Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma

• DOI: 10.1056/evidoa2400087
• Publication Date: 2024-09-24T13:31:59Z
• Authors: Paolo A. Ascierto; Mario Mandalà; Pier Francesco Fe...; Massimo Guidoboni; Piotr Rutkowski; Virginia Ferraresi; Ana Arance; Michele Guida; Evaristo Maiello; Helen Gogas; Erika Richtig; Pietro Quaglino; Céleste Lebbé; Hildur Helgadottir; Paola Queirolo; Francesco Spagnolo; Marco Tucci; Michele Del Vecchio; Maria Gonzalez-Cao; Alessandro Marco ...; Sabino De Placido; Miguel F. Sanmamed; Milena Casula; Jenny Bulgarelli; Marina Pisano; Claudia Piccinini; Luisa Piccin; Antonio Cossu; Domenico Mallardo; Miriam Paone; Maria Grazia Vitale; Ignacio Melero; Antonio M. Grimaldi; Diana Giannarelli; Giuseppe Palmieri; Reinhard Dummer; Vanna Chiarion Si...

The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAFV600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients.In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C).Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76).In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).