Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer
Authors: Marcelo V Negrao, Ferdinandos Skoulidis, Meagan Montesion, Katja Schulze, Ilze Bara, Vincent Shen, Hao Xu, Sylvia Hu, Dawen Sui, Yasir Y Elamin, Xiuning Le, Michael E Goldberg, Karthikeyan Murugesan, Chang-Jiun Wu, Jianhua Zhang, David S Barreto, Jacqulyne P Robichaux, Alexandre Reuben, Tina Cascone, Carl M Gay, Kyle G Mitchell, Lingzhi Hong, Waree Rinsurongkawong, Jack A Roth, Stephen G Swisher, Jack Lee, Anne Tsao, Vassiliki Papadimitrakopoulou, Don L Gibbons, Bonnie S Glisson, Gaurav Singal, Vincent A Miller, Brian Alexander, Garrett Frampton, Lee A Albacker, David Shames, Jianjun Zhang, John V Heymach
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background 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. Methods 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. Results High PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR , EGFR exon 20 and HER2 -mutant tumors, and 34%–55% in tumors with ALK , BRAF V600E, ROS1 , RET , or MET alterations. Compared with KRAS- mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p&lt;0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR , HER2 , ALK , ROS1 , RET , or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p&lt;0.001) were associated with longer PFS. Conclusions High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK , ROS1 , RET , and MET fusions 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.