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Clin Cancer Res. 2019 Aug 15;25(16):5015-5026. doi: 10.1158/1078-0432.CCR-19-0585. Epub 2019 May 13.

Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti-PD-(L)1 Therapies in Non-Small Cell Lung Cancer.

Author information

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China. zhangli6@mail.sysu.edu.cn fangwf@sysucc.org.cn yang.shao@geneseeq.com.
2
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
3
Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
4
Geneseeq Technology Inc., Toronto, Ontario, Canada.
5
Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. zhangli6@mail.sysu.edu.cn fangwf@sysucc.org.cn yang.shao@geneseeq.com.
6
School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
#
Contributed equally

Abstract

PURPOSE:

Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood.

EXPERIMENTAL DESIGN:

We performed genomic profiling of 78 patients with non-small cell lung cancer (NSCLC) who underwent anti-PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response.

RESULTS:

We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32-4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09-4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types.

CONCLUSIONS:

We identified novel genomic biomarkers that were predictive of response to anti-PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.

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