Epidermal Growth Factor Receptor Testing Research Articles

CLINICAL FACTORS PREDECTING T790M MUTATION IN NON-SMALL CELL LUNG CANCER PROGRESSED AFTER FIRST- AND SECOND-GENERATION TKI TREATMENT

Objective: We aimed to identify the T790M mutation rate and clinical factors predicting the occurrence of acquired T790M mutations in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after first- and second-generation tyrosine kinase inhibitor (TKI) treatment. Method: The EGFR-mutant NSCLC patients who experienced progression after first- and second-generation TKI treatment and underwent testing for EGFR using plasma samples between January 2021 and April 2023 were enrolled. The T90M mutation rate and related clinical factors were evaluated. We utilized the Chi-square test or Fisher’s exact test for univariate analysis and multivariable logistic binary regression for multivariate analysis. Results: A total of 247 patients were eligible for the study. Patients harbored the exon 19 deletion mutation (Del19), exon 21 L858R point mutation, and uncommon mutations in 63.2%, 34.4%, and 2.4% of cases, respectively. The overall T790M mutation rate was 33.6%. In multivariate analyses, the Del19 mutation versus L858R mutation, duration of first-line TKI exceeding 12 months versus below 12 months, and solitary lesion progression versus multiple lesion progression were identified as favorable prognostic factors for the occurrence of T790M mutation. Conclusion: Patients with EGFR exon 19 deletion, a prolonged treatment duration of first-line EGFR-TKI, and solitary lesion progression pattern are more likely to acquire the T790M mutation, as detected by the PCR method in plasma samples.

The value of dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting EGFR mutations

Objectives18F-fluorodeoxyglucose (FDG) PET/CT has been widely used for the differential diagnosis of cancer. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may make it difficult to differentiate between benign and malignant lesions. It is crucial to find reliable quantitative metabolic parameters to further support the diagnosis. This study aims to evaluate the value of the quantitative metabolic parameters derived from dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting epidermal growth factor receptor (EGFR) mutation status.MethodsWe included 147 patients with lung lesions to perform FDG PET/CT dynamic plus static imaging with informed consent. Based on the results of the postoperative pathology, the patients were divided into benign/malignant groups, adenocarcinoma (AC)/squamous carcinoma (SCC) groups, and EGFR-positive (EGFR+)/EGFR-negative (EGFR-) groups. Quantitative parameters including K1, k2, k3, and Ki of each lesion were obtained by applying the irreversible two-tissue compartmental modeling using an in-house Matlab software. The SUV analysis was performed based on conventional static scan data. Differences in each metabolic parameter among the group were analyzed. Wilcoxon rank-sum test, independent-samples T-test, and receiver-operating characteristic (ROC) analysis were performed to compare the diagnostic effects among the differentiated groups. P < 0.05 were considered statistically significant for all statistical tests.ResultsIn the malignant group (N = 124), the SUVmax, k2, k3, and Ki were higher than the benign group (N = 23), and all had-better performance in the differential diagnosis (P < 0.05, respectively). In the AC group (N = 88), the SUVmax, k3, and Ki were lower than in the SCC group, and such differences were statistically significant (P < 0.05, respectively). For ROC analysis, Ki with cut-off value of 0.0250 ml/g/min has better diagnostic specificity than SUVmax (AUC = 0.999 vs. 0.70). In AC group, 48 patients further underwent EGFR testing. In the EGFR (+) group (N = 31), the average Ki (0.0279 ± 0.0153 ml/g/min) was lower than EGFR (-) group (N = 17, 0.0405 ± 0.0199 ml/g/min), and the difference was significant (P < 0.05). However, SUVmax and k3 did not show such a difference between EGFR (+) and EGFR (-) groups (P>0.05, respectively). For ROC analysis, the Ki had a cut-off value of 0.0350 ml/g/min when predicting EGFR status, with a sensitivity of 0.710, a specificity of 0.588, and an AUC of 0.674 [0.523–0.802].ConclusionAlthough both techniques were specific, Ki had a greater specificity than SUVmax when the cut-off value was set at 0.0250 ml/g/min for the differential diagnosis of lung cancer. At a cut-off value of 0.0350 ml/g/min, there was a 0.710 sensitivity for EGFR status prediction. If EGFR testing is not available for a patient, dynamic imaging could be a valuable non-invasive screening method.

The association of EGFR amplification with aberrant exon 20 insertion report using the cobas EGFR Mutation Test v2.

Determining the exact type of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation in lung cancer has become important. We found that not all ex20ins mutations reported by cobas EGFR test v2 could be validated by Sanger sequencing even using surgical specimens with high tumor contents. This study aimed to validate the ex20ins results reported by the cobas test and to determine whether there were clinicopathological factors associated with aberrant cobas ex20ins report. In total, 123 cobas-reported cases with ex20ins were retrospectively collected and validated by Sanger sequencing and Idylla assay. Clinicopathological features between ex20ins cobas+/Sanger+ group (n = 71) and cobas+/Sanger- group (n = 52) were compared. The Idylla assay detected ex20ins in 82.6% of cobas+/Sanger+ cases but only in 4.9% of cobas+/Sanger- cases. The cobas+/Sanger- group was significantly associated with higher tumor contents, poorly differentiated patterns, tumor necrosis, and a lower internal control cycle threshold value reported by the Idylla which suggesting the presence of increased EGFR gene copy numbers. EGFR fluorescence in situ hybridization (FISH) revealed the majority of cobas+/Sanger- group had EGFR high copy number gain (16%) or amplification (76%) according to the Colorado criteria. Among cases reported to have concomitant classic EGFR and ex20ins mutations by the cobas, the classic EGFR mutations were all detected by Sanger sequencing and Idylla, while the ex20ins mutations were undetected by Sanger sequencing (0%) or rarely reported by Idylla assay (3%). FISH revealed high EGFR copy number gain (17.9%) and amplification (79.5%) in cases reported having concomitant classic EGFR and ex20ins mutations by the cobas. This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.

Abstract 783: Early impact assessment of in-house EGFR testing for NSCLC in Kenya

Abstract Introduction: Quality of life and survival among non-small cell lung cancer (NSCLC) patients have improved in the last two decades owing mainly to use of tyrosine kinase inhibitors (TKIs) and other targeted therapies. Low and middle-income countries (LMICs) especially in Africa, are lagging in realizing these benefits largely due to hurdles in molecular testing. In addition, quality histology and molecular data from LMICs is deficient. The aim of this study is to assess the immediate impact of improved access to epidermal growth factor receptor (EGFR) testing in Kenya, and to establish a long term-lung cancer data base. Methods: Staring mid-June 2023, an in-house PCR-based method was adopted for EGFR testing of NSCLC in order to side step the challenges of out-of-country send outs which was until then, the only option for EGFR testing. Further, a sponsored access program was created. From prospectively accrued samples, we performed a before-and-after assessment of the number of NSCLC cases intercepted, cost and turnaround times (TAT) as measures of impact. Demographic, histopathology, and EGFR mutation profiles were analyzed in comparison to Asia, USA and European data. Whole slide histology scanned images are made to compliment the database. Results: Over the four-month period, 62 NSCLC cases were accrued, median age at diagnosis was 63 with a range of 24 - 93. The male to female ratio was 1: 1.5. Adenocarcinomas comprised 89%, squamous cell carcinoma 5% and 3% were not classifiable. Metastatic disease was reported in 14 (22%) with the brain being the commonest site. EGFR mutations were identified in 16 (25%) with exon 19 deletions and L858R mutations constituting 94% of them. Monthly requisitions for EGFR have increased 3-fold, and the average TAT has been halved to 7 days. Conclusion: Similarities between our data and global patterns are noted; median age is in the seventh decade, NSCLC is more common in women, and so are the rates of EGFR mutations, adenocarcinomas are the predominant type, and there are high rates of brain metastasis at diagnosis. EGFR mutation rates appear to be higher than USA and European data but lower than Asian data. In-house and sponsored testing has had an immediate impact in reduction of costs and TAT and increased requisitions. Assessment of access to targeted therapy, clinical outcome, survival, expansion of molecular profiling beyond EGFR, and build-up of the database including virtual histology images for exploring artificial intelligence algorithms are our next steps. Citation Format: Allan Njau, Samuel Nguku, Joseph Abuodha. Early impact assessment of in-house EGFR testing for NSCLC in Kenya [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 783.

Text analysis framework for identifying mutations among non-small cell lung cancer patients from laboratory data

BackgroundLaboratory data can provide great value to support research aimed at reducing the incidence, prolonging survival and enhancing outcomes of cancer. Data is characterized by the information it carries and the format it holds. Data captured in Alberta’s biomarker laboratory repository is free text, cluttered and rouge. Such data format limits its utility and prohibits broader adoption and research development. Text analysis for information extraction of unstructured data can change this and lead to more complete analyses. Previous work on extracting relevant information from free text, unstructured data employed Natural Language Processing (NLP), Machine Learning (ML), rule-based Information Extraction (IE) methods, or a hybrid combination between them.MethodsIn our study, text analysis was performed on Alberta Precision Laboratories data which consisted of 95,854 entries from the Southern Alberta Dataset (SAD) and 6944 entries from the Northern Alberta Dataset (NAD). The data covers all of Alberta and is completely population-based. Our proposed framework is built around rule-based IE methods. It incorporates topics such as Syntax and Lexical analyses to achieve deterministic extraction of data from biomarker laboratory data (i.e., Epidermal Growth Factor Receptor (EGFR) test results). Lexical analysis compromises of data cleaning and pre-processing, Rich Text Format text conversion into readable plain text format, and normalization and tokenization of text. The framework then passes the text into the Syntax analysis stage which includes the rule-based method of extracting relevant data. Rule-based patterns of the test result are identified, and a Context Free Grammar then generates the rules of information extraction. Finally, the results are linked with the Alberta Cancer Registry to support real-world cancer research studies.ResultsOf the original 5512 entries in the SAD dataset and 5017 entries in the NAD dataset which were filtered for EGFR, the framework yielded 5129 and 3388 extracted EGFR test results from the SAD and NAD datasets, respectively. An accuracy of 97.5% was achieved on a random sample of 362 tests.ConclusionsWe presented a text analysis framework to extract specific information from unstructured clinical data. Our proposed framework has shown that it can successfully extract relevant information from EGFR test results.

Real world treatment patterns, healthcare resource use and costs in patients with advanced or metastatic non-small cell lung cancer by EGFR mutation type

Aims This study described treatment patterns, healthcare resource utilization (HRU) and costs among advanced or metastatic non-small cell lung cancer (a/mNSCLC) patients with different epidermal growth factor receptor (EGFR) mutation types. Materials and methods This retrospective study leveraged NeoGenomics NeoNucleus linked with IQVIA PharMetrics Plus between 01 January 2016 to 30 April 2021 (study period). Patients with evidence of a/mNSCLC between 01 July 2016 to 31 March 2021 (selection window) with EGFR test results indicating exon 19 deletion (exon19del), exon 21 L858R (L858R), or exon 20 insertion (exon20i) mutations were included; date of first observed evidence of a/mNSCLC was the index date. Treatment patterns, all-cause HRU and costs during ≥1 month follow-up were reported for each cohort (exon19del, L858R, and exon20i). Results A total of 106 exon19del, 75 L858R, and 13 exon20i patients met the study criteria. The prevalence of hospitalization was highest in the exon20i cohort (76.9%), followed by L858R (62.7%) and exon19del (55.7%) cohorts. A higher proportion of patients had evidence of hospice/end-of-life care in the exon20i (30.8%) and L858R (29.3%) cohorts relative to the exon19del cohort (22.6%). The exon20i cohort had higher median total healthcare costs per patient per month ($27,069) relative to exon19del ($17,482) and L858R ($17,763). EGFR tyrosine kinase inhibitors (TKI) were the most frequently observed treatment type for exon19del and L858R cohorts, while chemotherapy was the most observed treatment in exon20i cohort. Limitations The sample size for the study cohorts was small, thus no statistical comparisons were conducted. Conclusions This is one of the first real-world studies to describe HRU and costs among a/mNSCLC patients by specific EGFR mutation type. HRU and costs varied between EGFR mutation types and were highest among exon20i cohort, potentially reflecting higher disease burden and unmet need among patients with this mutation.

Rapid and reliable testing for clinically actionable EGFR mutations in non-small cell lung cancer using the IdyllaTM platform: a real-world two-center experience in Greece

ABSTRACT Background Limited information exists on epidermal growth factor receptor (EGFR) molecular epidemiology in Greece. Next-generation sequencing (NGS) is the recommended method for EGFR genotyping in NSCLC. The Idylla Biocartis platform is a fully automated system for actionable EGFR mutation detection. Research design and methods We describe the prevalence of EGFR mutations in NSCLC patients in two high-volume clinical centers in Greece and compare key methods used for their determination. Eight hundred and fifty-seven FFPE samples from NSCLC patients were tested for EGFR mutations at University of Crete (UoC; n = 324) and at Evangelismos Hospital, Athens (Evangelismos; n = 503). Results The prevalence of EGFR mutations was 11.1% in the whole cohort (11.5% in non-squamous). The detection rate was 11.0% by NGS, 9.8% by Sanger and 11.3% by Idylla for the whole cohort (12.0% in non-squamous). The agreement between Idylla and Sanger was 93.2%. A targetable EGFR mutation was detected in 10.0% using tissue NGS alone, and in 16.0% using concurrent Idylla ctEGFR testing. Conclusion The frequency of EGFR mutations was as expected for a Caucasian population. The Idylla EGFR test performance is comparable to reference methods and with a shorter TAT. Adding a concurrent plasma Idylla test to tissue NGS testing increases the detection rate of EGFR mutations in NSCLC.

Subregion-specific 18F-FDG PET-CT radiomics for the pre-treatment prediction of EGFR mutation status in solid lung adenocarcinoma.

This study aimed to assess the efficacy of fluor-18 fluorodeoxyglucose (18F-FDG) PET/CT using sub-regional-based radiomics in predicting epidermal growth factor receptor (EGFR) mutation status in pretreatment patients with solid lung adenocarcinoma. A retrospective analysis included 269 patients (134 EGFR+ and 135 EGFR-) who underwent pretreatment 18F-FDG PET/CT scans and EGFR mutation testing. The most metabolically active intratumoral sub-region was identified, and radiomics features from whole tumors or sub-regional regions were used to build classification models. The dataset was split into a 7:3 ratio for training and independent testing. Feature subsets were determined by Pearson correlation and the Kruskal Wallis test and radiomics classifiers were built with support vector machines or logistic regressions. Evaluation metrics, including accuracy, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were employed for different classifiers. Results indicated that the sub-region-based classifier outperformed the whole-tumor classifier in terms of accuracy (73.8% vs. 66.2%), AUC (0.768 vs. 0.632), specificity (65.0% vs. 50.0%), PPV (70.2% vs. 62.2%), and NPV (78.8% vs. 74.0%). The clinical classifier exhibited an accuracy of 75.0%, AUC of 0.768, sensitivity of 72.5%, specificity of 77.5%, PPV of 76.3%, and NPV of 73.8%. The combined classifier, incorporating sub-region analysis and clinical parameters, demonstrated further improvement with an accuracy of 77.5%, AUC of 0.807, sensitivity of 77.5%, specificity of 77.5%, and NPV of 77.5%. The study suggests that sub-region-based 18F-FDG PET/CT radiomics enhances EGFR mutation prediction in solid lung adenocarcinoma, providing a practical and cost-efficient alternative to invasive EGFR testing.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe

Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and2021. TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Real-world clinical evidence of lazertinib use in acquired EGFR T790M mutated non-small cell lung cancer.

Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting. Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%). The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40). Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.

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.

Cost-Effectiveness Analysis of Three Diagnostic Strategies for the Detection of EGFR Mutation in Advanced Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutation testing of tumor tissue should be conducted at diagnosis. Alternatively, circulating tumor DNA can be used to detect EGFR mutation. We compared the cost and clinical effect of three strategies according to the application of the EGFR test. Decision models were developed to compare the cost-effectiveness of tissue-only, tissue-first, and plasma-first diagnostic strategies as first- and second-line treatments for NSCLC from the perspective of the Korean national healthcare payer. Progression-free survival (PFS), overall survival (OS), and direct medical costs were assessed. A one-way sensitivity analysis was performed. The plasma-first strategy correctly identified numerous patients in the first- and second-line treatments. This strategy also decreased the cost of biopsy procedures and complications. Compared with that when using the other two strategies, the plasma-first strategy increased PFS by 0.5 months. The plasma-first strategy increased OS by 0.9 and 1 month compared with that when using the tissue-only and tissue-first strategies, respectively. The plasma-first strategy was the least expensive first-line treatment but the most expensive second-line treatment. First-generation tyrosine kinase inhibitor and the detection rate of the T790M mutation in tissues were the most cost-influential factors. The plasma-first strategy improved PFS and OS, allowing for a more accurate identification of candidates for targeted therapy for NSCLC and decreased biopsy- and complication-related costs.

The molecular characteristics of non-small cell lung cancer in the Northern Territory's Top End.

Indigenous Australians with lung cancer have poorer survival than non-Indigenous Australians. The reasons for the disparity are not fully understood and this study hypothesized that there may be a difference in the molecular profiles of tumors. The aim of this study, therefore, was to describe and compare the characteristics of non-small cell lung cancer (NSCLC) in the Northern Territory's Top End, between Indigenous and non-Indigenous patients, and describe the molecular profile of tumors in the two groups. A retrospective review was conducted of all adults with a new diagnosis of NSCLC in the Top End from 2017 to 2019. Patient characteristics assessed were Indigenous status, age, sex, smoking status, disease stage, and performance status. Molecular characteristics assessed were epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirsten rat sarcoma viral oncogene homolog (KRAS), mesenchymal-epithelial transition (MET), human epidermal growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1). Student's t-test and Fisher's Exact Test were used in the statistical analysis. There were 152 patients diagnosed with NSCLC in the Top End from 2017-2019. Thirty (19.7%) were Indigenous and 122 (80.3%) were non-Indigenous. Indigenous patients compared to non-Indigenous patients were younger at diagnosis (median age 60.7 years versus 67.1 years, p = 0.00036) but were otherwise similar in demographics. PD-L1 expression was similar between Indigenous and non-Indigenous patients (p = 0.91). The only mutations identified among stage IV non-squamous NSCLC patients were EGFR and KRAS but testing rates and overall numbers were too small to draw conclusions about differences in prevalence between Indigenous and non-Indigenous patients. This is the first study to investigate the molecular characteristics of NSCLC in the Top End.

Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial

The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Phenotypic and Genotypic Appraisal of Pulmonary Mucinous Adenocarcinoma: A Retrospective Study

Introduction: Lung cancer is the second most common cancer diagnosed in the world. According to GLOBOCAN 2020, it is approximately 11.4% of all malignancies and accounts for one in five cancer deaths worldwide. Several driver gene mutations are known in lung adenocarcinoma including Epidermal Growth Factor Receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog(KRAS), v-raf murine sarcoma viral oncogene homolog B1(BRAF), Human epidermal growth factor receptor2 (HER 2), anaplastic lymphoma kinase (ALK), Ros Protooncogene 1, Receptor Tyrosine Kinase (ROS1) and rearranged during transfection (RET). Among these, KRAS mutation has been classically defined as bearing a negative prognostic factor. They are described to have unfavourable survival rates as compared with KRAS wild- type tumours. However, its real significance remains controversial due to heterogeneity amongst studies. Aim: The aim of this study was to assess the histomorphology, immunophenotype, EGFR and KRAS mutation profile in invasive mucinous and mixed mucinous/non mucinous type lung carcinoma. Materials and Methods: This retrospective study was done at a tertiary cancer centre in the state of Kerala, South India to identify the frequency of EGFR and KRAS mutations in invasive mucinous or mixed mucinous/non mucinous type lung carcinoma diagnosed during the period June 2017 to March 2019. Immunohistochemical assays for CK7, CK20, TTF-1, Napsin-A, CDX-2 and p63 were done on all cases. EGFR mutation analysis for exons 18, 19, 20, 21 were done using ARMS PCR and KRAS mutation analysis for codons 12, 13, 61, 146 by Sanger sequencer. Descriptive statistics was used wherever applicable. Results: Out of a total of 290 patients of pulmonary adenocarcinoma during the two year study period, twelve cases (4.1%) were diagnosed as invasive mucinous or mixed mucinous/non mucinous types based on histomorphology and immunophenotype, on both lung tissue biopsies as well as material from metastatic sites. Of the twelve, nine (75%) were pure mucinous and three (25%) were mixed mucinous and non mucinous. All the twelve cases were subjected to molecular testing for both EGFR and KRAS. Three cases (25%) showed KRAS mutations in codon 12. EGFR mutation (TKI resistant T790M mutation) was found only in a single case which had a histology of mixed mucinous and non mucinous carcinoma and a coexistent mutation in KRAS (c12 G&gt;C) gene. Conclusions: Our study corroborates the described fact that pulmonary mucinous carcinoma differ from the conventional adenocarcinoma in terms of its histology, immunoprofile and molecular profile. KRAS mutation appears to be the main pathogenetic factor in this variant. In the current day practice, there is no demonstrable effective therapy for KRAS mutant lung adenocarcinoma and more trials are needed to identify newer mutations that can modify treatment outcomes.

The impact of population-based EGFR testing in non-squamous metastatic non-small cell lung cancer in Alberta, Canada

ObjectivesWhile Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies has been challenging to evaluate at the population-level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among non-squamous metastatic Non-Small Cell Lung Cancer (NSCLC) patients. Materials and methodsReal-world, population-level data were collected from all de novo non-squamous metastatic NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories. Differences in survival rates and overall survival (OS) pre (2004–2012) and post initiation (post) (2013–2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment was evaluated using multivariable Cox Proportional Hazards models. ResultsIn total, 4,578 non-squamous metastatic NSCLC patients were diagnosed pre-EGFR testing and 4,457 patients were diagnosed post-EGFR testing (2013–2019). Among patients diagnosed in the pre-EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95 % CI: 0.38–0.41), 0.22 (95 % CI: 0.21–0.23), and 0.09 (95 % CI: 0.08–0.10), while the survival probabilities for patients diagnosed in the post-EGFR testing period were 0.45 (95 % CI: 0.43–0.46), 0.29 (95 % CI: 0.27–0.30), and 0.16 (95 % CI: 0.15–0.17), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post-EGFR period was significantly improved compared to the pre-EGFR period (HR: 0.81; 95 % CI: 0.78–0.85). Among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95 % CI: 0.70–0.95). ConclusionThese results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among metastatic NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.

Real-world utilization of liquid biopsy for epidermal growth factor receptor (EGFR) testing in patients with metastatic non-small cell lung cancer (mNSCLC).

402 Background: Tissue biopsy (TB) testing is the standard of care to guide the selection of targeted therapy in EGFRm patients with mNSCLC. However, liquid biopsy (LB) tests are increasingly important in assessing tumor genomics at mNSCLC diagnosis. This study assessed real-world utilization of LB for EGFR testing in 1L setting and its influence on 1L treatment decisions in mNSCLC patients. Methods: Adults newly diagnosed with mNSCLC from January 1, 2019 to May 31, 2021 and treated with 1L were identified from the Flatiron EMR database. LB utilization and patterns (either used alone or in combination with TB) were evaluated. “Concurrent” (TB &amp; LB) testing was defined as patients with both test order dates prior to result dates for either test, while “sequential” (TB &amp; LB) testing was defined as patients having one test’s result date before the other test’s order date. As patients could have multiple biomarker tests, the first two EGFR tests following diagnosis were evaluated. Results: Of 5,036 patients that met the study criteria, 89.2% (N = 4,494) had EGFR testing following diagnosis. Among those tested for EGFRm, 63.7% (N = 2,864) had TB only, while 36.3% (N = 1,630) had LB (LB only: 37.9%; concurrent: 36.1%; sequential: 26.0%). Around 90% of patients with LB had NGS testing (87.7% received LB testing within 90 days of diagnosis). Among patients who initiated 1L after EGFR testing, the median (IQR) time in days from testing to 1L initiation varied by testing patterns: LB only: 18 (12-30); concurrent: 29 (22-39); sequential: 28 (18-41). Disagreement in test results was 10.6% for patients who had conclusive test results for both TB and LB tests. Among concurrent EGFRm patients (N = 130), 21.5% initiated 1L after receiving LB results (and before TB results) and 60.0% after receiving both test results. Among patients with sequential LB followed by TB (N = 10), 80.0% of them initiated 1L after receiving LB results and before TB results (Table). Conclusions: In this real-world study among mNSCLC patients in a 1L setting, more than one-third used LB for EGFR testing, either alone or in combination with TB. Among LB patients, majority had NGS testing.[Table: see text]

1001P Epidermal growth factor receptor (EGFR) testing and treatment patterns associated with diagnosis of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) in the US

With new targeted therapies approved for patients with NSCLC with EGFRex20ins, it is important to understand real-world diagnosis and treatment choice, as these mutations are associated with poor prognosis and require tailored treatment. The Flatiron Health electronic health record database was used to identify 75,067 patients with advanced NSCLC from 01/01/2011 to 12/31/2021. EGFR testing rates and proportion of tests done with next-generation sequencing (NGS) were described for all patients. First-line (1L) treatments were described for patients with EGFRex20ins(+) results in the last 5 years (2017-2021), stratified by initiation of 1L before or after EGFRex20ins(+) testing result. Overall, 67% of patients were tested for EGFR mutations (n=51,470). EGFR testing rates and the proportion of tests done with NGS increased from 2011 to 2021 (44.4 to 80.7% and <1.0 to 81.0%, respectively). Among patients with EGFRex20ins(+) results 2011-2017 (n = 250), 59 (24%) started 1L treatment prior to and 141 (56%) started 1L after their first EGFRex20ins(+) (50 were unknown). A higher proportion of patients received EGFR TKIs or were enrolled in clinical trials, and a lower proportion received chemotherapy if they started 1L treatment after their first EGFRex20ins(+) result, when compared to patients who started 1L treatment before. Similar proportions of patients were treated with IO monotherapy or IO + chemotherapy regardless of when treatment was started (table).Table: 1001P1L treatments in patients with EFRex20ins 2017-2021Started treatment before EGFRex20ins (+) result n (%)Started treatment after EGFRex20ins (+) result n (%)n = 59n = 141Chemotherapy27 (45.8)36 (25.5)IO monotherapy5 (8.5)16 (11.3)IO + chemotherapy21 (35.6)44 (31.2)EGFR TKI4 (6.8)32 (22.7)Clinical Trial1 (1.7)12 (8.5)Other1 (1.7)1 (0.7) Open table in a new tab EGFR testing increased over time; however, 20% of patients still remained untested in 2021. Among patients with EGFRex20ins mutations, a high proportion of patients started IO or EGFR TKIs after genetic testing despite limited effectiveness in this population. With the recent approval of therapies targeting EGFRex20ins mutations, increased testing and awareness of treatment outcomes in this population are needed.

Idylla EGFR assay on extracted DNA: advantages, limits and place in molecular screening according to the latest guidelines for non-small-cell lung cancer (NSCLC) patients

AimsIdylla epidermal growth factor receptor (EGFR) is a fast and fully automated mutation assay that is easy to implement. However, under the Biocartis-recommended technical conditions, tissue sections are directly introduced...

Prediction of EGFR Mutation Status in Non-Small Cell Lung Cancer Based on Ensemble Learning.

Objectives: We aimed to identify whether ensemble learning can improve the performance of the epidermal growth factor receptor (EGFR) mutation status predicting model. Methods: We retrospectively collected 168 patients with non–small cell lung cancer (NSCLC), who underwent both computed tomography (CT) examination and EGFR test. Using the radiomics features extracted from the CT images, an ensemble model was established with four individual classifiers: logistic regression (LR), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost). The synthetic minority oversampling technique (SMOTE) was also used to decrease the influence of data imbalance. The performances of the predicting model were evaluated using the area under the curve (AUC). Results: Based on the 26 radiomics features after feature selection, the SVM performed best (AUCs of 0.8634 and 0.7885 on the training and test sets, respectively) among four individual classifiers. The ensemble model of RF, XGBoost, and LR achieved the best performance (AUCs of 0.8465 and 0.8654 on the training and test sets, respectively). Conclusion: Ensemble learning can improve the model performance in predicting the EGFR mutation status of patients with NSCLC, showing potential value in clinical practice.