Positive Epidermal Growth Factor Receptor Mutation Research Articles

Association of mean platelet volume (MPV), MPV/PLATELET (PLT) ratio, and lymphocyte/monocyte ratio (LMR) as poor prognostic factor in EGFR-mutant lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor.

Platelets (PLT) and host systemic inflammatory response (SIR) are known to be effective in the aggregation of cancer cells and the formation of metastasis. There are studies pointing out to the prognostic efficacy of lymphocyte-monocyte ratio (LMR) showing SIR activation and mean platelet volume (MPV) values indicating platelet activation in various cancer types. We predict that easy-to-access hemogram parameters such as MPV, MPV/PLT, and LMR can be guiding in the clinical follow-up period of patients with epidermal growth factor receptor (EGFR) positive mutation and who received EGFR, tyrosine kinase inhibitor (TKI) in the first-line treatment in predicting the progression of the disease, predicting the survival time of the patients, and evaluating the response to treatment. The study is retrospective and included patients with stage III and stage IV pulmonary adenocarcinoma with positive EGFR mutations and for whom TKI was used in the first-line treatment between January 2011 and January 2021. MPV, MPV/PLT, and LMR values of the patients were calculated before treatment. Age, sex, comorbidity, smoking history, TNM stage, metastasis localizations, EGFR mutation types, TKI treatments used in first-line treatment, and MPV, MPV/PLT, and LMR values at the 1st month of treatment were recorded. With Kaplan-Meier, six-month, one-year, three-year, and five-year survival rates, average life expectancy, and 95% confidence intervals for these periods were calculated. Variables that may affect progression and overall survival (OS) were determined by performing univariate and multivariate Cox regression analysis. One hundred and two patients were included in the study. The mean age of the patients was 64.30 ± 12.6 years. Eighty-four patients were in stage IV at the time of diagnosis. The expected mean progression-free survival (PFS) period of the cases was found to be 13.3 months. The mean life expectancy of the cases was found to be 35.1 months. Web-based Cutoff Finder algorithm written in the R program (http://molpath.charite.de/cutoff) was used to determine the ideal cut points for MPV, MPV/PLT, and LMR. The cut-off values were found to be 7.55 fL for MPV, 0.251 for MPV/PLT, and 2.615 for LMR, respectively. In univariate Cox regression analysis, LMR level lower than 2.615 increased the rate of progression 1.747 times (95% confidence interval: 1.129-2.705) and the death rate 2.056 times (95% confidence interval: 1.217-3.475) (p= 0.012, p= 0.007). The mean PFS LMR cut-off value was 10.3 months, and 15.3 months, and mean OS durations were 25.1 months and 40.8 months for the groups with low and high cut-off values respectively (p= 0.011, p= 0.006 log-rank test). According to the results of multivariate Cox regression analysis, MPV/PLT < 0.251, smoking, presence of pleural and adrenal metastases, and gefitinib treatment were independent factors in determining PFS. The independent factors determining OS in multivariate Cox regression analysis were being male, platelet increase, MPV > 7.55, gefitinib treatment, and smoking. MPV, MPV/PLT, and LMR are potential biomarkers that can be used for the clinical follow-up of lung ADC patients receiving EGFR-TKI treatment.

Correlation of FDG PET/CT, tumor markers and Ki-67 index with EGFR mutation or positive ALK expression in patients with non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the two most common druggable targets in non-small cell lung cancer (NSCLC). To investigate whether the EGFR mutation and ALK rearrangement could be predicted by the combination of FDG avidity, tumor markers and Ki-67 Index. A total of 168 newly diagnosed NSCLC patients who had undergone 18F-FDG PET/CT for staging were enrolled. PET/CT parameters of primary tumors including maximum standardized uptake value (pSUVmax), metabolic tumor volume (pMTV) and total lesion glycolysis (pTLG) were measured. Five serous tumor markers for lung cancer were recorded. Ki-67 labeling index was counted by immunohistochemical staining. EGFR mutation and ALK status were detected by ARMS-PCR and RT-PCR, respectively. Univariate and multivariate analyses were applied to identify the predictors of EGFR mutation and ALK positivity. EGFR mutation rate was 38.1% (64/168), which were found more frequently in female, ≤60 years old, non-smokers and adenocarcinoma patients, and were not related to lymph node involvements, distant metastases, stage and serum tumor markers. Low pSUVmax, pMTV, pTLG and Ki-67 were significantly associated with EGFR mutation. Logistic regression demonstrated that pSUVmax <6.75 and gender (female) were the independent factors affecting EGFR mutation, and the combination of them had a certain predictive value with the area under the curve of 0.784. ALK positive rate was 6.0% (10/168), all of them were adenocarcinoma patients, which were more common in non-smokers, low serum cytokeratin-19 fragment antigen (CYFRA21-1) and low Ki-67, and were not related to FDG activity. No independent factor for ALK positivity was found on Logistic regression. Low pSUVmax, rather than tumor markers or Ki-67, was correlated with EGFR mutation independently, which could be integrated with gender (female) to improve the identification for EGFR mutation in NSCLC patients.

Machine learning-based radiomics strategy for prediction of acquired EGFR T790M mutation following treatment with EGFR-TKI in NSCLC

The epidermal growth factor receptor (EGFR) Thr790 Met (T790M) mutation is responsible for approximately half of the acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) in non-small-cell lung cancer (NSCLC) patients. Identifying patients at diagnosis who are likely to develop this mutation after first- or second-generation EGFR-TKI treatment is crucial for better treatment outcomes. This study aims to develop and validate a radiomics-based machine learning (ML) approach to predict the T790M mutation in NSCLC patients at diagnosis. We collected retrospective data from 210 positive EGFR mutation NSCLC patients, extracting 1316 radiomics features from CT images. Using the LASSO algorithm, we selected 10 radiomics features and 2 clinical features most relevant to the mutations. We built models with 7 ML approaches and assessed their performance through the receiver operating characteristic (ROC) curve. The radiomics model and combined model, which integrated radiomics features and relevant clinical factors, achieved an area under the curve (AUC) of 0.80 (95% confidence interval [CI] 0.79–0.81) and 0.86 (0.87–0.88), respectively, in predicting the T790M mutation. Our study presents a convenient and noninvasive radiomics-based ML model for predicting this mutation at the time of diagnosis, aiding in targeted treatment planning for NSCLC patients with EGFR mutations.

Immunotherapy strategies for EGFR-mutated advanced NSCLC after EGFR tyrosine-kinase inhibitors failure.

This study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test. A total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group. NSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

CT-based non-invasive identification of the most common gene mutation status in patients with non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are mutually exclusive, and they are two important genes that are most prone to mutation in patients with non-small cell lung cancer. This retrospective study investigated the ability of radiomics to predict the mutation status of EGFR and KRAS in patients with non-small cell lung cancer (NSCLC) and guide precision medicine. Computed tomography images of 1045 NSCLC patients from five different institutions were collected, and 1204 imaging features were extracted. In the training set (EGFR: 678, KRAS: 246), Max-Relevance and Min-Redundancy and least absolute shrinkage and selection operator logistic regression were used to screen radiomics features. The combination of selected radiomics features and clinical factors was used to establish the combined models in identifying EGFR and KRAS mutation status, respectively, through stepwise logistic regression. Then, on two independent external validation sets (EGFR: 203/164, KRAS: 123/95), the performance of each model was evaluated separately, and then the overall performance of predicting the two mutation states was calculated. In the EGFR and KRAS groups, radiomics signatures comprised 14 and 10 radiomics features, respectively. They were mutually exclusive between the tumors with positive EGFR mutation and those with positive KRAS mutation in imaging phenotype. For the EGFR group, the area under the curve (AUC) of the combined model in the two validation sets was 0.871 (95% CI: 0.821-0.926) and 0.861 (95% CI: 0.802-0.911), respectively, whereas the AUC of the combined model in the two validation sets was 0.798 (95% CI: 0.739-0.850) and 0.778 (95% CI: 0.735-0.821), respectively, for the KRAS group. Considering both EGFR and KRAS, the overall precision, recall, and F1-score of the combined model in the two validation sets were 0.704, 0.844, and 0.768, as well as 0.754, 0.693, and 0.722, respectively. Our study demonstrates the potential of radiomics in the non-invasive identification of EGFR and KRAS mutation status, which may guide patients with non-small cell lung cancer to choose the most appropriate personalized treatment. This method can be used when biopsy will bring unacceptable risk to patients with NSCLC.

The relation between epidermal growth factor receptor mutations profiles and smoking patterns in patients with lung adenocarcinoma: A cross‐sectional study

AbstractBackgroundNon‐small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, with smoking being a critical risk factor. The identification of NSCLC patients harboring epidermal growth factor receptor (EGFR) mutations, sensitized to tyrosine kinase inhibitors, has revolutionized treatment plans, resulting in improved clinical responses and reduced chemotherapy toxicity. This study aimed to assess the relationship between EGFR mutations and smoking patterns in patients diagnosed with lung adenocarcinoma referred to major pathologic laboratories.MethodsThis cross‐sectional study included 217 NSCLC patients aged above 18 years. Molecular abnormalities of the EGFR gene were analyzed by polymerase chain reaction amplification of exons 18–21 accompanied by Sanger sequencing. Then, the data were analyzed using the SPSS 26 software. Logistic regression analysis, χ2 test, and Mann–Whitney U test were used to evaluate the relation between EGFR mutations and smoking patterns.ResultsEGFR mutations were identified in 25.3% of patients, predominantly involving deletion in exon 19 (61.8%). For most of the mutant EGFR patients, the majority were nonsmokers (81.8%), and 52.7% were female patients. Besides, the median duration of smoking was 26 years and the median frequency of smoking was 23 pack‐years in the mutant EGFR group, both of which were lower compared to the wild mutant group. Moreover, female gender, current, and heavy smoking were significantly correlated with EGFR mutations based on the univariate logistic regression analysis (p: 0.004, 0.005, and 0.001, respectively).ConclusionsFemale gender and nonsmoker status were strongly associated with positive EGFR mutations. While guidelines traditionally recommended EGFR testing primarily for female nonsmokers with advanced NSCLC, our study in line with the recently published evidence has shown a significant prevalence of positive EGFR mutations among male patients and smokers. Therefore, routine mutation testing is suggested for all NSCLC patients. Considering the limited access to EGFR testing laboratories in developing countries, the results of such epidemiological surveys can assist oncologists in choosing the most suitable treatment plan.

Advanced Non-small Cell Lung Cancer: EGFR Mutation Analysis Using Pyrosequencing and the Fully Automated qPCR-Based IdyllaTM System.

Epidermal growth factor receptor (EGFR) mutation status is of a major clinical significance in non-small cell lung cancer (NSCLC) management, as it guides therapeutic decision making to target patients for a better response to therapy. This implicates the introduction of EGFR mutation analysis as the standard of care for Moroccan NSCLC patients, which in itself entails the implementation of targeted methods for routine EGFR mutation analysis in our laboratories. In this study, we aimed to present 2 targeted methods for EGFR mutation identification and to determine the prevalence and spectrum of EGFR mutations in NSCLC Moroccan patients. A retrospective investigation of a cohort of 340 patients was undertaken to analyze somatic EGFR mutations in exons 18 to 21 using pyrosequencing and the IdyllaTM system. Of the enrolled patients, 70.9% were males and 29.1% were females. Predominately, 92% of cases had adenocarcinoma, and 53.7% of patients self-reported a history of smoking. Overall, 73 patients (21.7%) harbored an EGFR mutation, the most prevalent of which were the exon 19 deletions (53.4%) followed by exon 21 substitutions (31%). Exon 18 mutations and exon 20 alterations occurred in 8.1% and 6.7% of the positive EGFR mutation cases, respectively. Of the analyzed cases, all of the EGFR-mutated patients had adenocarcinoma. EGFR mutation prevalence was significantly higher in females (females vs males: 38.4% vs 14.5%, P < .001) and non-smokers (non-smokers vs non-smokers: 36% vs 10.3%, P < .001). The featured pyrosequencing and the IdyllaTM system are targeted methods endowed with high sensitivity and specificity as well as other compelling characteristics which make them great options for routine EGFR mutation testing for advanced NSCLC patients. These findings underline the imperious need for implementing quick and efficient targeted methods for routine EGFR mutation testing among NSCLC patients, which is particularly useful in determining patients who are more likely to benefit from targeted therapy.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmax[brain] ) 22 min (median, Tmax[brain] ) after injection. Total volume of distribution (VT ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.

Predicting EGFR gene mutation status in lung adenocarcinoma based on multifeature fusion

Purpose:Adenocarcinoma is the most common histopathological type of lung cancer, and histopathological images are important for assessing the stage and subtype of tumors. Patients with lung adenocarcinoma may have genetic alterations in oncogenic drivers, including EGFR, ALK, ROS1, BRAF, among others. Among them, the EGFR mutation-positivity in Asians is as high as 40%–60%. However, no research has explored the relationship between the morphological information of pathological cells and the oncogenic driver gene EGFR. Methods:In this paper, we propose a novel automatic analysis framework and joint semantic, spatial, and clinical information for exploring the relationship between tumor microenvironment features and EGFR gene mutations, namely, JSSC-Net. Our approach consists of the following modules: the semantic feature encoding module, spatial feature encoding module, clinical information feature encoding module, and feature fusion module. Results:We collected 248 digital WSIs images acquired from 248 patients with lung adenocarcinoma, and verified the effectiveness of our proposed model on this dataset. Our proposed method achieved the accuracy of predicting EGFR mutation state was 0.7778, performing significantly better than the baseline methods. In addition, we attempted to learn the associations between histopathological images and the types of EGFR gene mutation, achieving an accuracy was 0.6428. Conclusions:In this study, we proposed a novel deep learning-based method to predict the mutation state of EGFR gene in lung adenocarcinoma. The experiments proved that the conformation of tumor pathology is associated with EGFR mutation-positivity, that is, the tumor microenvironment of different types is predictive of genetic alterations in oncogenic drivers. Significance:We have demonstrated that the proposed deep learning-based analysis framework can automatically and efficiently predict the relationship between tumor microenvironment features and EGFR gene mutations. This information is critical for applying appropriate and targeted therapies to lung cancer patients, thereby increasing the scope and performance of precision medicine.

Evaluation of Cost-Effectiveness of Adjuvant Osimertinib in Patients with Resected EGFR Mutation-Positive Non-small Cell Lung Cancer.

For many patients with resected epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), current standard of care (SoC) is adjuvant chemotherapy; however, disease recurrence remains high. Based on positive results from ADAURA (NCT02511106), adjuvant osimertinib was approved for treatment of resected stage IB‒IIIA EGFRm NSCLC. The aim was to assess the cost-effectiveness of adjuvant osimertinib in patients with resected EGFRm NSCLC. A five-health-state, state-transition model with time dependency was developed to estimate lifetime (38 years) costs and survival of resected EGFRm patients treated with adjuvant osimertinib or placebo (active surveillance), with/without prior adjuvant chemotherapy, using a Canadian Public Healthcare perspective. Transitions between health states were modeled using ADAURA and FLAURA (NCT02296125) data, Canadian life tables, and real-world data (CancerLinQ Discovery®). The model used a 'cure' assumption: patients remaining disease free for 5 years after treatment completion for resectable disease were deemed 'cured.' Health state utility values and healthcare resource usage estimates were derived from Canadian real-world evidence. In the reference case, adjuvant osimertinib treatment led to a mean 3.20 additional quality-adjusted life-years (QALYs; (11.77 vs 8.57) per patient, versus active surveillance. The modeled median percentage of patients alive at 10 years was 62.5% versus 39.3%, respectively. Osimertinib was associated with mean added costs of Canadian dollars (C$)114,513 per patient and a cost/QALY (incremental cost-effectiveness ratio) of C$35,811 versus active surveillance. Model robustness was demonstrated by scenario analyses. In this cost-effectiveness assessment, adjuvant osimertinib was cost-effective compared with active surveillance for patients with completely resected stage IB‒IIIA EGFRm NSCLC after SoC.

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2–IA3 EGFR-Mutated NSCLC: ADAURA2

IntroductionOsimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non–small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2–IA3 EGFRm NSCLC, following complete tumor resection. Patients and MethodsADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated. ResultsStudy enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.

Real-world analysis of the prognostic value of EGFR mutation detection in plasma ctDNA from patients with advanced non-small cell lung cancer.

The plasma sample has emerged as a promising surrogate sample for EGFR mutation detection in advanced non-small cell lung cancer (NSCLC). In clinical practice, whether EGFR variants in baseline plasma ctDNA of advanced NSCLC can predict prognosis in addition to guiding targeted therapy remains to be further explored. In total, 315 NSCLC patients were retrospectively enrolled. EGFR mutation data from tissue detected by ARMS-PCR and paired plasma samples within 1 month of admission detected by SuperARMS or ARMS-PCR were collected. The correlation between baseline plasma ctDNA EGFR mutation status and survival was compared. EGFR mutation detection rates in tumor samples and plasma samples were 65.1% (205/315) and 43.8% (138/315). Referred to tissue results, the consistent rate of test ctDNA EGFR alteration by SuperARMS was higher than that detected by ARMS (79.5% vs. 69.0%, p=0.04), either in stage I-IIIA patients (85.7% vs. 50.0%, p=0.4) or stage IIIB-IV patients (79.1% vs. 69.4%, p=0.04). Patients' treatment status and pathological subtype were the two factors that affected plasma ctDNA EGFR alteration detection accuracy. The concordance in non-adenocarcinoma patients was obviously higher than that in adenocarcinoma (p=0.02), and the concordance in treatment naïve patients was significantly higher than that in relapse patients (p=0.047). In treatment naïve patients, the median PFS (mPFS) in plasma ctDNA EGFR-positive patients was shorter than that in plasma ctDNA EGFR negative patients (7.0 vs. 10.0 months, p=0.01). In relapsed patients, the mPFS in plasma ctDNA EGFR-positive patients was 9.0months versus 11.0months in plasma ctDNA EGFR negative patients (p=0.1). A plasma sample could be an alternative for a molecular test when tissue samples was unavailable. The SuperARMS-PCR detection method has high sensitivity in real-world clinical practice. Furthermore, in patients with stage IIIB-IV, baseline plasma ctDNA EGFR mutation positivity not only guides targeted therapy but also predicts a worse prognosis.

Osimertinib for EGFR-Mutant Non-Small-Cell Lung Cancer Central Nervous System Metastases: Current Evidence and Future Perspectives on Therapeutic Strategies.

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology-European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood-brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB-IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapy/radiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases.

Heterogeneity and Clinical Effect of Epidermal Growth Factor Receptor in Primary Lung and Brain Metastases of Nonsmall Cell Lung Cancer

IntroductionThis study aimed to analyze the heterogeneity in epidermal growth factor receptor (EGFR) gene mutation and its impact on clinical outcomes in primary tumor and corresponding brain metastasis (BM) in nonsmall cell lung cancer (NSCLC). Materials and methodsPrimary pulmonary tumors and paired BMs of 27 NSCLC patients were surgically removed. All brain lesions were histologically confirmed as metastatic NSCLC. EGFR gene mutation status was detected by using amplification refraction mutation system. McNemar test was performed to compare EGFR mutation status between lung primary tumors and metastatic brain tumors and Kappa test was performed to quantify the agreement between the two. ResultsOf the 27 patients, nine cases were found to have EGFR mutations in BMs and 10 had a positive EGFR mutation status in primary lung tumor tissue. The rate of consistency of the matched tumor was 24/27 (88.9%). Among the three cases presenting EGFR mutational heterogeneity, two patients harbored an EGFR mutation in the primary tumor but not in the BMs; meanwhile, the last patient demonstrated the opposite pattern. Compared to patients with consistent EGFR mutations, patients with inconsistent mutations showed better outcomes. Further analysis revealed that the two patients whose EGFR mutant-type primary tumor progressed to wild-type cerebral metastatic tumor had longer overall survival than the patient whose EGFR wild-type primary tumor progressed to mutant-type brain metastatic tumor. ConclusionsHeterogeneity of EGFR mutation status was observed between primary NSCLC and paired BM. Patients possessing a wild-type EGFR mutation in BM might have better outcomes, especially those with transition from mutant to wild-type.

Liquid biopsy for detecting epidermal growth factor receptor mutation among patients with non-small cell lung cancer treated with afatinib: a multicenter prospective study

BackgroundThis study aimed to determine the effectiveness of liquid biopsy in detecting epidermal growth factor receptor (EGFR) mutations at diagnosis, disease progression, and intermediate stages.MethodsThis prospective, multicenter, observational study included 30 patients with non-small cell lung cancer treated with afatinib, harboring a major EGFR mutation confirmed by tumor tissue biopsy. We collected blood samples for liquid biopsy at diagnosis, intermediate stage, and progressive disease. Tissue and liquid biopsies were examined using Cobas ® EGFR Mutation Test v2.ResultsLiquid biopsy detected EGFR mutations in 63.6% of the patients at diagnosis. The presence of metastasis in the extrathoracic, brain, and adrenal glands correlated positively with the detection of EGFR mutations. Patients with positive EGFR mutations at diagnosis had significantly shorter overall and progression-free survival than patients with negative EGFR mutations. Four of the 18 patients (22.2%) who reached progressive disease had positive EGFR T790M mutations. Three of 10 patients (30.0%) with progressive disease were positive and negative for T790M using tumor re-biopsy and liquid biopsy, respectively. The results of EGFR mutation by tissue re-biopsy were the same as those of liquid biopsy in the three patients who were positive for significant EGFR mutations but negative for the T790M mutation using liquid biopsy at progressing disease. Only two patients were positive for major EGFR mutations at intermediate levels.ConclusionsLiquid biopsy can be a prognostic factor in EGFR-tyrosine kinase inhibitor treatments at diagnosis. Tumor re-biopsy can be omitted in patients with positive EGFR mutations by liquid biopsy at PD.

The prognostic impact of lung adenocarcinoma predominance classification relating to pathological factors in lobectomy, the Japanese Joint Committee of Lung Cancer Registry Database in 2010

ObjectiveWe studied the prognosis and clinicopathological background of lung adenocarcinoma predominance among patients who underwent lobectomy using data from the Japanese Joint Committee of Lung Cancer Registry.MethodsTwo thousand eight hundred sixty-three cases were extracted. Recurrence free survival (RFS) rates, overall survival (OS) rates and clinicopathological factors and epidermal growth factor receptor (EGFR) mutation status were examined.ResultsMedian follow-up period was 65.5 months. Adenocarcinoma predominance was sub-grouped according to OS and RFS rate. In pathological stage I, 5-year RFS and OS rates were respectively 92.2% and 95.8% in group A (adenocarcinoma-in-situ + minimally invasive adenocarcinoma), 89.3% and 92.1% in group B (lepidic), 79.2% and 89.7% in group C (papillary + acinar + variants) and 69.0% and 79.0% in group D (solid + micropapillary). In pathological stage II + IIIA, they were, 43.6% and 72.4% in B, 39.5% and 66.9% in C and 31.0% and 53.7% in D. Group D showed significant worst outcome both in stage I and II + IIIA. Up stage rate from clinical stage I to pathological stage II + IIIA was 0.0%, 3.7%, 15.9% and 33.3%. The frequency of lymph-vessel, vascular, pleura invasion and positive EGFR mutation were 0.0%, 0.0%, 0.0% and 57.1% in group A, 15.6%, 10.0%, 12.1% and 55.1% in B, 36.6%, 31.8%, 29.7% and 44.9% in C, 50.2%, 57.8%, 38.9% and 21.3% in D. In group D, lymph-vessel, vascular and pleura invasion were most, EGFR mutation was least frequent not only in pathological stage I but also stage II + IIIA. In multivariate analysis, age, pathological stage, vascular invasion, and group D were independent factors affected RFS and OS.ConclusionLimited to lobectomy cases, solid + micropapillary was independent prognostic factor both in early and locally advanced stage. Its malignant degree was related to the frequency of pathological invasive factors and EGFR mutation status.

Treatment patterns and outcomes in resectable early stage NSCLC: Interim analysis of a global real-world study.

e18803 Background: Complete surgical resection is the preferred treatment for early stage NSCLC, with adjuvant chemotherapy as the standard of care in resected stage II/III and select stage IB NSCLC. Osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is approved as adjuvant therapy in patients (pts) with resected stage IB–IIIA EGFR mutation-positive (EGFRm) NSCLC following results from the Phase III ADAURA trial. Understanding real-world clinical outcomes in early stage NSCLC, including EGFRm prevalence, will help inform unmet needs and further development of new treatment strategies in this population. We report interim results from a global non-interventional retrospective study of pts with resectable NSCLC using clinical data from medical records. Methods: Eligible pts (aged ≥18 yrs) had completely resected stage IA–IIIA NSCLC diagnosed between Jan 1, 2014 and Dec 31, 2017 with EGFR test results available and were followed to at least Dec 31, 2020. Primary endpoints included EGFRm prevalence, treatment patterns, and overall survival (OS); disease-free survival (DFS) was an exploratory endpoint estimated by Kaplan-Meier at predefined landmark timepoints. Results: Of 463 pts from 6 countries (31% from Taiwan, 21% Canada, 17% US, 13% Austria, 10% South Korea, 9% France), median age was 66 yrs (range: 33–86); 172 pts (37%) had stage IA NSCLC at initial diagnosis and 291 (63%) had stage IB–IIIA (22% IB, 13% IIA, 10% IIB, 18% IIIA). 213/463 pts (46%) were EGFRm (43% stage IA, 61% IB, 43% IIA, 26% IIB, 47% IIIA), of who 46% were from Taiwan, 21% South Korea, 14% Austria, 8% Canada, 7% US, and 4% France. In pts with EGFRm vs EGFR wild-type (wt) NSCLC, 84/213 (39%) and 83/250 (33%), respectively, received (neo)adjuvant therapy, of who 156/167 pts (93%) had stage IB–IIIA NSCLC. 106/156 pts (68%) had disease recurrence or death from time of surgery; recurrence rates were similar in pts with EGFRm vs EGFRwt NSCLC, though median DFS was longer in the EGFRm group (Table). Recurrence rates were high in both EGFRm and EGFTwt groups, with landmark DFS probability of 72% vs 77% at 12 mo and 29% vs 32% at 60 mo, respectively. Conclusions: In this real-world global study of surgically resected stage IA–IIIA NSCLC in pts who received an EGFR test, nearly half of the study cohort were EGFRm positive, of who 70% were treated in Taiwan/South Korea. The high rate of recurrence in pts with stage IB–IIIA NSCLC despite receiving (neo)adjuvant therapy reinforces the need for early diagnosis and EGFR testing to identify pts who might benefit from EGFR-targeted therapy, helping optimize clinical outcomes.[Table: see text]

Durvalumab (durva) after chemoradiotherapy (CRT) in unresectable, stage III, EGFR mutation-positive (EGFRm) NSCLC: A post hoc subgroup analysis from PACIFIC.

8541 Background: Standard of care for patients (pts) with unresectable (UR) stage III NSCLC is the ‘PACIFIC regimen’, based on data from the phase 3 placebo (pbo)-controlled trial where consolidation durva following CRT improved overall survival (OS; hazard ratio [HR], 0.68 [95% CI, 0.53, 0.87]) and progression-free survival (PFS; HR, 0.52 [95% CI 0.42, 0.65]), in an all-comer population. However, the benefit of immunotherapy (IO) in pts with EGFRm stage III NSCLC is unclear. We report a post hoc exploratory efficacy and safety analysis from 35 pts with EGFRm NSCLC from the PACIFIC trial (NCT02125461). Methods: Pts with stage III UR-NSCLC, WHO performance status (PS) 0/1 and no progression after ≥2 cycles platinum-based concurrent CRT were randomized 2:1 (1–42 days post CRT) to receive durva (10mg/kg IV q2w for up to 1 year) or pbo, stratified by age, sex, and smoking history; enrollment was not restricted by oncogenic driver gene mutation status or PD-L1 expression. Primary endpoints: PFS (BICR; RECIST v1.1) and OS; key secondary endpoints: objective response rate (ORR) and safety. Treatment effects for the EGFRm subgroup were estimated using an unstratified Cox proportional hazard model; medians were estimated using the Kaplan–Meier method. Statistical analyses were exploratory. Data cut-off (DCO) for the EGFRm subgroup efficacy analysis was 11 January 2021. Results: Of 713 pts randomized, 35 had EGFRm NSCLC based on local testing (durva n = 24, pbo n = 11). In the EGFRm subgroup, more pts in the pbo vs durva arm were male (73% vs 54%), had stage IIIA disease (64% vs 46%), PS 0 (64% vs 54%) and received pre-CRT induction chemotherapy (36% vs 8%). More pts in the durva arm were Asian (63% vs 55%) and had PD-L1 on &lt; 25% tumor cells (67% vs 36%); median age was consistent across arms. At DCO, median duration of follow-up for survival was 42.7 months (range, 3.7–74.3 months) for all randomized pts in the subgroup. Median PFS was 11.2 months (95% CI 7.3, 20.7) with durva vs 10.9 months (95% CI 1.9, not evaluable [NE]) with pbo; HR 0.91 (95% CI 0.39, 2.13). Median OS was 46.8 months (95% CI 29.9, NE) with durva vs 43.0 months (95% CI 14.9, NE) with pbo; HR 1.02 (95% CI 0.39, 2.63). ORR was 26.1% (95% CI, 10.2, 48.4) and 18.2% (95% CI 2.3, 51.8) with durva and pbo, respectively. The safety profile for durva was consistent with the overall population. In the durva and pbo subgroup arms, radiation pneumonitis was reported in 42% vs 36% of pts, and pneumonitis was reported in 17% vs 18% of pts (1 grade 3, pbo arm), respectively. Conclusions: In this post hoc exploratory analysis of 35 pts, PFS and OS outcomes with durva were similar to pbo in the EGFRm population, with wide CIs. The benefit of IO in this population remains unclear. The ongoing LAURA study (NCT03521154) is investigating the efficacy and safety of maintenance osimertinib in pts with locally advanced EGFRm stage III UR-NSCLC with no progression after CRT. Clinical trial information: NCT02125461.

Machine Learning-Based Radiomics for Prediction of Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinoma.

Identifying an epidermal growth factor receptor (EGFR) mutation is important because EGFR tyrosine kinase inhibitors are the first-line treatment of choice for patients with EGFR mutation-positive lung adenocarcinomas (LUAC). This study is aimed at developing and validating a radiomics-based machine learning (ML) approach to identify EGFR mutations in patients with LUAC. We retrospectively collected data from 201 patients with positive EGFR mutation LUAC (140 in the training cohort and 61 in the validation cohort). We extracted 1316 radiomics features from preprocessed CT images and selected 14 radiomics features and 1 clinical feature which were most relevant to mutations through filter method. Subsequently, we built models using 7 ML approaches and established the receiver operating characteristic (ROC) curve to assess the discriminating performance of these models. In terms of predicting EGFR mutation, the model derived from radiomics features and combined models (radiomics features and relevant clinical factors) had an AUC of 0.79 (95% confidence interval (CI): 0.77-0.82), 0.86 (0.87-0.88), respectively. Our study offers a radiomics-based ML model using filter methods to detect the EGFR mutation in patients with LUAC. This convenient and low-cost method may be of help to noninvasively identify patients before obtaining tumor sample for molecule testing.

85P Adjuvant osimertinib in patients (pts) with stage IB–IIIA EGFR mutation-positive (EGFRm) NSCLC after complete tumour resection: ADAURA China subgroup analysis

Osimertinib is a third-generation, EGFR-TKI with demonstrated efficacy in NSCLC, including CNS metastases. In Chinese pts with NSCLC, prevalence of EGFRm disease is high. In the global phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs placebo (PBO) in pts with resectable stage II-IIIA (hazard ratio [HR] 0.17 [99.06% CI: 0.11, 0.26]; p<0.0001) and stage IB-IIIA (HR 0.20 [99.12% CI: 0.14, 0.30]; p<0.0001) EGFRm NSCLC.