Molecular and immune profiling of <i>BRAF</i> -mutated ( <i>BRAF</i> ^MUT ) non-small cell lung cancer (NSCLC).

Abstract

8653 Background: BRAF MUT occur in 6-7% of NSCLC and comprise of biologically distinct classes showing variable therapeutic responses. While Class 1 benefits from targeted therapy, molecular and immune determinants distinguishing BRAF classes remain incompletely characterized. We performed comprehensive profiling to identify class-specific biomarkers. Methods: 51,692 (BRAF wild-type [ BRAF WT ]: n=48,288; BRAF MUT : n=3404) NSCLC specimens underwent DNA (592-gene panel/whole-exome) and/or RNA (whole-transcriptome) sequencing at Caris Life Sciences. BRAF MUT tumors were classified into 3 Classes, other pathogenic variants (O PV ), and unknown/unclassified variants (VUS). The tumor microenvironment (TME) was estimated using the QuanTIseq method. Overall survival (OS) and IO-associated survival (IO-OS) were derived from insurance claims and calculated from the date of tumor biopsy (OS) or IO initiation (IO-OS) to last contact using Kaplan-Meier estimates. Statistical significance was determined by Fisher’s Exact, chi-square, and Mann-Whitney U test with adjustments for multiple comparisons ( P &lt;0.05). Results: Class 1 was significantly enriched for SETD2 mutations (mut) and more frequently PDL1+ (22c3, TPS&gt;=1) while showing a lower prevalence of TMB-high (&gt;=10 mut/Mb), TP53, STK11 and KEAP1 mut (Table). Class 2/3 tumors were moderately PDL1+ and TMB-high and enriched for STK11 and KEAP1 muts (Table). While both OPV and VUS were enriched for TMB-high and not PDL1, OPV was enriched in STK11, and VUS was enriched in TP53 mut (Table). Among BRAFMUT, Class 1 exhibited the highest infiltration of M1 macrophages (1.1-1.3-fold), neutrophils (1.2-1.3-fold) and the lowest infiltration of dendritic cells (0.4-0.8-fold). Class 2 and 3 had largely overlapping immune profiles. In metastatic NSCLC, only Class 1 and VUS demonstrated improved OS and IO-OS (vs BRAFWT, both p&lt;0.05, Table). OPV had the poorest outcomes, exhibiting the shortest OS and shorter IO-OS relative to Class 1 and Class 2 (all p&lt;0.05, Table). Conclusions: BRAF MUT classes represent distinct molecular, immune and clinical phenotypes. Improved OS and IO-OS in Class 1 and VUS (vs WT) appears to arise from divergent molecular and immune interactions. These findings underscore the importance of evaluating of BRAF MUT NSCLC beyond class 1-3, suggesting the expanded classification may have therapeutic and prognostic consequences. Molecular features (odds ratio) and survival outcomes (median months [95% CI]) among BRAF MUT classes. Genes Class 1 (n=695) Class 2 (n=741) Class 3 (n=701) O PV (n=123) VUS (n=936) WT SETD2 21.5 s 1.2 1.0 0.6 1.4 0.2 s TP53 0.4 s 1.0 1.0 0.8 1.6 s 1.1 s STK11 0.1 s 1.7 s 2.3 s 2.1 s 0.8 0.9 s KEAP1 0.1 s 1.5 s 1.7 s 1.5 1.1 1 TMB-high 0.3 s 1.8 s 2.3 s 2.3 s 3.3 s 0.6 s PDL1+ 3.4 s 1.3 s 1.1 0.9 1.0 0.7 s med OS 18(14-21) 14(12-18) 13(11-16) 8(4-11) 16(12-20) 12(12-12) med IO-OS 27(19-40) 20(15-24) 18(12-24) 8(2-15) 24(19-32) 17(17-18) P &lt;0.05 denoted by s .