Giulia Berzero1, Luisa Bellu1,2, Capucine Baldini3, François Ducray4, David Guyon5, Marica Eoli6, Antonio Silvani6, Caroline Dehais1, Ahmed Idbaih1, Nadia Younan1, Ludovic Nguyen Them7, Stephan Gaillard8, Francesco Pasqualetti9, Coralie Lepage-Seydoux10, Sakina Sekkate11, Patricia Tresca12, Aurélie Kas13, Julie Gratieux14, Samy Ammari15, Edouard Saragoussi16, Julien Savatovsky16, Jean-Yves Delattre1, Khê Hoang-Xuan1, David Meyronet17, Chiara Villa18, Franck Bielle19,20, Marc Sanson1,20, Mehdi Touat1, Anna Luisa Di Stefano21,5. 1. Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Epinière, and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France. 2. Radiation Therapy Unit, Imaging and Medical Physics Department, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy. 3. Drug Development Department, Institut Gustave Roussy and Université Paris-Saclay, Villejuif, France. 4. Department of Neuroncology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France. 5. Department of Neurology, Hôpital Foch, Suresnes, France. 6. Neuro-oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 7. Service de Neurologie, Centre Hospitalier Perpignan, France. 8. Department of Neurosurgery, Hôpital Foch, Suresnes, France. 9. Radiation Oncology, Department of Medicine and Oncology, University Hospital, Pisa, Italy. 10. Service de Pharmacie, Hôpital Foch, Suresnes, France. 11. Department of Oncology, Hôpital Foch, Suresnes, France. 12. Clinical Research Unit, Institut Curie, Paris, France. 13. Department of Nuclear Medicine, AP-HP GH Pitié-Salpêtrière, Paris, France. 14. Department of Neuroradiology, Hôpital Foch, Suresnes, France. 15. Department of Diagnostic Radiology, Institut Gustave Roussy, Villejuif, France. 16. Neuroradiology Unit, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France. 17. Department of Pathology, Eastern Hospital Group, Lyon Civil Hospices, Lyon, France. 18. Department of Pathology, Hôpital Foch, Suresnes, France. 19. Department of Neuropathology, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France. 20. Onconeurotek Tumor Bank, Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France. 21. Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Epinière, and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France al.di-stefano@hopital-foch.com.
Abstract
OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNT), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of six neuroncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNT treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n=9), pleomorphic xanthoastrocytomas (n=9), and diffuse gliomas (n=10) were included in the study. At the time treatment with RAFi/MEKi was started, all tumors displayed radiological features of high-grade neoplasms. Thirteen patients received RAFi as single agents [vemurafenib (n=11), dabrafenib (n=2)], and 15 combinations of RAFi/MEKi [vemurafenib+cobimetinib (n=5), dabrafenib+trametinib (n=10)]. Eleven patients achieved a partial or complete response (11/28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p=0.047). Responders had better KPS (p=0.018), tended to be younger (p=0.061) and to be treated earlier (p=0.099) compared to non-responders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in two. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the clinical benefits of RAFi/MEKi in adult patients with BRAF-mutant GGNT, encourages the systematic screening and rechallenge in responders.
OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNT), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of six neuroncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNT treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n=9), pleomorphic xanthoastrocytomas (n=9), and diffuse gliomas (n=10) were included in the study. At the time treatment with RAFi/MEKi was started, all tumors displayed radiological features of high-grade neoplasms. Thirteen patients received RAFi as single agents [vemurafenib (n=11), dabrafenib (n=2)], and 15 combinations of RAFi/MEKi [vemurafenib+cobimetinib (n=5), dabrafenib+trametinib (n=10)]. Eleven patients achieved a partial or complete response (11/28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p=0.047). Responders had better KPS (p=0.018), tended to be younger (p=0.061) and to be treated earlier (p=0.099) compared to non-responders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in two. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the clinical benefits of RAFi/MEKi in adult patients with BRAF-mutant GGNT, encourages the systematic screening and rechallenge in responders.
Authors: Alberto Picca; David Guyon; Orazio Santo Santonocito; Capucine Baldini; Ahmed Idbaih; Alexandre Carpentier; Antonio Giuseppe Naccarato; Mario Caccese; Giuseppe Lombardi; Anna Luisa Di Stefano Journal: Cancers (Basel) Date: 2022-02-22 Impact factor: 6.639