Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer
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 th...
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BMJ Publishing Group
2021-08-01
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Series: | Journal for ImmunoTherapy of Cancer |
Online Access: | https://jitc.bmj.com/content/9/8/e002891.full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianhua Zhang Hao Xu Alexandre Reuben Brian Alexander Jack Lee Tina Cascone Jianjun Zhang Kyle G Mitchell Marcelo V Negrao Stephen G Swisher John V Heymach Don L Gibbons Jack A Roth Ferdinandos Skoulidis Yasir Y Elamin Xiuning Le Anne Tsao Chang-Jiun Wu Vincent A Miller Bonnie S Glisson Karthikeyan Murugesan Meagan Montesion Garrett Frampton Katja Schulze Ilze Bara Vincent Shen Sylvia Hu Dawen Sui Michael E Goldberg David S Barreto Jacqulyne P Robichaux Carl M Gay Lingzhi Hong Waree Rinsurongkawong Vassiliki Papadimitrakopoulou Gaurav Singal Lee A Albacker David Shames |
spellingShingle |
Jianhua Zhang Hao Xu Alexandre Reuben Brian Alexander Jack Lee Tina Cascone Jianjun Zhang Kyle G Mitchell Marcelo V Negrao Stephen G Swisher John V Heymach Don L Gibbons Jack A Roth Ferdinandos Skoulidis Yasir Y Elamin Xiuning Le Anne Tsao Chang-Jiun Wu Vincent A Miller Bonnie S Glisson Karthikeyan Murugesan Meagan Montesion Garrett Frampton Katja Schulze Ilze Bara Vincent Shen Sylvia Hu Dawen Sui Michael E Goldberg David S Barreto Jacqulyne P Robichaux Carl M Gay Lingzhi Hong Waree Rinsurongkawong Vassiliki Papadimitrakopoulou Gaurav Singal Lee A Albacker David Shames Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer Journal for ImmunoTherapy of Cancer |
author_facet |
Jianhua Zhang Hao Xu Alexandre Reuben Brian Alexander Jack Lee Tina Cascone Jianjun Zhang Kyle G Mitchell Marcelo V Negrao Stephen G Swisher John V Heymach Don L Gibbons Jack A Roth Ferdinandos Skoulidis Yasir Y Elamin Xiuning Le Anne Tsao Chang-Jiun Wu Vincent A Miller Bonnie S Glisson Karthikeyan Murugesan Meagan Montesion Garrett Frampton Katja Schulze Ilze Bara Vincent Shen Sylvia Hu Dawen Sui Michael E Goldberg David S Barreto Jacqulyne P Robichaux Carl M Gay Lingzhi Hong Waree Rinsurongkawong Vassiliki Papadimitrakopoulou Gaurav Singal Lee A Albacker David Shames |
author_sort |
Jianhua Zhang |
title |
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
title_short |
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
title_full |
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
title_fullStr |
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
title_full_unstemmed |
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
title_sort |
oncogene-specific differences in tumor mutational burden, pd-l1 expression, and outcomes from immunotherapy in non-small cell lung cancer |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2021-08-01 |
description |
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. |
url |
https://jitc.bmj.com/content/9/8/e002891.full |
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doaj-deb634044c5641f5a4d7746a8b39b5982021-08-12T14:30:03ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-08-019810.1136/jitc-2021-002891Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancerJianhua Zhang0Hao Xu1Alexandre Reuben2Brian Alexander3Jack Lee4Tina Cascone5Jianjun Zhang6Kyle G Mitchell7Marcelo V Negrao8Stephen G Swisher9John V Heymach10Don L Gibbons11Jack A Roth12Ferdinandos Skoulidis13Yasir Y Elamin14Xiuning Le15Anne Tsao16Chang-Jiun Wu17Vincent A Miller18Bonnie S Glisson19Karthikeyan Murugesan20Meagan Montesion21Garrett Frampton22Katja Schulze23Ilze Bara24Vincent Shen25Sylvia Hu26Dawen Sui27Michael E Goldberg28David S Barreto29Jacqulyne P Robichaux30Carl M Gay31Lingzhi Hong32Waree Rinsurongkawong33Vassiliki Papadimitrakopoulou34Gaurav Singal35Lee A Albacker36David Shames37Aff1 grid.240145.60000000122914776The University of Texas MD Anderson Cancer Center Houston TX USA 4 Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Aff1 grid.240145.60000000122914776Surgical OncologyMD Anderson Cancer Center Houston TX USA R&D, Foundation Medicine Inc, Cambridge, Massachusetts, USADivision of Biomedical Engineering and Imaging Sciences, King's College London, London, UKAff2 0000 0001 2291 4776grid.240145.6Department of Thoracic/Head and Neck Medical OncologyThe University of Texas MD Anderson Cancer Center Houston TX USA Aff2 0000 0001 2291 4776grid.240145.6Department of Thoracic/Head and Neck Medical OncologyThe University of Texas MD Anderson Cancer Center Houston TX USA Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USAThoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USAThoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USAThoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USAThoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United StatesThoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Thoracic Head and Neck Medical Oncology, UTMDACC, Houston, Texas, USAUniversity of Texas MD Anderson Cancer Center, Houston, TX, USAUniversity of Texas MD Anderson Cancer Center, Houston, TX, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USA2Foundation Medicine, Inc., Cambridge, Massachusetts, USA3 Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Foundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAGenentech Inc, South San Francisco, California, USAGenentech Inc, South San Francisco, California, USAGenentech Inc, South San Francisco, California, USAGenentech Inc, South San Francisco, California, USADepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAFoundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Radiology, Breast Imaging and Interventional Center, The George Washington University, Washington, DC, USADepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAPfizer Inc, New York, New York, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAGenentech Inc, South San Francisco, California, USABackground 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.https://jitc.bmj.com/content/9/8/e002891.full |