EGFR-mutant Non-small Cell Lung Cancer Patients Research Articles

Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy.

BackgroundFew treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients.MethodsNSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan−Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors.ResultsA total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy.ConclusionsOur results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed.

The efficacy of immune checkpoint inhibitors in advanced EGFR-Mutated non-small cell lung cancer after resistance to EGFR-TKIs: Real-World evidence from a multicenter retrospective study.

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting.Patients and methodsWe collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients’ objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed.ResultsThe ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009).ConclusionsOur study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.

RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer

BackgroundRET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor (EGFR) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood.MethodsTargeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary RET fusions and 71 EGFR-mutated NSCLC patients who acquired RET fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs).ResultsPrimary RET fusions were more likely associated with females and younger age, with KIF5B being the predominant fusion partner. In baseline patients, both SMAD4 (5.3% vs. 0.0%, P = 0.044) and MYC copy-number gain variants (6.9% vs. 0.0%, P = 0.009) were more frequently co-mutated with KIF5B-RET than CCDC6-RET. By contrast, CDKN2A (11.3% vs. 2.4%, P = 0.003) mutations were significantly enriched in CCDC6-RET-rearranged baseline patients. A significant increase in the proportion of CCDC6-RET was observed in acquired RET-rearranged patients (47.3% vs. 22.5%, P < 0.001). The median progression-free survival (PFS) of patients harboring RB1 and TP53 double-mutations (5.5 vs. 10.0 months, P = 0.020) or ERBB2 amplification (5.6 vs. 10.0 months, P = 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that RET fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs.ConclusionsIn conclusion, we depicted the mutational profiles of NSCLC patients who harbor RET fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that RET fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC.

948TiP Efficacy and safety of almonertinib in the adjuvant treatment of resectable stage I non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-sensitizing mutations in solid and/or micropapillary components

Pathological subtypes are prognostic indicators independent of TNM stage, and patients with micropapillary and solid components have poorer prognosis. Previous studies have found that the presence of a micropapillary component was significantly associated with worse recurrence-free survival in patients with stage I lung adenocarcinoma, even the components are less than 5%, and postoperative adjuvant chemotherapy can still bring benefit to those patients even with stage IA. Third-generation EGFR-TKI have recently shown striking benefit for postoperative adjuvant therapy in patients with EGFR-mutated NSCLC. At present, there is no systematic study on the efficacy and safety of third-generation EGFR-TKI in stage I NSCLC patients with high-risk recurrence factors, such as solid and micropapillarycomponents. The third-generation EGFR-TKI, aumolertinib(HS-10296), showed promising efficacy in advanced NSCLC patients with sensitive EGFR mutation. This is the first study to explore the efficacy and safety of aumolertinib as adjuvant therapy in patients with EGFR mutant stage I NSCLC with solid and/or micropapillary component. Approximately 52 stage I EGFR-mutated NSCLC patients with solid and/or micropapillary components ≥10% will be enrolled in this multicenter single-arm study. After radical lung cancer surgery, they will receive oral almonertinib 110 mg/d as adjuvant therapy for 3 years. The primary endpoint is 2-year disease free survival (DFS) rates, and secondary endpoints included the 3-, 4-, and 5-year DFS rates, 5-year overall survival rates, safety and quality of life, Circulating tumor DNA will also be monitored during the study. Recruitment of this study is ongoing, and the first patient had been enrolled in January 2022. The author.

EP08.02-155 The Difference in Clinical Outcomes Between Osimertinib and EGFR-TKI plus Anti-angiogenic Agent in EGFR-mutant NSCLC Patients

The aim of this study was to investigate the difference of the efficacy between osimertinib and Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor (TKI)s combined anti-angiogenic agents as first line treatment in advanced and recurrence EGFR-mutant Non-small Cell Lung Cancer (NSCLC) patients.

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.

EP08.02-091 Disease Monitoring of EGFR-mutated NSCLC Patients Treated with TKIs via EGFR Status in Circulating ctDNA

Circulating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status.

EP08.02-164 The Effect of Metformin on Survival Outcomes of Advanced EGFR-mutant NSCLC Patients Treated with EGFR TKIs in Thailand

EGFR tyrosine kinase inhibitor (TKI) is mainstay treatment of advanced mutant NSCLC. Mechanism of action of EGFR TKI is inhibitory effects on cell proliferation via through down regulation of AKT and MAPK signaling pathways. Metformin may have direct effect on cancer cells by the similar pathway. The synergistic effect of metformin and EGFR TKI on survival outcomes has been explored. This is the first study in Thailand aim to evaluate the progression free survival (PFS) and overall survival (OS) in advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with or without type 2 diabetes (T2DM) who were treated with EGFR TKI and metformin/ or other oral hypoglycemic agent, and EKFR TKI alone, respectively.

1050P Association of ctDNA quantification with prognosis and early prediction of response to first-line osimertinib in NSCLC patients

Osimertinib is the new standard of care in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The MELROSE study, a multicentric, open label, phase II trial (NCT03865511) was designed to identify resistance mechanisms at the time of disease progression in treatment-naive EGFR-mutated NSCLC patients receiving osimertinib. While these analyses are in progress, we explored secondary endpoints including ctDNA analysis.

EP08.02-035 Clinical Utility of Liquid Biopsy After Progression to First and Second-Generation TKIs in Advanced EGFR Mutant NSCLC Patients

Liquid biopsy (LB) has increased its usefulness in selecting precise therapy during different treatment phases in advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). In addition, it has played a prognostic and predictive role in EGFRm patients. Detection of main oncogenic driver alteration on LB has been associated with worse oncological outcomes and increased disease burden. This study aims to assess survival and clinical characteristics associated with LB findings at first EGFR-TKI progression.

1123P Real-world outcomes of first-line osimertinib for EGFR mutated advanced NSCLC patients in China: Interim analysis of the FLOURISH study

Osimertinib is currently the first-line standard of care for EGFR mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) based on its superior efficacy in FLAURA study. However, limited real-world data is available in China. FLOURISH is a multicenter, prospective, non-interventional study to evaluate the real-world efficacy and safety of first-line therapy of osimertinib for EGFRm NSCLC patients in China.

Expression of SARS-CoV-2-Related Surface Proteins in Non-Small-Cell Lung Cancer Patients and the Influence of Standard of Care Therapy.

Simple SummarySARS-CoV-2 is a respiratory virus that uses ACE2 for host cell entry and the spike protein is primed by, among others, TMPRSS2 and FURIN. The goal of this study was to determine in which non-small-cell lung cancer (NSCLC) patients these proteins are expressed on the membrane of the lung cancer cells and in which patients this increased ACE2 expression results in higher levels of soluble (s)ACE2 in their serum. In addition, we studied the influence of standard of care (SOC) therapies on sACE2 levels. Membranous (m)ACE2 was co-expressed with mFURIN and/or mTMPRSS2 in 16% of the NSCLC patients, and mACE2 and sACE2 were more frequently expressed in mutant EGFR patients but not mutant-KRAS patients. Importantly, systemic SOC therapies did not result in increased sACE2 levels. This indicates that cancer cells can be infected by SARS-CoV-2 in these patients, as well as that soluble ACE2 could impact the course of COVID-19.In this study, we aimed to study the expression of SARS-CoV-2-related surface proteins in non-small-cell lung cancer (NSCLC) cells and identify clinicopathological characteristics that are related to increased membranous (m)ACE2 protein expression and soluble (s)ACE2 levels, with a particular focus on standard of care (SOC) therapies. ACE2 (n = 107), TMPRSS2, and FURIN (n = 38) protein expression was determined by immunohistochemical (IHC) analysis in NSCLC patients. sACE2 levels (n = 64) were determined in the serum of lung cancer patients collected before, during, or after treatment with SOC therapies. Finally, the TCGA lung adenocarcinoma (LUAD) database was consulted to study the expression of ACE2 in EGFR- and KRAS-mutant samples and ACE2 expression was correlated with EGFR/HER, RAS, BRAF, ROS1, ALK, and MET mRNA expression. Membranous (m)ACE2 was found to be co-expressed with mFURIN and/or mTMPRSS2 in 16% of the NSCLC samples and limited to the adenocarcinoma subtype. TMPRSS2 showed predominantly atypical cytoplasmic expression. mACE2 and sACE2 were more frequently expressed in mutant EGFR patients, but not mutant-KRAS patients. A significant difference was observed in sACE2 for patients treated with targeted therapies, but not for chemo- and immunotherapy. In the TCGA LUAD cohort, ACE2 expression was significantly higher in EGFR-mutant patients and significantly lower in KRAS-mutant patients. Finally, ACE2 expression was positively correlated with ERBB2-4 and ROS1 expression and inversely correlated with KRAS, NRAS, HRAS, and MET mRNA expression. We identified a role for EGFR pathway activation in the expression of mACE2 in NSCLC cells, associated with increased sACE2 levels in patients. Therefore, it is of great interest to study SARS-CoV-2-infected EGFR-mutated NSCLC patients in greater depth in order to obtain a better understanding of how mACE2, sACE2, and SOC TKIs can affect the course of COVID-19.

A Multicenter Two-arm, Phase II Trial Assessing the Safety and Efficacy of First-line Lazertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR-mutant Non-small Cell Lung Cancer (ABLATE, KCSG-LU21-11)

BackgroundThe current standard treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation is upfront EGFR targeted therapy. However, patients invariably experience disease progression at primary tumors or metastatic sites. Adding stereotactic body radiation therapy (SBRT) to systemic therapy can improve progression-free survival (PFS) and overall survival (OS). This multicenter, 2-arm, phase II study aims to evaluate the efficacy and safety of lazertinib, a third generation EGFR tyrosine kinase inhibitor, combined with upfront locally ablative radiotherapy in EGFR-mutant NSCLC patients with synchronous oligometastatic disease (ClinicalTrials.gov: NCT05167851). Patients and MethodsKey inclusion criteria are biopsy-proven EGFR-mutated adenocarcinoma with synchronous, oligometastatic (≤5 metastases) NSCLC. Patients will be randomized 1:1 to receive lazertinib or lazertinib + SBRT to the primary tumor and metastatic sites. The primary endpoint is PFS according to RECIST: Response Evaluation Criteria in Solid Tumor version 1.1, and the secondary endpoints are OS, objective response rate, and safety. ResultsPatient enrolment began in January 2021 and is ongoing at 7 sites in the Republic of Korea. ConclusionThis trial will provide valuable information on the efficacy and safety of lazertinib in combination with SBRT in patients with synchronous, oligometastatic EGFR-mutant NSCLC.

PD-L1 expression, tumor mutational burden, and immune cell infiltration in non-small cell lung cancer patients with epithelial growth factor receptor mutations.

BackgroundImmunotherapy using programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors seems less effective in non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations. Varied responses to PD-1/PD-L1 inhibitors have recently been observed in NSCLC patients harboring different types of EGFR mutations. Some EGFR-mutated NSCLC patients may benefit from PD-1/PD-L1 inhibitors. At present, PD-L1 expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME) are biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients. We retrospectively evaluated PD-L1 expression, TMB, and immune cell infiltration in NSCLC patients with EGFR mutation subtypes.MethodsPD-L1 expression, TMB, and the abundance of immune cell infiltration in NSCLC patients were evaluated in public databases and clinical samples. TMB was detected using the NGS technique, PD-L1 was detected using immunohistochemistry, and the abundance of immune cell infiltration in NSCLC samples was detected using multiple immunohistochemistry.ResultsPD-L1 expression and TMB were lower in EGFR-mutated NSCLCs than in wild-type patients. Differences in the abundance of immune cell infiltration were also observed between EGFR-mutated and wild-type NSCLC. The expression of PD-L1, TMB, and abundance of immune cell infiltration were different in patients harboring different subtypes of EGFR mutations. Patients with uncommon EGFR mutations, especially the G719X mutation, showed higher TMB and expressions of PD-L1 than classical EGFR mutations. M1 macrophages were higher in uncommon EGFR mutations than classical EGFR mutations.ConclusionsThe expression of PD-L1 and TMB in uncommon EGFR-mutated NSCLCs, especially the G719X mutation, were higher than those for classical EGFR-mutated NSCLCs and similar to EGFR wild-type. The abundance of immune cell infiltration in uncommon EGFR-mutated NSCLCs was similar to that in EGFR wild-type. Our findings suggest that uncommon EGFR-mutated NSCLCs may benefit from PD-1/PD-L1 inhibitors.

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors.

BackgroundAlthough immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations.MethodsThe profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated.ResultsPatients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002).ConclusionPatients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.

The histone deacetylase SIRT6 promotes glycolysis through the HIF-1α/HK2 signaling axis and induces erlotinib resistance in non-small cell lung cancer

Erlotinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Overcoming erlotinib resistance is crucial to improve the survival of advanced non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. It is also an important clinical problem that urgently needs a solution. In this study, we explored strategies to overcome erlotinib resistance from the perspective of energy metabolism. SIRT6 is a histone deacetylase. Here, we found that high expression of SIRT6 is associated with poor prognosis of lung adenocarcinoma, especially in EGFR-mutated NSCLC patients. The next cell experiment found that SIRT6 expression increased in erlotinib-resistant cells, and SIRT6 expression was negatively correlated with the sensitivity of NSCLC to erlotinib. Inhibition of SIRT6 promoted erlotinib-induced apoptosis in erlotinib-resistant cells, and glycolysis in drug-resistant cells was also inhibited. Functional studies have shown that SIRT6 increases glycolysis through the HIF-1α/HK2 signaling axis in drug-resistant cells and inhibits the sensitivity of NSCLC cells to erlotinib. In addition, the HIF-1α blocker PX478-2HCL attenuated the glycolysis and erlotinib resistance induced by SIRT6. More importantly, we confirmed the antitumor effect of SIRT6 inhibition combined with erlotinib in NSCLC-bearing mice. Our findings indicate that the cancer metabolic pathway regulated by SIRT6 may be a new target for attenuating NSCLC erlotinib resistance and has potential as a biomarker or therapeutic target to improve outcomes in NSCLC patients.

Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects.

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

Simple SummaryDenosumab, a bone-modifying agent, has been approved for the prevention of or reduction in skeletal-related events (SREs) in non-small cell lung cancer (NSCLC) patients with bone metastasis. However, the effect of denosumab on survival of epidermal growth factor receptor (EGFR)-mutated NSCLC patients with bone metastasis has been insufficiently investigated. The present study showed that denosumab treatment was significantly correlated with improved overall survival (OS) in EGFR-mutated NSCLC patients with bone metastasis. In subgroup analyses, denosumab adjuvant therapy prolonged SRE-free survival (SRE-FS) in patients without initial SREs and was correlated with a better OS in patients with initial or pre-existing SREs. This study provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34–0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37–0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41–0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19–0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Prognostic impact of pretreatment T790M mutation on outcomes for patients with resected, EGFR-mutated, non-small cell lung cancer

BackgroundMany previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear.MethodsWe previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017.ResultsThe median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01–2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99–3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03–2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11–4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy.ConclusionsMinor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC.

A rare case of Exon 19 deletion transforming to Exon 20 insertion in a case of adenocarcinoma of lung

Epidermal growth factor receptor (EGFR) gene mutations play an important role in the presentation, prognosis, and management of non-small cell lung cancer (NSCLC) patients. Several clinical studies claimed the incidence of EGFR Exon 20 insertion mutations in NSCLC and have similar clinical characteristics to those with common EGFR mutations but poorer prognosis. Insertion mutations within the Exon 20 of the EGFR gene are typically located after the C-helix of the tyrosine kinase to result in the domain of EGFR and have been reported to increase the kinase activity of the protein. This eventually leads to the ligand-independent activation of several downstream pathways such as mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (Pi3K)-(mTOR) mammalian target of rapamycin pathways, which are involved in several cellular processes such as cell proliferation, metastasis, and migration while preventing apoptosis. Thus, EGFR exon insertion mutations are gain of function mutations. Specific EGFR and frame-in insertions occur in 3–7% of NSCLC and are known to predict primary resistance to treatment with all clinically available EGFR-tyrosine kinase inhibitors (TKIs). Many clinical and preclinical studies have reported significant antitumor activity with various first and second-generation EGFR TKIs such as Erlotinib, Gefitinib, and Afatinib and have led to prolonged survival in EGFR mutated patients, as compared to wild-type EGFR tumors with chemotherapy. In addition, third-generation EGFR TKIs, such as Osimertinib, have shown encouraging results in metastatic NSCLC patients harboring EGFR mutations including EGFR, p. Thr790Met-mutations, that have shown to confer resistance to first and second-generation EGFR TKIs and who have progressed on prior TKI therapy. Drugs such as Afatinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib have already gained FDA approval for use in EGFR-mutated metastatic NSCLC patients. Here, we report the case of a 47-year-old man who is a non-smoker with an EGFR Exon 19 positive NSCLC treated with Gefitinib developed an EGFR Exon 20 insertion positive brain metastasis initiated on Afatinib as the targeted therapy and responded well to the treatment.