Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors
Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.
Authors
- Steven G. DuBois (ORCID: https://orcid.org/0000-0003-0882-738X)
- Noah Federman (ORCID: https://orcid.org/0000-0002-2627-6772)
- Vadim Bernard-Gauthier
- Esther De La Cuesta (ORCID: https://orcid.org/0000-0001-7072-1493)
- Soledad Gallego (ORCID: https://orcid.org/0000-0002-4712-9624)
- C. Michel Zwaan (ORCID: https://orcid.org/0000-0001-6892-8268)
- Neerav Narendra Shukla (ORCID: https://orcid.org/0000-0003-2516-2965)
- Julia Chisholm (ORCID: https://orcid.org/0000-0003-3479-7997)
- Stefan Bielack (ORCID: https://orcid.org/0000-0003-2144-3153)
- Daniel A. Morgenstern (ORCID: https://orcid.org/0000-0002-4859-1108)
- Ramamoorthy Nagasubramanian (ORCID: https://orcid.org/0000-0003-4629-3139)
- Catherine M. Albert (ORCID: https://orcid.org/0000-0001-7610-9932)
- Hiroaki Goto (ORCID: https://orcid.org/0000-0001-6737-1509)
- Johannes H. Schulte (ORCID: https://orcid.org/0000-0003-0671-1201)
- Cormac Owens (ORCID: https://orcid.org/0000-0001-6559-3239)
- Alberto S. Pappo (ORCID: https://orcid.org/0000-0002-5338-3979)
- Yizhuo Zhang (ORCID: https://orcid.org/0000-0002-6128-3476)
- Birgit Geoerger (ORCID: https://orcid.org/0000-0003-4361-3643)
- Daniel H. Orbach (ORCID: https://orcid.org/0000-0002-2520-139X)
- Cornelis Martinus van Tilburg (ORCID: https://orcid.org/0000-0001-5274-910X)
- Leo Mascarenhas (ORCID: https://orcid.org/0000-0001-7790-0777)
- Theodore Willis Laetsch (ORCID: https://orcid.org/0000-0002-8497-3138)
- Sébastien Perreault (ORCID: https://orcid.org/0000-0002-4417-7698)
- Natascha Neu
Institutions
- Cedars-Sinai Medical Center (US)
- Seattle Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Royal Marsden NHS Foundation Trust (GB)
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Institute of Cancer Research (GB)
- Bayer (United States) (US)
- Inserm (FR)
- Sun Yat-sen University (CN)
- University of California, Los Angeles (US)
- German Cancer Research Center (DE)
- University of Toronto (CA)
- University of Washington (US)
- Heidelberg University (DE)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Hospital for Sick Children (CA)
- Institut Gustave Roussy (FR)
- Erasmus MC (NL)
- University Hospital Heidelberg (DE)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Fred Hutch Cancer Center (US)
- Bayer (Canada) (CA)
- National Center for Tumor Diseases (DE)
- Olgahospital (DE)
- Kanagawa Children's Medical Center (JP)
- Hopp Children's Cancer Center Heidelberg (DE)
- Royal Marsden Hospital (GB)
- University Children's Hospital Tübingen (DE)
- Princess Máxima Center (NL)
- Vall d'Hebron Hospital Universitari (ES)
- Our Lady's Hospital (IE)
- Sun Yat-sen University Cancer Center (CN)
- Nemours Children's Clinic (US)
- Klinikum Stuttgart (DE)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Charité - Universitätsmedizin Berlin (DE)
- University of Pennsylvania (US)
- Institut Curie (FR)
- Erasmus University Rotterdam (NL)
- Philadelphia University (US)
Publication Details
- Journal
- Journal of Clinical Oncology
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1200/jco.24.00848
- Citations
- 10
- Primary Topic
- Sarcoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 15.18
Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Amgen
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Jazz Pharmaceuticals
- Royal Marsden NHS Foundation Trust
- Y-mAbs Therapeutics
- National Institute for Health and Care Research
- Bayer HealthCare
- Eisai
- Genentech
- Loxo Oncology