Clinical outcomes of EGFR+/METamp+ vs. EGFR+/METamp‐ untreated patients with advanced non‐small cell lung cancer

Abstract

Background: MET dysregulation has been implicated in the development of primary and secondary resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. However, the clinicopathological characteristics and outcomes of patients harboring EGFRsensitive mutations and de novo MET amplifications still need to be explored. Methods: A total of 54 patients from our hospital with non-small cell lung cancer harboring EGFR-sensitive mutations and/or de novo MET amplifications were included in this study. Survival rates were estimated by the Kaplan-Meier method with logrank statistics. Lung cancer organoids (LCOs) were generated from patient-derived malignant pleural effusion to perform drug sensitivity assays. Results: Fifty-four patients with the appropriate clinicopathological characteristics were enrolled. MET FISH was performed in 40 patients who were stratified accordingly into two groups: EGFR+/METamp-(n = 22) and EGFR+/METamp + (n = 18). Survival rates for EGFR+/METamp-and EGFR+/METamp + patients respectively, were as follows: the median progression-free survival (PFS) was 12.1 and 1.9 months (p<0.001); the median post-progression overall survival (pOS) was 25.6 and 11.6 months (p = 0.023); the median overall survival (OS) was 33.2 and 12.7 months (p = 0.013). Drug testing conducted in LCOs derived from malignant pleural effusion from EGFR+/METamp + patients showed that dual targeted therapy was more effective than TKI monotherapy. Conclusion: EGFR+/METamp + patients treated with first-line TKI monotherapy had poor clinical outcomes. Dual targeted therapy showed potent anticancer activity in the LCO drug testing assay, suggesting that it is a promising first-line treatment for EGFR+/METamp + patients. Randomized controlled trials are needed to further validate these results.K E Y W O R D S de novo MET amplification, EGFR-sensitive mutation, non-small cell lung cancer, patient-derived organoid, targeted therapy Kai-Cheng Peng and Jun-Wei Su contributed equally.

Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments

“…Results from two studies demonstrated a significant statistical association between MET amp and a higher proportion of programmed cell death protein 1 ligand (PD-L1) expression ( 25 , 35 ). Overall, most studies (8/10) found no statistical association between MET amp and a positive smoking history ( 24 , 26 , 27 , 32 , 33 , 44 , 45 , 47 , 50 , 51 ). Among two studies that evaluated patients with EGFR- mutant NSCLC who experienced progression on an EGFR-TKI, one study found that history of smoking was associated with a high probability of secondary MET amp (p=0.011), and one study found no association between smoking status and presence of MET amp (p=0.45) ( 24 , 27 ).…”

“…A summary of results from 16 US- or non-US based studies that evaluated demographic and clinical characteristics of patients with NSCLC with or without MET amp is found in Supplementary Table 4 ( 24 – 27 , 29 , 32 , 33 , 35 – 37 , 44 – 47 , 50 , 51 ). Results from the identified studies show that the following characteristics were consistently considered not associated with MET amp (either primary, secondary, or not specified): age (11 studies), sex (11 studies), and NSCLC sub-type (adenocarcinoma vs non-adenocarcinoma, squamous cell carcinoma, or other; 6 studies) ( 24 , 26 , 27 , 32 , 33 , 36 , 44 , 45 , 47 , 50 , 51 ). Results from two studies demonstrated a significant statistical association between MET amp and a higher proportion of programmed cell death protein 1 ligand (PD-L1) expression ( 25 , 35 ).…”

“…Results from two different studies evaluating NSCLC tumor samples found that MET amp was identified in a significantly higher number of NSCLC brain metastases samples (including lung adenocarcinoma brain metastases) compared with samples from primary tumors ( 29 , 37 ). Results from one study evaluating patients with advanced NSCLC with EGFR mutations found that rates of brain metastases did not significantly differ among patients with primary MET amp versus no MET amp ( 45 ).…”

“…A total of 29 publications providing information on disease characteristics of METamp NSCLC were identified . A summary of results from 16 US-or non-US based studies that evaluated demographic and clinical characteristics of patients with NSCLC with or without METamp is found in Supplementary 29,32,33,[35][36][37][44][45][46][47]50,51). Results from the identified studies show that the following characteristics were consistently considered not associated with METamp (either primary, secondary, or not specified): age (11 studies), sex (11 studies), and NSCLC sub-type (adenocarcinoma vs non-adenocarcinoma, squamous cell carcinoma, or other; 6 studies) (24,26,27,32,33,36,44,45,47,50,51).…”

The application of patient-derived organoid in the research of lung cancer

“…PDO is also an important pre-clinical model for predicting the efficacy of targeted therapies and can be used for prospective adjuvant targeted therapy experiments to reduce treatment costs and improve success rates [ 63 ]. In preliminary studies, clinical outcomes were consistent with drug response in PDO models [ 64 ]. LUAD PDO carrying EGFR and BRAF mutations successfully captures the clinical response of the tumor to Dabrafenib/Trametinib combination therapy [ 4 ].…”