Journal Article

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

Robichaux, Jacqulyne P, Xu, Hao, Reuben, Alexandre, Glisson, Bonnie S, Wu, Chang-Jiun, Shen, Vincent, Roth, Jack A, Hong, Lingzhi, Mitchell, Kyle G, Cascone, Tina, Frampton, Garrett, Montesion, Meagan, Negrao, Marcelo V, Miller, Vincent A, Skoulidis, Ferdinandos, Murugesan, Karthikeyan, Barreto, David S, Shames, David, Sui, Dawen, Rinsurongkawong, Waree, Lee, Jack, Zhang, Jianhua, Bara, Ilze, Goldberg, Michael E, Hu, Sylvia, Gay, Carl M, Albacker, Lee A, Papadimitrakopoulou, Vassiliki, Swisher, Stephen G, Tsao, Anne, Zhang, Jianjun, Schulze, Katja, Le, Xiuning, Singal, Gaurav, Alexander, Brian, Heymach, John V, Elamin, Yasir Y, Gibbons, Don L

2021

Overview

BackgroundNon-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.MethodsThree 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.ResultsHigh 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.ConclusionsHigh 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.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - biosynthesis / B7-H1 Antigen - immunology / Biomarkers / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - pathology / Chemotherapy / Clinical outcomes / Cohort Studies / Humans / Immune Checkpoint Inhibitors - pharmacology / Immunotherapy / Immunotherapy - methods / Immunotherapy Biomarkers / Laboratories / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Medical prognosis / Mutation / Oncogenes / Progression-Free Survival / Statistical analysis / Treatment Outcome / Tumor Burden