Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors

Abstract

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. Chisquare 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.

Molecular and Clinical Features of Hospital Admissions in Patients with Thoracic Malignancies on Immune Checkpoint Inhibitors

“…The survival outcome that we observed was also previously confirmed in a larger cohort by our group, yet further investigation is required [ 50 ]. The MET gene encodes a transmembrane receptor tyrosine kinase, and its ligand hepatocyte growth factor (HGF) is involved in the MET/HGF signaling pathway.…”

Outcome of non-small-cell lung cancer with driven mutations treated with anti-PD-(L)1 agents: A systematic review

“…We ultimately included 46 studies in the final analysis (Figure 1). 1,7-52 In the included studies, researchers analysed a total of 2261 patients, mostly with EGFR mutation (Table 1). Except for patients enrolled in Impower 150, in many patients (n=22 studies), nonsquamous or adenocarcinoma was the prevalent histology, and they were primarily included in the pretreated setting.…”

Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer

“…The previous studies documented that higher TMB or PD-L1 expression correlated with better outcomes as compared with lower TMB or PD-L1 expression (11,12,25,40). However, in 70 of 75 patients from Hellmann cohort who had all three biomarkers data, correlation between TMB and PD-L1 expression was not significant (R=-0.14, p-value=0.24).…”