Abstract 5996: New therapeutic approaches in NUT carcinoma: An unmet need

Abstract Background: NUT carcinoma (NC) is a rare, aggressive tumor with poor prognosis and no standard treatment. NC arises from NUTM1 gene rearrangements, which drive epigenetic dysregulation and uncontrolled proliferation via enhanced RNA polymerase II (RNA-pol II) activity. An analysis of our registry (70 patient) revealed limited benefits from current systemic therapies. Among patients on first-line (26), progression-free survival was modest: immunotherapy (5.4months-mo-, 95%CI 3.6-7.1), chemo-immunotherapy(CTIO) (4.8mo, 95%CI 0.2-8.8), BET inhibitors (4.3mo, 95%CI 1-17.1), and chemotherapy (3.9mo, 95%CI 1.7-52.1). Given Lurbinectedin’s (LUR) RNA-pol II-dependent mechanism and its regulation of BRD4, a critical partner of NUTM1, we investigated its potential therapeutic value in NC. Methods: LUR efficacy was assessed in three settings. First, in vitro studies by 4 BRD4:NUTM1 cell lines treated with escalating doses of LUR for 72 hours, and cell viability evaluated by MTT assays. Second, in vivo, with 2 patient-derived xenograft (PDX) models. Finally, under compassionate use, 3 patients with BRD4:NUTM1. Results: NC cell lines demonstrated high sensitivity to LUR, with IC50: 22-122nM. Ongoing PDX model experiments are evaluating in vivo sensitivity. Clinically, a 54-year-old woman with metastatic thoracic NC pretreated with CTIO, showed rapid clinical and radiological response to second-line LUR, with a 3mo duration of response. A 20-year-old man with head and neck metastatic NC pretreated with VDC/IE, had clinical improvement (ECOG-PS, weight gain, and reduced morphine use) after a first cycle (imaging pending for response confirmation). The third patient, recently initiated second-line LUR. Conclusion: Preliminary results suggest that LUR shows promising activity in NC, both in vitro and in early clinical cases. LUR offers a biologically informed therapeutic strategy in NC. These findings highlight the importance of leveraging tumor biology to guide treatment development for rare and aggressive cancers Citation Format: Maria Virginia Sanchez-Becerra, Carmen Escudero-Iriarte, Ludovic Bigot, Tian V Tian, Pablo Aviles-Marin, Magdalena Knetki-Wróblewska, Sinead Oreilly, Mateo Bover, José Carlos Benitez-Montañez, Paloma Martin-Martorell, Sergio Sandiego Contreras, Maria Rosa Ghigna, Christos Markellos, Mickael Burgy, Camille Travert, Pauline Hulo, Mangon Quentin, Rodrigo Motta Guerrero, Jeanne Chapron, Nathalie Cozic, Luc Friboulet, Yohann Loriot, Antoine Italiano, Benjamin Besse. New therapeutic approaches in NUT carcinoma: An unmet need [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5996.