591-026-04340-7. Epub 2026 Apr 16. Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial. Grohar PJ(1), Heise R(2), Wedekind MF(3), Ballman K(4), Mascarenhas L(5), DuBois SG(6), Maki RG(7), Boguslawski EA(8), Gedminas JM(9), Wilson ER(10), Thomas E(3), Segers B(10), Surrey LF(11), Ricker C(6), Klega K(6), Navid F(12), Lam GY(13), The S(13), Kaufman R(10), Roberts RD(14), Hayashi M(15), Mena E(16), Overman L(17), Peer C(18), Schmidt K(18), Diamond MS(19), Figg WD(18), Bagatell R(10), Liza Lindenberg M(16), Choyke PL(16), Crompton BD(6), Widemann BC(3), Glod JW(3), Laetsch TW(10), Reinke DK(20), Chugh R(20). Author information: (1)Division of Pediatric Hematology/Oncology, University of Michigan Medical School, C.S. Mott Children's Hospital, Rogel Cancer Center, Ann Arbor, MI, USA. grohar@med.umich.edu. (2)Weill Cornell Medicine, New York, NY, USA. (3)Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (4)Mayo Clinic, Rochester, MN, USA. (5)Guerin Children's and Cedars Sinai Cancer, Cedars Sinai Health Sciences University, Los Angeles, CA, USA. (6)Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA. (7)Memorial Sloan-Kettering Cancer Center, New York, NY, USA. (8)Division of Pediatric Hematology/Oncology, University of Michigan Medical School, C.S. Mott Children's Hospital, Rogel Cancer Center, Ann Arbor, MI, USA. (9)Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Iowa, Iowa City, IA, USA. (10)Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (11)Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (12)Cancer and Blood Disease Institute, Children's Hospital of Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (13)Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. (14)Department of Pediatrics, Center for Childhood Cancer, Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA. (15)Department of Pediatrics, University of Colorado Anschutz Medical Campus and Center for Cancer and Blood Disorders, Children's Hospital of Colorado, Aurora, CO, USA. (16)Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (17)Sarcoma Alliance for Research through Collaboration, Ann Arbor, MI, USA. (18)Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19)Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20)University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is absolutely dependent on the EWS::FLI1 transcription factor for cell survival. No compound has been shown to reverse EWS::FLI1 activity in patients, and outcomes for relapsed patients remain poor. Trabectedin above a threshold concentration reverses the activity of EWS::FLI1 and is potentiated by low-dose irinotecan in vivo. This open-label phase 1/2 trial of trabectedin with irinotecan (SARC037) enrolled 37 relapsed/refractory patients with ES. The primary objectives were to determine the safety, tolerability, recommended phase 2 dose (RP2D; phase 1) and objective response rate (ORR; phase 2) of trabectedin administered as a 1-hour infusion in combination with low-dose irinotecan in patients with ES. The secondary objectives were to determine the progression-free survival (PFS), 6-month PFS, duration of response and 18F-fluorothymidine positron emission tomography (18F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1.0 mg m-2 over 1 hour (day 1) and irinotecan 25 mg m-2 (days 2 and 4) of a 21-day cycle. Toxicities were manageable with grade 3 or higher toxicities (>15%) of myelosuppression and alanine aminotransferase elevations at RP2D. The phase 2 ORR was 33% (39%, including RP2D phase 1 patients), and 6-month PFS was 48%. Transcriptional profiling demonstrated reversal of the EWS::FLI1 transcriptome in tumors from a subset of patients. Additional correlative objectives captured molecular profiling, circulating tumor DNA levels, pharmacokinetics and 18F-FLT PET avidity. Here we provide the basis for further development of trabectedin/irinotecan for patients with ES by the international cooperative groups. ClinicalTrials.gov: NCT04067115 . © 2026. The Author(s), under exclusive licence to Springer Nature America, Inc. DOI: 10.1038/s41591-026-04340-7 PMCID: PMC13321597