Epidermal Growth Factor Receptor Mutant Non-small Cell Lung Cancer Patients Research Articles

Correlation between carcinoembryonic antigen (CEA) expression and EGFR mutations in non-small-cell lung cancer: a meta-analysis.

The purpose of this meta-analysis was to investigate the relationship between serum carcinoembryonic antigen (CEA) expression and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). Databases such as PubMed, Cochrane, EMBASE and Google Scholar were systematically searched to identify studies assessing the association of serum CEA expression with EGFR mutations. Across 19 studies, 4168 patients were included between CEA expression and EGFR mutations odds ratio (OR) conjoint analysis of correlations. Compared with CEA-negative NSCLC, CEA-positive tumors had an increased EGFR mutation rate (OR = 1.85, 95% confidence interval: 1.48-2.32, P < 0.00001). This association was observed in both stage IIIB/IV patients (OR = 1.60, 95% CI: 1.18-2.15, P = 0.002) and stage I-IIIA (OR = 1.67, 95% CI: 1.01-2.77, P = 0.05) patients. In addition, CEA expression was associated with exon 19 (OR = 1.97, 95% CI: 1.25-3.11, P = 0.003) and exon 21 (OR = 1.51, 95% CI: 1.07-2.12, P = 0.02) EGFR mutations. In ADC pathological type had also showed the correlation (OR = 1.84, 95% CI: 1.31-2.57, P = 0.0004). This meta-analysis indicated that serum CEA expression was associated with EGFR mutations in NSCLC patients. The results of this study suggest that CEA level may play a predictive role in the EGFR mutation status of NSCLC patients. Detecting serum CEA expression levels can give a good suggestion to those patients who are confused about whether to undergo EGFR mutation tests. Moreover, it may help better plan of the follow-up treatment.

Tumor-liver interface in MRI of liver metastasis enables prediction of EGFR mutation in patients with lung cancer: A proof-of-concept study.

Preoperative prediction of the epidermal growth factor receptor (EGFR) status in non-small-cell lung cancer (NSCLC) patients with liver metastasis (LM) may have potential clinical values for assisting in treatment decision-making. To explore the value of tumor-liver interface (TLI)-based magnetic resonance imaging (MRI) radiomics for detecting the EGFR mutation in NSCLC patients with LM. This retrospective study included 123 and 44 patients from hospital 1 (between Feb. 2018 and Dec. 2021) and hospital 2 (between Nov. 2015 and Aug. 2022), respectively. The patients received contrast-enhanced T1-weighted (CET1) and T2-weighted (T2W) liver MRI scans before treatment. Radiomics features were extracted from MRI images of TLI and the whole tumor region, separately. The least absolute shrinkage and selection operator (LASSO) regression was used to screen the features and establish radiomics signatures (RSs) based on TLI (RS-TLI) and the whole tumor (RS-W). The RSs were evaluated by the receiver operating characteristic (ROC) curve analysis. A total of 5 and 6 features were identified highly correlated with the EGFR mutation status from TLI and the whole tumor, respectively. The RS-TLI showed better prediction performance than RS-W in the training (AUCs, RS-TLI vs. RS-W, 0.842vs. 0.797), internal validation (AUCs, RS-TLI vs. RS-W, 0.771vs. 0.676) and external validation (AUCs, RS-TLI vs. RS-W, 0.733vs. 0.679) cohort. Our study demonstrated that TLI-based radiomics can improve prediction performance of the EGFR mutation in lung cancer patients with LM. The established multi-parametric MRI radiomics models may be used as new markers that can potentially assist in personalized treatment planning.

Efficacy of ICI-based treatment in advanced NSCLC patients with PD-L1≥50% who developed EGFR-TKI resistance.

Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of immuno checkpoint inhibitor (ICI) based treatments for EGFR mutated NSCLC patients who carried programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50% progressed after EGFR-TKI therapy. In this study, we retrospectively investigated the outcomes of ICI-based treatments for EGFR mutated NSCLC patients carried PD-L1 TPS≥50% after developing EGFR-TKI resistance and to explore the population that may benefited from ICI-based treatment. We retrospectively collected data of advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation at Shanghai Chest Hospital between January 2018 and June 2021. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of this study. A total of 146 patients were included. Up to June 20th, 2022, median follow-up was 36.7 months (IQR, 12.5-44.2 months). Among the population, 66 patients (45.2%) received chemotherapy, the remaning (54.8%) received ICI-based treatment, including 56 patients(70.0%) received ICI combined with chemotherapy (IC) and 24 patients (30.0%) received ICI monotherapy (IM). In IC group,31 patients received ICI combined with chemotherapy,19 patients received ICI combined with antiangiogenic therapy and remaing received ICI combined with chemotherapy and antiangiogenic therapy. Survival analysis shown that patients who received ICI-based treatment had better progress-free survival (PFS) and overall survival (OS) compared with those treated with other therapy (median PFS, 10.0 vs. 4.0 months, P<0.001; median OS, 39.5 vs. 24.2 months, P<0.001). What's more, patients who treated with IC treatment had a superior survival time than those received IM treatment (median PFS, 10.3 vs. 7.0 months, P<0.001; median OS, 41.6 vs. 32.4 months, P<0.001). Subgroup analysis found that the PFS and OS benefit of IC was evident in all subgroups. For advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation, ICI-based treatment could provide a more favorable survival than classical chemotherapy. What' s more, compared with ICI monotherapy, ICI combined with chemotherapy seems to be the preferred treatment.

81P Is PD-1 inhibitor based treatment better than chemotherapy for metastatic NSCLC patients with PD-L1≥50% who develop EGFR-TKI resistance? A real-world investigation

Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of PD-1 inhibitor based treatments for EGFR mutated NSCLC patients who carried PD-L1 TPS ≥ 50% progressed after EGFR-TKI therapy. Thus, we aimed to investigate the outcomes of PD-1 inhibitor based treatments for these patients and to explore the population that may benefited from PD-1 inhibitor based therapies.

EP08.05-004 The Optimal Intervention Timing of Hypofractionated Stereotactic Radiotherapy for EGFR Mutated NSCLC Patients With Limited Brain Metastases

Tyrosine kinase inhibitors (TKIs) plus stereotatic radiosurgery/hypofractionated stereotactic radiotherapy (SRS/HSRT) are a common treatment strategy for epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients with limited brain metastases (BMs). However, for patients who eventually receive both TKIs and brain radiotherapy, the optimal intervention timing of radiotherapy is not clear. We performed this retrospective analysis aimed to partly solve this problem.

Gefitinib plus chemotherapy versus gefitinib alone in untreated patients with EGFR-mutated non–small cell lung cancer and brain metastases (GAP Brain): An open-label, randomized, multicenter, phase 3 study.

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P &lt; 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P &lt; 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

Predicting EGFR mutation, ALK rearrangement, and uncommon EGFR mutation in NSCLC patients by driverless artificial intelligence: a cohort study

BackgroundTimely identification of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement status in patients with non-small cell lung cancer (NSCLC) is essential for tyrosine kinase inhibitors (TKIs) administration. We aimed to use artificial intelligence (AI) models to predict EGFR mutations and ALK rearrangement status using common demographic features, pathology and serum tumor markers (STMs).MethodsIn this single-center study, demographic features, pathology, EGFR mutation status, ALK rearrangement, and levels of STMs were collected from Wuhan Union Hospital. One retrospective set (N = 1089) was used to train diagnostic performance using one deep learning model and five machine learning models, as well as the stacked ensemble model for predicting EGFR mutations, uncommon EGFR mutations, and ALK rearrangement status. A consecutive testing cohort (n = 1464) was used to validate the predictive models.ResultsThe final AI model using the stacked ensemble yielded optimal diagnostic performance with areas under the curve (AUC) of 0.897 and 0.883 for predicting EGFR mutation status and 0.995 and 0.921 for predicting ALK rearrangement in the training and testing cohorts, respectively. Furthermore, an overall accuracy of 0.93 and 0.83 in the training and testing cohorts, respectively, were achieved in distinguishing common and uncommon EGFR mutations, which were key evidence in guiding TKI selection.ConclusionsIn this study, driverless AI based on robust variables could help clinicians identify EGFR mutations and ALK rearrangement status and provide vital guidance in TKI selection for targeted therapy in NSCLC patients.

1O Furmonertinib versus gefitinib in treatment-naïve EGFR mutated non-small cell lung cancer: A randomized, double-blind, multi-center, phase III study (FURLONG)

Furmonertinib (AST2818) is an irreversible, selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This study aimed to compare the efficacy and safety of furmonertinib versus gefitinib in untreated advanced non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutations. FURLONG was a randomized, double-blind, phase III study conducted in 55 centers across mainland China. Stage IIIB/IIIC/IV NSCLC patients with EGFR Ex19Del or L858R mutation positive were enrolled to receive either furmonertinib 80 mg/d or gefitinib 250 mg/d as first-line therapy. The primary endpoint was progression-free survival (PFS) assessed by an independent review center (IRC). Between May 30, 2019 and Dec 5, 2019, 358 patients were randomized to receive furmonertinib (n=178) or gefitinib (n=180) treatment. In the furmonertinib and gefitinib groups, 35% and 32% had central nervous system (CNS) metastases at baseline, respectively. As of Sep 15 2021, the median follow-up was both 21.0 months in each group. The median PFS with furmonertinib was significantly longer than with gefitinib (20.8 versus 11.1 months; HR 0.44 [95%CI 0.34-0.58]; p<0.0001). The clinical benefit of PFS was consistent across all pre-specified subgroups including patients with CNS metastases (HR 0.50 [95%CI 0.32-0.80]). The median duration of exposure was 18.3 months in the furmonertinib group and 11.2 months in the gefitinib group, whereas the frequency of grade≥3 treatment-related adverse events (TRAEs) was 11% in the furmonertinib group and 18% in the gefitinib group. Furmonertinib significantly prolonged PFS and showed less grade≥3 TRAEs compared with gefitinib as first-line treatment in advanced EGFR mutated NSCLC patients.

Dysregulated circulating miR-4429 serves as a novel non-invasive biomarker and is correlated with EGFR mutation in patients with non-small cell lung cancer.

This study aimed to investigate the correlation between microRNA (miR)-4429 and epidermal growth factor receptor (EGFR), the expression, and clinical significance of miR-4429 in patients with non-small cell lung cancer (NSCLC), and the relationship between miR-4429 and EGFR mutation in NSCLC patients. Blood samples were collected from 122 NSCLC patients and 72 healthy volunteers. miR-4429 expression and EGFR mRNA expression were detected by real-time quantitative polymerase chain reaction. Correlation between miR-4429 and EGFR was evaluated by dual-luciferase reporter assay and the Pearson correlation analysis. The ability of serum miR4429 to discriminate between NSCLC patients and healthy controls, and to discriminate between EGFR wild-type (EGFR-W) and EGFR mutant-type (EGFR-M) patients was assessed using receiver operating characteristic analysis. The relationship between miR-4429 and NSCLC patients’ survival was identified by KaplanMeier survival curves and log-rank test. The prognostic value of miR-4429 in NSCLC patients was evaluated by Cox regression analysis. miR-4429 could directly bind to EGFR. Serum miR-4429, decreased in NSCLC patients, was negatively correlated with serum EGFR mRNA expression in NSCLC patients. In addition, miR-4429 had a high diagnostic value for screening NSCLC patients from healthy controls, and was independently correlated with survival prognosis of NSCLC patients. Moreover, miR4429 was decreased in EGFR-M patients, which had a certain screening ability for EGFRM patients. Our findings indicate that miR-4429 is negatively correlated with EGFR in NSCLC, and may function as a diagnostic and prognostic biomarker for NSCLC patients. Additionally, miR-4429 is associated with EGFR mutation in NSCLC patients.

Survival analysis of different kinds of tyrosine kinase inhibitors in the treatment of patients with epidermal growth factor receptor mutated non-small cell lung cancer and leptomeningeal metastasis

Objective: To explore the prognosis of patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC) treated with different kinds of tyrosine kinase inhibitors (TKIs). Methods: From January 2016 to June 2021, the clinicopathological data of 70 patients confirmed by histologically or cytologically EGFRm LM who received different types of TKIs in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively analyzed. According to treatment patterns, patients were divided into the first-and second-generation EGFR-TKIs treatment group and the third-generation EGFR-TKIs treatment group [Osimertinib 80 mg once a day], and the prognosis and prognostic factors (with Cox proportional hazards model) of patients in different treatment group were assessed. The next-generation sequencing (NGS) of paired samples of cerebrospinal fluid (CSF) and plasma from 64 patients at the time of LM diagnosis was performed simultaneously. Results: There were 20 males and 50 females in 70 EGFRm NSCLC patients with LM. The age ranged from 35 to 69 years, with a median age of 56 years. A total of 24 patients received the first-and second-generation EGFR-TKIs treatment, and 46 received the third-generation EGFR-TKIs treatment. Twenty-four patients developed disease progression on the first-and second EGFR-TKIs treatments, followed by treatment with the third-generation EGFR-TKIs (Osimertinib) in 12 cases, chemotherapy or anti-angiogenesis therapy in 4 cases, and the optimal supportive treatment in 8 cases. Among the 70 patients, 18 had partial response (PR), 48 had stable disease (SD), and 4 had progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) were 26% (18/70) and 94% (66/70), respectively. The median follow-up time was 16.5 months. The median progression-free survival (PFS) was 5.3 months(95%CI: 2.8-7.8)in the first-and second-generation EGFR-TKIs and 10.8 months (95%CI: 7.9-13.6) in the third-generation EGFR-TKIs, and the difference was statistically significant (P=0.019). The median overall survival (OS) was 14.9 months (95%CI: 9.7-20.0) and 15.7 months (95%CI: 13.3-18.1) in the two groups, respectively, but no statistical differences was observed (P=0.713). Univariate analysis showed that the PFS of patients with EGFRm LM were related to gender and different types of EGFR-TKIs (P˂0.05). Multivariate analysis demonstrated that male (HR=2.30, 95%CI: 1.31-4.03, P=0.004) and the first-and second-generation EGFR-TKIs (HR=2.03, 95%CI: 1.20-3.41, P=0.008) were independent risk factors for PFS in patients with EGFRm LM. The EGFR mutation was detected in 61 (95%) CSF and in 27 (42%) plasma samples. Conclusion: In EGFRm NSCLC patients with LM, the dose of Osimertinib 80 mg (once a day) has a significant PFS benefit compared with the first-and second-generation EGFR-TKIs.

Cluster analysis of deterioration sites after first-line epidermal growth factor receptor-tyrosine kinase inhibitor in epidermal growth factor receptor mutated non-small cell lung cancer.

IntroductionFor epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC), no studies have treated the site of recurrence after first-line tyrosine kinase inhibitor (TKI) treatment as a “metastasis pattern”. This study aims to assess whether these patients have a specific “metastasis pattern” at the site of recurrence after the treatment.Material and methodsData were collected from all consecutive EGFR mutated NSCLC patients between 2009 and 2021. Metastatic patterns were analyzed using cluster analysis in patients with EGFR mutated NSCLC.ResultsDuring the study period, 83 EGFR mutated NSCLC patients were treated with EGFR-TKI. Patients who had no metastases at the time of diagnosis were divided into two groups according to the presence or absence of recurrence of metastases after TKI administration. Patients with metastases at diagnosis were divided into 4 groups by cluster analysis. A statistically significant difference in metastasis frequency was confirmed among these 6 groups (χ2 test, p = 0.0001). Furthermore, when the frequency of metastasis recurrence after TKI administration in these 6 groups was examined, a statistically significant difference was confirmed (χ2 test, p = 0.0001).ConclusionsEven in EGFR mutation-positive patients, the knowledge of the recurrent patterns might be useful for clinical practice in the foreseeable future, as it enables more efficient detection of metastatic disease through imaging, and more effective treatment at predicted metastatic sites.

A Computed Tomography-Derived Radiomics Approach for Predicting Uncommon EGFR Mutation in Patients With NSCLC.

PurposeThis study aims to develop a CT-based radiomics approach for identifying the uncommon epidermal growth factor receptor (EGFR) mutation in patients with non-small cell lung cancer (NSCLC).MethodsThis study involved 223 NSCLC patients (107 with uncommon EGFR mutation-positive and 116 with uncommon EGFR mutation-negative). A total of 1,269 radiomics features were extracted from the non-contrast-enhanced CT images after image segmentation and preprocessing. Support vector machine algorithm was used for feature selection and model construction. Receiver operating characteristic curve analysis was applied to evaluate the performance of the radiomics signature, the clinicopathological model, and the integrated model. A nomogram was developed and evaluated by using the calibration curve and decision curve analysis.ResultsThe radiomics signature demonstrated a good performance for predicting the uncommon EGFR mutation in the training cohort (area under the curve, AUC = 0.802; 95% confidence interval, CI: 0.736–0.858) and was verified in the validation cohort (AUC = 0.791, 95% CI: 0.642–0.899). The integrated model combined radiomics signature with clinicopathological independent predictors exhibited an incremental performance compared with the radiomics signature or the clinicopathological model. A nomogram based on the integrated model was developed and showed good calibration (Hosmer–Lemeshow test, P = 0.92 in the training cohort and 0.608 in the validation cohort) and discrimination capacity (AUC of 0.816 in the training cohort and 0.795 in the validation cohort).ConclusionRadiomics signature combined with the clinicopathological features can predict uncommon EGFR mutation in NSCLC patients.

The Survival of Advanced Non-small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Thailand: A Single Institution Review

Background: Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase inhibitor (TKI) can improve progression free survival in patients with treatment naive EGFR mutant metastatic non-small cell lung cancer (NSCLC) compared with platinum-based chemotherapy, but no statistically significant difference is observed in overall survival. The survival time of EGFR mutant NSCLC patients treated with at least two systemic chemotherapy regimens and one EGFR TKI was 34.8 months in a previous study. Objective: The present study was to determine the median survival time of advanced NSCLC patients who received EGFR-TKIs in Chulabhorn Hospital. Materials and Methods: We retrospectively reviewed the medical records of advanced NSCLC cases treated with EGFR TKIs in Chulabhorn Hospital during 2009 to 2011. Results: Among 243 advanced NSCLC cases, 72 patients received EGFR TKIs. EGFR mutation status was positive in 14 (19.17%) patients. The median overall survival time was 30.04 months (95% CI: 18.71 to 49.48 months) in all patients, compared with 49.49 months (95% CI: 15.93 to NR) in EGFR mutation-positive patients (n=14). No statistically significant difference of overall survival was noted between EGFR mutation status groups (p=0.51). Conclusion: The median survival time for Thai patients treated with EGFR TKIs was comparable to historical data and irrespective of EGFR mutation status. Keywords: Metastatic non-small cell lung cancer, EGFR TKIs, Survival

Osimertinib for the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer patients with leptomeningeal metastases and different T790M status.

BackgroundLeptomeningeal metastasis (LM) is a catastrophic complication for patients with non-small cell lung cancer (NSCLC) and carries an extremely poor prognosis. The efficacy of osimertinib 80 mg once daily for epidermal growth factor receptor-mutated (EGFRm) NSCLC with LM has yet to be fully assessed. This study aimed to investigate the efficacy of osimertinib in such patients and their genetic profiles at the time of LM diagnosis.MethodsFrom January 2016 to April 2020, pretreated EGFRm NSCLC patients who had progressed with cytologically confirmed symptomatic LM and received osimertinib 80 mg once daily were enrolled retrospectively. The objective response rate (ORR) and disease control rate (DCR) were evaluated, along with progression-free survival (PFS) and overall survival (OS). Next-generation sequencing of paired samples of cerebrospinal fluid and plasma collected at LM diagnosis was performed simultaneously.ResultsForty cases of EGFRm lung adenocarcinoma with LM were analyzed. Females accounted for 75.0% of enrollees. Of the patients, 37.5% had a poor Eastern Cooperative Oncology Group score (≥2). Twelve patients had received at least 2 prior lines of treatment. All patients received osimertinib treatment regardless of their T790M status. According to the Response Assessment in Neuro-Oncology (RANO)-LM criteria, the ORR and DCR were 20.0% and 95.0%, respectively. The median PFS and OS were 10.0 (95% CI: 7.7–12.3) and 15.1 months (95% CI: 11.0–19.4), respectively. No significant difference was observed between T790M-negative patients (n=24) and T790M-positive patients (n=16) with respect to PFS [median, 10.8 (95% CI: 7.7–13.8) vs. 8.8 months (95% CI: 7.3–10.3), HR=0.595, P=0.158] or OS [median, 17.2 (95% CI: 8.7–25.7) vs. 11.4 months (95% CI: 3.9–19.0), HR=0.913, P=0.822]. The detection rate of EGFR sensitizing mutations in cerebrospinal fluid was higher than that in plasma (97.5% vs. 50%, P=0.311), whereas the incidence of T790M detection in cerebrospinal fluid was significantly lower than that in plasma (20.0% vs. 32.5%, P=0.043).ConclusionsOsimertinib 80 mg once daily shows good efficacy in pretreated EGFRm NSCLC patients with LM regardless of their T790M status. Combining cerebrospinal fluid and plasma testing can aid in revealing more genetic information.

Unveiling mutational dynamics in non-small cell lung cancer patients by quantitative EGFR profiling in vesicular RNA.

The mutational status of the epidermal growth factor receptor (EGFR) guides the stratification of non‐small cell lung cancer (NSCLC) patients for treatment with tyrosine kinase inhibitors (TKIs). A liquid biopsy test on cell‐free DNA is recommended as a clinical decision‐supporting tool, although it has limited sensitivity. Here, we comparatively investigated the extracellular vesicle (EV)‐RNA as an independent source for multidimensional and longitudinal EGFR profiling in a cohort of 27 NSCLC patients. We introduced and validated a new rapid, highly specific EV‐RNA test with wild‐type (WT) and mutant‐sensitive probes (E746‐A750del, L858R, and T790M). We included a cohort of 20 NSCLC patients with EGFR WT tumor tissues and systematically performed molecular EV‐RNA and circulating tumor DNA analyses with clinical data statistics and biophysical profiles of EVs. At the single‐patient level, we detected variegated tumor heterogeneity dynamics supported by combinations of driver EGFR mutations. EV‐RNA‐based mutation analysis showed an unprecedented sensitivity of over 90%. The resistance‐associated mutation T790M frequently pre‐existed at baseline with a gained EV‐transcript copy number at progression, while the general mutational burden was mostly decreasing during the intermediate follow‐up. The biophysical profile of EVs and the quantitative assessment of T790M revealed an association with tumor size determined by the sum of the longest diameters in target lesions. Vesicular RNA provides a validated tool suitable for use in clinical practice to investigate the dynamics of common driver EGFR mutations in NSCLC patients receiving TKIs.

135P The real-world use of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor mutated (EGFRm) advanced (stage IIIb/IIIc/IV) non-small cell lung cancer (NSCLC) patients

Background: Given the role of EGFRm in the development of NSCLC, EGFR is an established target for treating the disease. While EGFR-TKIs are the recommended first-line (1L) treatment option for advanced EGFRm NSCLC, there is limited evidence describing the use of EGFR-TKIs in clinical practice. This study investigated the real-world treatment patterns in advanced EGFRm NSCLC patients.

Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib.

Simple SummaryOsimertinib, a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown marked clinical benefit for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, resistance to osimertinib inevitably develops and heterogeneous mechanisms of acquired resistance have been documented. Therefore, new strategies to bypass resistance are urgently needed. In this study, we investigated the potential activity of abemaciclib as second-line therapeutic approach after osimertinib progression and the effect of combining abemaciclib with osimertinib on the appearance of resistance in osimertinib-sensitive models. Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore

Objective Non-small cell lung cancer (NSCLC) accounts for 80–90% of all lung cancer cases and is usually associated with a poor prognosis. However, targeted therapy with first and second generation tyrosine kinase inhibitors (TKIs) has so far improved progression-free survival of epidermal growth factor receptor (EGFR) mutant NSCLC patients. Osimertinib, a third generation EGFR TKI has recently shown improved overall survival of 6.8 months in previously untreated EGFR mutant NSCLC patients. We assessed the cost-effectiveness of osimertinib versus standard EGFR TKIs (gefitinib or erlotinib) as first-line treatment for advanced or metastatic EGFR mutant NSCLC patients in Singapore. Methods A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from the Singapore healthcare payer perspective. Survival curves based on the overall trial population from the FLAURA trial were extrapolated beyond trial period over a 10-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from public healthcare institutions in Singapore. Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. Results Compared with first or second generation TKI, osimertinib had a base-case incremental cost-effectiveness ratio (ICER) of SG$418,839 (US$304,277) per quality-adjusted life year gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon and variations in progression-free utility values. Scenario analyses showed that a 50% reduction in the cost of osimertinib was still associated with a high ICER that was unlikely to be deemed cost effective. Conclusions Osimertinib is not cost effective as a first-line treatment compared to standard EGFR TKIs in advanced EGFR mutant NSCLC patients in Singapore. The findings from our evaluation, alongside other considerations including the lack of survival benefit in the Asian subgroup of the FLAURA trial, will be useful to inform policy makers on funding decisions for NSCLC treatments in Singapore.

PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy.

BackgroundSeveral mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.MethodsA total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.ResultsForty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn’t receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35–4.3 months, range, 0.9–4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).ConclusionsOur study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

The Diagnostic Accuracy of Liquid Biopsy in EGFR-Mutated NSCLC: A Systematic Review and Meta-Analysis of 40 Studies.

Epidermal growth factor receptor (EGFR) mutations are the most common carcinogenic driver mutations in non-small-cell lung cancer (NSCLC) patients, while invasive tissue biopsy has certain inherent defects. PubMed, Ovid Medline, Embase, and the Cochrane Library were systematically searched on January 4, 2020, using the keywords "liquid biopsy," "EGFR," and "NSCLC." The pooled sensitivity and specificity of EGFR mutations in paired tissue and blood were calculated. The accuracy was assessed by receiver operating characteristic curve. The meta-regression of the subgroup was performed to analyze the heterogeneity. Hazard ratio (HR) and 95% confidence interval (CI) were combined for evaluating the impact of EGFR mutation in tissue and liquid blood biopsy. A total of 40 studies with 5,995 patients were involved in the study. The pooled sensitivity was 68% (95% CI = 60-75%), and the specificity was 98% (95% CI = 95-99%). The diagnostic odds ratio was 88 (95% CI = 40-195), and the area under the curve was 0.91 (95% CI = 0.88-0.93). In the meta-regression, the sensitivity and specificity remain lower in the Asian studies than non-Asian studies (sensitivity: 66% vs. 73%, P = 0.04; specificity: 96% vs. 97%, P = 0.03, respectively). The EGFR mutation was associated with a better progression-free survival than wild type in both tissue (HR = 0.54, 95% CI = 0.34-0.85, P = 0.007) and blood (HR = 0.81, 95% CI = 0.71-0.92, P = 0.001) detection. Peripheral blood liquid biopsy had a better specificity for detecting EGFR mutation in NSCLC patients, while tissue biopsy still needs to be undertaken for negative blood biopsy patients due to its lower sensitivity.