Impact of BRAF mutations on outcomes in metastatic melanoma with central nervous system metastases treated with immune checkpoint inhibitors.
Authors: De Sa Hong , Dedousis Demitrios , Tirumani Sree Harsha , Ardeshir-Larijani Fatemeh , Nelson Ariel Ann , Martin Petra , Mendiratta Prateek , Sloan Andrew E. , Choi Serah , Mansur David B. , Selfridge Jennifer Eva , Ramaiya Nikhil H. , Hoimes Christopher J. 
Published: June 2021

e21500

Background: Half of patients (pts) with melanoma (mel) develop central nervous system (CNS) metastases (mets), leading to death in over 90% in the pre-immune checkpoint inhibitor (ICI) era. Overall survival (OS) has improved in the ICI era for those with CNS mets, yet the association of survival with ICI treatment for those with tumors harboring genomic variants (var) remains unclear. Methods: We retrospectively reviewed our electronic medical records to identify pts with mel and CNS mets who received ICI from 2010 to 2018. Treatment history, systemic and CNS responses, and genomic data were recorded. Genomic var were categorized as BRAFV600E (BRAF), NRAS, cKIT, other var, and no var. Concurrent RT (CRT) was defined as RT to CNS mets within 30 days of ICI. OS was calculated from date of first ICI or RT to date of death or last follow up, and comparison analyses made using Kaplan-Meier estimate. Fisher's exact or Chi-squared tests were used to compare categorical variables and Wilcoxon or Kruskal-Wallis tests to compare continuous variables. A two-sided p-value of < 0.05 was considered statistically significant. Results: A total of 49 pts were identified; 37 had var results available. BRAFV600E was the most common var identified (32%), followed by NRAS (19%), cKIT (5%), and other (5%); 38% had no var. BRAFV600K was not identified. Pts with BRAF had lower rates of CNS progression on ICI at 3 and 6 months than all other pts (17% vs 50%, p< 0.01 and 12.5% vs 40%, p< 0.01, respectively). Of 38 pts (10 BRAF) who had CNS mets at the start of ICI, 6-month OS was 50% in pts with BRAF, compared to 0% in pts with non-BRAF var ( p= 0.01) and 36% in pts with no var ( p= 0.7). 4 of the 10 pts with BRAF who had CNS mets at start of ICI received BRAF-targeted therapy after ICI. On ICI, only 30% of pts with BRAF developed new CNS mets, compared to 57% of all other pts ( p= 0.08). Pts who developed new CNS mets on ICI had worse OS than pts who did not (median OS (mOS) 314 days vs 662 days, p= 0.04). A majority of pts (55%) received anti-CTLA4 monotherapy as first ICI, and 39% received anti-CTLA4 plus anti-PD1. Pts with BRAF were just as likely to receive dual anti-CTLA4/PD-1 as pts without BRAF (33% vs 40%, p= 0.74). 40 pts underwent RT for CNS mets, of whom 22 received CRT. There was no difference in mOS between pts who received CRT and non-concurrent RT/no RT (468 days vs 314 days, p= 0.8). Rates of CRT between pts with BRAF and pts without BRAF were similar ( p> 0.9), and there was no difference in mOS between these groups (400 days vs 536 days, p= 0.9). Conclusions: Pts with BRAF-mutated mel with CNS mets receiving ICI had lower rates of progression in CNS and improved OS compared to other var. CRT was not associated with improved survival over non-concurrent RT. There has been significant improvement in OS of pts with mel CNS mets in the era of ICI and additional studies are warranted to understand the biology of BRAF var and the host immune system response in the CNS.