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