Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome. Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression. High PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classicEGFR,EGFRexon 20 andHER2-mutant tumors, and 34%–55% in tumors withALK,BRAFV600E,ROS1,RET, orMETalterations. Compared withKRAS-mutant tumors,BRAFnon-V600E group had higher TMB (9.6 vsKRAS7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups withEGFR,HER2,ALK,ROS1,RET, orMETalterations had short progression-free survival (PFS; 1.8–3.7 months), whileBRAFV600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vsKRAS3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vsKRAS24%; PFS 7.4 vsKRAS2.8 months, HR 0.36, p=0.026).KRASG12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis,BRAFV600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS. High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboringBRAFmutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. MeanwhileEGFRandHER2mutations andALK,ROS1,RET, andMETfusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.