Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma
Paolo A. Ascierto, Mario Mandalà, Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Pietro Quaglino, Célèste Lebbé, Hildur Helgadóttir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzalez-Cao, Alessandro Marco Minisini, 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 Maria Grimaldi, Diana Giannarelli, Giuseppe Palmieri, Reinhard Dummer, Vanna Chiarion‐Sileni
Abstract
BACKGROUND: V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.).