TY - JOUR
T1 - Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors
AU - Zhao, Dan
AU - Mambetsariev, Isa
AU - Li, Haiqing
AU - Chen, Chen
AU - Fricke, Jeremy
AU - Fann, Patricia
AU - Kulkarni, Prakash
AU - Xing, Yan
AU - Lee, Peter P.
AU - Bild, Andrea
AU - Massarelli, Erminia
AU - Koczywas, Marianna
AU - Reckamp, Karen
AU - Salgia, Ravi
N1 - Funding Information:
This work was supported by the National Cancer Institute of the National Institutes of Health under awards number R01CA218545, P30CA033572 and U54CA209978.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/8
Y1 - 2020/8
N2 - Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients. Materials and methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis. Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06−0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15–47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03−0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05). Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.
AB - Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients. Materials and methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis. Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06−0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15–47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03−0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05). Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.
KW - FANCA
KW - Immune checkpoint inhibitors
KW - Immunotherapy
KW - Lung cancer
KW - Molecular
KW - Next-generation sequencing (NGS)
KW - PD-L1
KW - TET2
KW - TMB
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U2 - 10.1016/j.lungcan.2020.05.025
DO - 10.1016/j.lungcan.2020.05.025
M3 - Article
C2 - 32554069
AN - SCOPUS:85086411220
SN - 0169-5002
VL - 146
SP - 174
EP - 181
JO - Lung Cancer
JF - Lung Cancer
ER -