Encorafenib and biNimetinib Followed by CEmiplimab and FiAnLimab in Patients With BRAF Mutant melanOma and Symptomatic Brain Metastases

Summary

Brain metastases in patients with advanced and metastatic melanoma are a frequent complication and a significant cause of morbidity and mortality in this patient population. As the incidence of brain metastases continues to increase in patients with metastatic melanoma, it is urgent that the investigators identify effective therapies. ENCEFALO is a Phase II, single arm, multicentre clinical trial designed to evaluate the activity of encorafenib plus binimetinib followed by cemiplimab and fianlimab in patients with BRAF mutated melanoma and symptomatic brain metastases, following the simon design Two-stage minimax. The objective main is to evaluate the 6 month intracranial progression-free survival (icPFS) proportion of Encorafenib plus Binimetinib followed by Cemiplimab plus Fianlimab in patients with BRAF-mutated melanoma and symptomatic brain metastases according RECIST criteria The trial hypothesis is: For patients with BRAF-mutated melanoma and symptomatic brain metastases, an induction treatment with encorafenib and binimetinib (EB) for about two months (i.e. 8 weeks) followed by cemiplimab plus fianlimab (CF) would allow a 6 month icPFS rate of 40% in comparison to historical control of 20% based on CM204 symptomatic arm (Tawbi et al 2021).

Timeline

Start

2025-05-29

Primary completion

2028-01

Completion

2028-01

Publications

• Results Marquez-Rodas I, Alvarez A, Arance A, Valduvieco I, Berciano-Guerrero MA, Delgado R, Soria A, Lopez Campos F, Sanchez P, Romero JL, Martin-Liberal J, Lucas A, Diaz-Beveridge R, Conde-Moreno AJ, Alamo de la Gala MDC, Garcia-Castano A, Prada PJ, Gonzalez Cao M, Puertas E, Vidal J, Foro P, Aguado de la Rosa C, Corona JA, Cerezuela-Fuentes P, Lopez P, Luna P, Aymar N, Puertolas T, Sanagustin P, Berrocal A. Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study). Neuro Oncol. 2024 Nov 4;26(11):2074-2083. doi: 10.1093/neuonc/noae116.
• Results Lau PKH, Feran B, Smith L, Lasocki A, Molania R, Smith K, Weppler A, Angel C, Kee D, Bhave P, Lee B, Young RJ, Iravani A, Yeang HA, Vergara IA, Kok D, Drummond K, Neeson PJ, Sheppard KE, Papenfuss T, Solomon BJ, Sandhu S, McArthur GA. Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES). J Immunother Cancer. 2021 Oct;9(10):e002995. doi: 10.1136/jitc-2021-002995.
• Results Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutierrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. doi: 10.1056/NEJMoa2109970.
• Results Panella TJ, Thomas SS, McKean M, et al: A phase 3 trial comparing fianlimab (anti-LAG-3) plus cemiplimab (anti-PD-1) to pembrolizumab in patients with completely resected high-risk melanoma. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS9598-TPS9598.
• Results Baramidze A, Gogishvili M, Makharadze T, et al: A phase 3 trial of fianlimab (anti-LAG-3) plus cemiplimab (anti-PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma. Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) TPS9602-TPS960
• Results Hamid O, Lewis KD, Weise A, McKean M, Papadopoulos KP, Crown J, Kim TM, Lee DH, Thomas SS, Mehnert J, Kaczmar J, Lakhani NJ, Kim KB, Middleton MR, Rabinowits G, Spira AI, Yushak M, Mehmi I, Fang F, Chen S, Mani J, Jankovic V, Wang F, Fiaschi N, Brennan L, Paccaly A, Masinde S, Salvati M, Fury MG, Kroog G, Lowy I, Gullo G. Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma. J Clin Oncol. 2024 Aug 20;42(24):2928-2938. doi: 10.1200/JCO.23.02172. Epub 2024 Jun 20.
• Results Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Marquez-Rodas I, Del Vecchio M, Lebbe C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):863-873. doi: 10.1016/S1470-2045(17)30429-1. Epub 2017 Jun 4.
• Results Long GV, Atkinson V, Lo S, et al: Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol. 2021;39(15_suppl):9508-950
• Results Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.
• Results Ramanujam S, Schadendorf D, Long GV. Systemic therapies for melanoma brain metastases: which drug for whom and when? Chin Clin Oncol. 2015 Jun;4(2):25. doi: 10.3978/j.issn.2304-3865.2015.06.06.
• Results Chukwueke U, Batchelor T, Brastianos P. Management of Brain Metastases in Patients With Melanoma. J Oncol Pract. 2016 Jun;12(6):536-42. doi: 10.1200/JOP.2016.011882.
• Results Tawbi HA, Forsyth PA, Hodi FS, Algazi AP, Hamid O, Lao CD, Moschos SJ, Atkins MB, Lewis K, Postow MA, Thomas RP, Glaspy J, Jang S, Khushalani NI, Pavlick AC, Ernstoff MS, Reardon DA, Kudchadkar R, Tarhini A, Chung C, Ritchings C, Durani P, Askelson M, Puzanov I, Margolin KA. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021 Dec;22(12):1692-1704. doi: 10.1016/S1470-2045(21)00545-3. Epub 2021 Nov 10.

Drugs

Indications