Mutant Lung Cancer Research Articles

DEGBOE: Discrete time Evolution modeling of Gene mutation through Bayesian inference using qualitative Observation of mutation Events

An important aspect of cancer progression concerns the way in which gene mutations accumulate in cellular lineages. Comprehensive efforts into cataloging cancer genes have revealed that tumors demonstrate variability in genes that accumulate mutations which depend on the presence or absence of other mutations. However, understanding the stochastic process by which mutations arise across the genome is an important open problem of this nature in biology due to modeling discrete variate time-series is the most challenging, and, as yet, least well-developed of all areas of research in time-series. In this paper, a DEGBOE framework is proposed to model the mutation time-series given the sequence data of the gene mutations. The method relates the discrete-time, nonlinear and nonstationary series of gene mutations to the time-varying autoregressive moving average model. It presents the observation as a nonlinear function dependent on two variables: gene mutation, and gene-gene interactions characterizing the effects of the varying presence or absence of other gene mutations on a mutations’ occurrence and evolution. DEGBOE is applied to model the dynamics of frequently mutated genes in lung cancer, includingEGFR,KRAS, and TP53. The results of the model are analyzed and compared to the original simulated data of theDNAwalk, and experimental lung cancer mutations data. It identifies the driver role of TP53 mutations in lung cancer progression.

The Role of Neighborhood Air Pollution Exposure on Somatic Non-Small Cell Lung Cancer Mutations in the Los Angeles Basin (2013-2018).

Limited previous work has identified a relationship between exposure to ambient air pollution and aggressive somatic lung tumor mutations. More work is needed to confirm this relationship, especially using spatially resolved air pollution. We aimed to quantify the association between different air pollution metrics and aggressive tumor biology. Among patients treated at City of Hope Comprehensive Cancer Center in Duarte, CA (2013–2018), three non-small cell lung cancer somatic tumor mutations, TP53, KRAS, and KRAS G12C/V, were documented. PM2.5 exposure was assessed using state-of-the art ensemble models five and ten years before lung cancer diagnosis. We also explored the role of NO2 using inverse-distance-weighting approaches. We fitted logistic regression models to estimate odds ratio (OR) and their 95% confidence intervals (CIs). Among 435 participants (median age: 67, female: 51%), an IQR increase in NO2 exposure (3.5 μg/m3) five years before cancer diagnosis was associated with an increased risk in TP53 mutation (OR, 95% CI: 1.30, 0.99–1.71). We found an association between highly-exposed participants to PM2.5 (>12 μg/m3) five and ten years before cancer diagnosis and TP53 mutation (OR, 95% CI: 1.61, 0.95–2.73; 1.57, 0.93–2.64, respectively). Future studies are needed to confirm this association and better understand how air pollution impacts somatic profiles and the molecular mechanisms through which they operate.

1002P Compared with the difference in efficacy between EGFR-TKIs alone and EGFR-TKIs combined with craniocerebral radiotherapy in EGFR mutant lung adenocarcinoma patients with brain metastasis. A propensity-score matched analysis

Epidermal growth factor receptor (EGFR)-mutant lung cancers have a high risk of developing brain metastases (BM). Craniocerebral radiotherapy has been considered as cornerstone for treatment of BM while BRAIN clinical trial showed that EGFR-TKI alone has effect on craniocerebral metastases. However, whether EGFR-TKIs combined with craniocerebral radiotherapy can further increase the efficacy and improve the prognosis of patients still need to be further discussed. This retrospective study aimed to evaluate the difference in efficacy between targeted therapy alone and targeted combined radiotherapy in EGFR mutant lung adenocarcinoma patients with BM.

EP08.02-082 Treatment Patterns and Outcomes of First-line Osimertinib-treated Advanced EGFR Mutated NSCLC Patients: A Real-world Study

Based on the survival benefit seen in the FLAURA trial, first-line osimertinib has become the standard-of-care for patients with EGFR mutation in advanced non-small cell lung cancer (NSCLC). However, treatment options are limited after progression on osimertinib. We explored survival outcomes, subsequent treatment lines, and metastatic sites post-osimertinib in patients with EGFR-mutated NSCLC treated with first-line osimertinib in a real-world setting.

107P Systematic characterization of MET activating mutations in non-small cell lung cancer

Alterations in mesenchymal epithelial transition factor (MET) as primary oncogenic drivers or secondary resistance mechanisms to tyrosine kinase inhibitors (TKI) often involve distinct MET mutation subtypes. While MET activating mutations primarily mediates resistance to MET TKIs, increasing evidence suggest that MET activating mutations also exist in the primary tissues. The molecular signatures and clinical relevance of MET activating mutations remain to be elucidated.

MA05.08 MET Exon 14 Skipping Mutation in Non-Small Cell Lung Cancer (NSCLC) by Specific Mutation, Histology, and Smoking History

MET exon 14 skipping mutations (METex14) are a heterogeneous family of oncogenic mutations (mt) found in NSCLC that can be effectively treated with approved targeted agents. While more commonly found in lung adenocarcinoma, METex14 is also known to occur in squamous NSCLC and in patients with a smoking history, unlike many other actionable drivers. We evaluated the association of histology and smoking history with the mutational landscape among patients with NSCLC harboring METex14 mutations.

EP08.02-072 The Predictive Value of Longitudinal Monitoring of Mutated EGFR in Plasma of Advanced NSCLC Patients on First-Line EGFR-TKIs

The analysis of cell-free DNA in plasma, so called liquid biopsy, significantly improved the detectability of activating and resistance EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients prior EGFR-TKI therapy and upon clinical progression, in particular when sufficient tumor tissue material is not available. Since the acquired resistance to EGFR-TKIs develops gradually under the inhibitor-specific selective pressure, the longitudinal analysis of mutated EGFR in both qualitative and quantitative manner may be more beneficial in term of the real-time treatment monitoring and early detection of resistance mutations.

EP16.03-032 Structure-Based Classification of Chinese Patients with Non-Canonical EGFR-Mutant Non-Small Cell Lung Cancer

Non-canonical EGFR mutations in non-small cell lung cancer (NSCLC) could be re-classified into four subtypes (Classical-like, P-loop and αC-helical compressing (PACC), T790M-like, and exon 20 loop insertions) based on unique structures as well as response to various types of tyrosine kinase inhibitors (TKIs). Since EGFR most frequently mutated in East-Asian population, it is clinically crucial to investigate the distribution of structure-based EGFR classification in Chinses NSCLC patients.

EP03.01-002 Co-occurring Mutations, Smoking Status and Prognosis of Early-stage Resected NSCLCs with EGFR Mutations

Co-occurring pathological mutations in non-small cell lung cancer (NSCLC) may account for clinical heterogeneity not explained by the single driver mutation model. The prognostic significance of various co-mutations and adjuvant treatment modalities has been explored in early-stage NSCLC, but there has not been a focus on the impact of smoking and EGFR co-mutations in early-stage NSCLC. This study aims to characterize the frequency of co-mutations in EGFR-mutated (EGFRm) early-stage resected NSCLC; to describe relationships between smoking history and co-mutation status; and to determine whether prognosis differs by co-mutation status and smoking status among patients with EGFRm NSCLC.

EP08.02-109 A Drug-Drug Interaction Study of Mobocertinib and Midazolam in Patients With Advanced Non-Small Cell Lung Cancer

Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target epidermal growth factor receptor (EGFR) exon 20 insertion (EGFR ex20ins) mutations in non-small cell lung cancer (NSCLC). In vitro studies indicated the potential for time-dependent inhibition and/or induction of cytochrome P450 (CYP) 3A after mobocertinib administration. Thus, a phase 1 drug-drug interaction study (NCT04051827) was conducted to assess the effect of repeat-dose administration of mobocertinib on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A substrate.

1179P Real-world insights into non-small cell lung cancer patients with MET exon 14 skipping mutations: A Swedish retrospective study from two university hospitals

There is a paucity of real-world evidence addressing mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in non-small cell lung cancer (NSCLC). Incidence is 3–4% for all histological subtypes. Recently, METex14 has emerged as a target lesion sensitive to MET inhibitors (METi) in advanced NSCLC, with overall response rates varying between 3–46%. Furthermore, some studies suggest improved sensitivity to immune checkpoint inhibitors (ICIs). However, the role of METex14 in clinical routine treatment remains unclear.

Structure-based classification of EGFR mutations in operable pre-invasive and invasive non-small cell lung cancer: a cross-sectional study.

BackgroundIt has been reported that the structure-based approach for defining functional groups of epidermal growth factor receptor (EGFR) mutations predicts the efficacy of EGFR inhibitors better than the traditional exon-based approach in the advanced stage. However, less is known about this structure-based classification of EGFR mutations in operable early-stage lung adenocarcinoma.MethodsNon-small cell lung cancer (NSCLC) patients with pathological stage I–III or adenocarcinoma in situ (AIS) who had EGFR mutations identified in next-generation sequencing (NGS) testing were recruited. Both exon-based and structure-based groupings of EGFR mutations were compared between the AIS and stage I–III patients using Fisher’s exact test.ResultsIn total 1,012 patients including 66 AIS and 946 stage I–III patients were analyzed in the study. A total of 1185 EGFR mutations were identified in the 1,012 NSCLC patients, of whom 84.39% harbored a single EGFR mutation and 15.61% harbored complex EGFR mutations. As expected, L858R was more common than 19del in our population (39.33% vs. 35.67%). Interestingly, concurrent L858R and 19del mutations were identified in 9 patients (0.89%), and all these patients were diagnosed with multiple primary lung cancer. A higher percentage of atypical EGFR mutations was identified in the AIS cohort than in the stage I–III NSCLC cohort (33.33% vs. 21.66%, P=0.03). According to the structure-based classification of EGFR mutations, 86.07%, 7.11%, 5.04%, and 1.78% of the EGFR mutations were classified as classical-like, P-loop and α C-helix compressing (PACC), exon 20 insertions (Ex20ins), and T790M-like mutations, respectively. The composition of EGFR mutations was different between patients <65 and ≥65 years (P=0.0267) but similar between patients with AIS and stage I–III NSCLC (P=0.1436). However, a higher percentage of Ex20ins occurred in younger (<65 years) patients, nonsmoking patients, and patients with AIS (6.7% vs. 2.5%, P=0.003; 5.8% vs. 0.8%, P=0.0107; and 10.6% vs. 4.7%, P=0.0423, respectively).ConclusionsThis large cross-sectional study delineated the structure-based classification of EGFR mutations in patients with operable NSCLC. While the traditional exon-based EGFR grouping showed difference between AIS and stage I–III NSCLC cohort, no difference was identified in the structural approach. Which approach had better prediction of targeted therapy efficacy in adjuvant settings warrants further investigation.

1172P High activity of poziotinib in G778_P780dup HER2 exon 20 insertion mutations in non-small cell lung cancer (NSCLC)

Poziotinib is an oral pan-ErbB tyrosine kinase inhibitor (TKI) with demonstrated clinical activity and an expected safety profile. Patients with NSCLC harboring HER2 exon 20 insertion mutations (ex20ins) have poor outcomes and lack approved targeted treatments. The G778_P780dup (G778) mutation is one of the most common, representing 9-19% of HER2 ex20ins in NSCLC. Previous studies have reported an overall response rate (ORR) ranging from 10-60% with TKIs in patients with G778. Here we report the effects of poziotinib in patients harboring the HER2 ex20ins G778 mutation in a relatively large population of treatment-naïve (C4) and previously treated (C2) patients with NSCLC.

EP08.02-137 Prospective Study of Aumolertinib in NSCLC Patients with EGFR Sensitive Mutations Who Are Intolerant to Osimertinib Treatment

Data from phase II and phase III clinical studies of the third-generation EGFR-TKI Aumolertinib showed significant treatment efficacy and a favorable safety profile for patients with EGFR-sensitive mutations (EGFRm+) in advanced non-small cell lung cancer (NSCLC). There is a difference in the incidence of AEs caused by osimertinib with the same 3rd generation EGFR-TKI, especially the low incidence of AEs caused by Aumolertinib in interstitial lung disease, cardiotoxicity, and hematotoxicity. The aim of this study was to evaluate the safety and efficacy of Aumolertinib in EGFRm+ advanced NSCLC patients with safety intolerance after treatment with oxitinib.

EP08.02-151 A Real World Evidence of Lorlatinib for Taiwanese with advanced ALK Positive Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) rearrangement is a rare driver mutation in non-small cell lung cancer and lorlatinib is the 3rd generation ALK tyrosine kinase inhibitor (TKI) approved for treating such patients. We aimed to report result of lorlatinib in real-world practice.

EP08.02-079 The Use of Lung Adenocarcinoma Patient-Derived Xenografts and Organoids to Study GDP-KRAS G12C Inhibitor Resistance

KRAS-mutations are present in 25-30% of the most common form of lung cancer, lung adenocarcinoma (LUAD), and KRASG12C mutations account for 40% of KRAS-mutations in LUAD. Recent development of covalent GDP-KRASG12C inhibitors (G12Ci) have reignited efforts to target the once “undruggable” protein. Preclinical studies have identified mechanisms of adaptive resistance in cell lines. However, patient-derived xenografts (PDX) and xenograft-derived organoids (XDO) have not yet been extensively used to study mechanisms of primary and acquired resistance.

EP02.01-005 The Efficacy of Platinum-Based Chemotherapy as Adjuvant Therapy in EGFR Mutant Lung Adenocarcinoma

The ADAURA trial reported that osimertinib improved disease-free survival (DFS) compared with placebo as an adjuvant chemotherapy for stage II-IIIA EGFR mutant lung cancer. Currently, platinum-based adjuvant chemotherapy is the standard adjuvant therapy for patients with and without EGFR mutations. This study aimed to evaluate the efficacy of platinum-based adjuvant chemotherapy in stage II-IIIA EGFR mutant lung adenocarcinoma.

EP08.02-070 High Incidence of Peridiagnosis Thromboembolic Events In Patients with BRAF Mutant Lung Cancer

A higher risk of thromboembolic events (TEE) has been recently reported in patients (pts) with non-small-cell lung cancer (NSCLC) harboring ALK or ROS1 gene rearrangements (incidence rate 20-30%). BRAF mutations have been described in 4% of NSCLC. Whether pts with BRAF mutant NSCLC show higher risk of TEE is unknown. We aimed to describe the incidence, characteristics and time of onset of TEE in pts with advanced BRAF mutant NSCLC.

EP08.02-097 Prevalence, Clinical Characteristics and Survival of Patients With Brain Metastases and KRAS Mutation Lung Cancer in Argentina

Between 20-35% of lung adenocarcinomas harbor KRAS gene mutations (KRASm). With the development of KRAS G12C covalent inhibitors as novel targeted therapies in this population, there is renewed interest in understanding the clinical features and outcomes of patients with KRAS mutant non-small cell lung cancer (NSCLC) worldwide.

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy.

Simple SummaryTumor mutation burden (TMB) represents the mutational load in the tumor cell genome and serves as a surrogate marker for tumor neoantigen production and potential immunogenicity. TMB has been widely explored as a complementary or alternative biomarker for immune checkpoint inhibitors in various malignancies including lung cancer. However, its clinical implication in the targeted-therapy setting is scarcely investigated. This study demonstrates that high TMB is independently associated with poor progression-free and overall survivals, and a low frequency of secondary T790M mutation in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma that are treated with tyrosine kinase inhibitors (TKIs). To the best of our knowledge, this is the first study demonstrating the significant association between the TMB level and resistance pattern after TKI failure.This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients’ subgroup warranting tailored therapeutic approaches.