Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Research Articles

Efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitors treatment failure

Objective: To investigate the efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer (NSCLC) who failed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. Methods: A retrospective analysis was made on the clinical data of 60 NSCLC patients who were treated with immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure in the Affiliated Cancer Hospital of Shandong First Medical University from January 2019 to March 2022. Patients were followed up by telephone or outpatient review up to October 1, 2022, with a median follow-up of 8.2 months (95%CI: 7.1-9.3). All 60 patients were followed up. The response evaluation criteria in solid tumors were used to evaluate the short-term efficacy. The adverse reactions of patients were evaluated according to the common terminology criteria for adverse events. The survival curve was drawn by Kaplan-Meier method. Cox proportional hazard regression models were utilized to analyze the influencing factors of progression-free survival (PFS). Results: Among the 60 NSCLC patients, 22 were males. The age ranged from 41 to 75 years, with a median age of 61 years. Eleven patients had partial response, 19 patients had stable disease and 30 patients had progressive disease. The median PFS was 8.2 months (95%CI: 7.2-9.2). The median PFS of patients with low expression of programmed death receptor-ligand 1 (PD-L1) [Tumor cell Proportion Score (TPS)<1%], moderate expression of PD-L1 (1%≤TPS≤49%), and high expression of PD-L1 (TPS≥50%) were 6.4 (95%CI: 4.8-8.0), 8.3 (95%CI: 7.3-9.3) and 10.6 months (95%CI: 7.2-14.1), respectively, and there were statistically significant differences (χ2=13.58, P<0.001). Multivariate Cox proportional risk regression model analysis showed that age>65 years old (HR=4.017, 95%CI: 1.468-10.992, P=0.007) was a risk factor for PFS in NSCLC patients who received immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure. Moderate expression of PD-L1 (HR=0.360, 95%CI: 0.139-0.930, P=0.035) and high expression of PD-L1 (HR=0.155, 95%CI: 0.039-0.625, P=0.009) were protective factors for PFS. Most of the treatment-related adverse reactions in the whole group were grade 1-2, including bone marrow suppression (n=24), nausea (n=25), decreased appetite (n=24), fatigue (n=22), vomiting (n=18), abnormal liver function (n=17), blood creatinine increased (n=10), and so on. These were tolerated by the patients. Conclusions: NSCLC patients who failed EGFR-TKIs treatment can tolerate adverse reactions related to immunotherapy combined with chemotherapy and bevacizumab treatment. PFS is significantly prolonged in those aged≤65 years and those with moderate and high expression of PD-L1.

Genomic characterisation of de novo EGFR copy number gain and its impact on the efficacy of first-line EGFR-tyrosine kinase inhibitors for EGFR mutated non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation generally respond well to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, genomic characterisation of de novo EGFR copy number gain (CNG) and its impact on the efficacy of first-line EGFR-TKIs remains unclear. MethodsThis multicenter, retrospective and real-world study included two cohorts that enroled EGFR mutant NSCLC patients. EGFR CNG was tested by next-generation sequencing of untreated tissue specimens. Cohort 1 detected the impact of EGFR CNG on first-line EGFR-TKIs treatment, and cohort 2 explored the genomic characterisation. ResultsCohort 1 enroled 355 patients from four cancer centres between January 2013 and March 2022. The patients were divided into three groups, included the EGFR non-CNG, EGFR CNG, and EGFR uncertain-CNG. No significant difference in progression-free survival (PFS) was found between the three groups (10.0 months vs. 10.8 months vs. 9.9 months, respectively, p = 0.384). Furthermore, the overall response rate was not statistically significant in the EGFR CNG group compared to the EGFR non-CNG or uncertain arm (70.3% vs. 63.2% vs. 54.5%, respectively, p = 0.154). Cohort 2 included 7876 NSCLC patients with 16.4% showing EGFR CNG. Gene mutations such as TP53, IKZF1, RAC1, MYC, MET, CDKN2A/B and alterations of the metabolic-related and ERK signalling pathway were significantly associated with patients with EGFR CNG compared to those without. ConclusionsDe novo EGFR CNG had no effect on the efficacy of first-line EGFR-TKI treatment in EGFR mutant NSCLC patients, and tumours with EGFR CNG had more complex genomic profiles than those without.

Abstract CT066: HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor

Abstract Background: Standard therapies for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) that has progressed after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs) offer only limited benefit. Human epidermal growth factor receptor 3 (HER3) is often expressed in primary NSCLC tumors, and HER3 expression is commonly observed in patients with EGFR mutations. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3-DXd demonstrated efficacy and safety in a phase 1 study in patients with EGFRm NSCLC that progressed following an EGFR TKI and platinum-based chemotherapy (PBC) (U31402-A-U102; NCT03260491). In previously reported results from dose-escalation/expansion, HER3-DXd 5.6 mg/kg demonstrated a manageable safety profile and promising efficacy (confirmed objective response rate by blinded independent central review [BICR] of 39%, median duration of response of 7.0 months, and median progression-free survival of 8.2 months) in a subset of patients (n=44) with advanced EGFRm NSCLC that progressed after ≥1 line of PBC and a third-generation EGFR TKI. Trial Design: HERTHENA-Lung02 (NCT05338970) is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of HER3-DXd vs PBC in patients (≈560) with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have received 1 or 2 lines of EGFR TKI treatment including a third-generation EGFR TKI and had disease progression following treatment with a third-generation EGFR TKI. Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no). The primary endpoint is progression-free survival by BICR (per RECIST v1.1). The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America. Citation Format: Balazs Halmos, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, Tony Mok. HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT066.

Inequalities in survival and care across social determinants of health in a cohort of advanced lung cancer patients in Quebec (Canada): A high-resolution population-level analysis.

Advanced lung cancer patients exposed to breakthrough therapies like EGFR tyrosine kinase inhibitors (EGFR-TKI) may experience social inequalities in survival, partly from differences in care. This study examined survival by neighborhood-level socioeconomic and sociodemographic status, and geographical location of advanced lung cancer patients who received gefitinib, an EGFR-TKI, as first-line palliative treatment. Differences in the use and delay of EGFR-TKI treatment were also examined. Lung cancer patients receiving gefitinib from 2001 to 2019 were identified from Quebec's health administrative databases. Accounting for age and sex, estimates were obtained for the median survival time from treatment to death, the probability of receiving osimertinib as a second EGFR-TKI, and the median time from biopsy to receiving first-line gefitinib. Among 457 patients who received first-line treatment with gefitinib, those living in the most materially deprived areas had the shortest median survival time (ratio, high vs. low deprivation: 0.69; 95% CI: 0.47-1.04). The probability of receiving osimertinib as a second EGFR-TKI was highest for patients from immigrant-dense areas (ratio, high vs. lowdensity: 1.95; 95% CI: 1.26-3.36) or from Montreal (ratio, other urban areas vs. Montreal: 0.39; 95% CI: 0.16-0.71). The median wait time for gefitinib was 1.27 times longer in regions with health centers peripheral to large centers in Quebec or Montreal in comparison to regions with university-affiliated centers (95% CI: 1.09-1.54; n = 353). This study shows that real-world variations in survival and treatment exist among advanced lung cancer patients in the era of breakthrough therapies and that future research on inequalities should also focus on this population.

Abstract 933: Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy

Abstract Background:Third generation EGFR TKIs have emerged as a first line treatment of choice for aNSCLC patients with qualifying EGFR mutations due to high and durable response rates; however most patients will progress on therapy and may receive further treatment. Second line (2L) options include other EGFR TKIs, chemotherapy (C) and chemoimmunotherapy (C-IO). An optimal treatment strategy and utility of biomarkers in this 2L setting remain uncharacterized. In this study, we aim to describe the real-world treatment patterns and outcomes of patients with aNSCLC after treatment with first line (1L) EGFR TKIs to elucidate the potential for biomarker-guided approaches. Methods:We selected patients with non-squamous aNSCLC treated with 1L EGFR TKIs on or after April 1, 2018 (based on 1L approval of osimertinib) within the US-based de-identified Flatiron Health-Foundation Medicine (FMI) real world clinico-genomic database. Real world overall survival (rwOS) and progression free survival (rwPFS) curves and estimates of median survival time were generated using the Kaplan-Meier method. PD-L1 and tumor mutational burden (TMB) were summarized overall and by 2L treatment regimen. Results:Among 428 patients who received 1L EGFR TKI treatment, 386 (90%) received osimertinib, 30 (7%) received afatinib and 11 (3%) received erlotinib. For patients with known 2L treatment information (n=139, 32%) most received EGFR TKI alone (n=43, 31%), followed by C-IO (n=38, 27%), and C alone (n=14, 10%). Median rwOS following 2L treatment with EGFR TKI, C-IO, and C was 21.0 (95% CI 17.4-28.7) months, 9.9 (95% CI 7.7-19.8) months, and 17.4 (95% CI 4.3-NA) months respectively. Median rwPFS for the EGFR-TKI, C-IO, and C cohorts was 5.1 (95% CI 3.4-12.5) months, 5.5 (95% CI 3.3-7.0) months, and 3.5 (95% CI 1.9-NA) months. 416 (97%) of 428 patients harbored an EGFR mutation detected by FoundationOne®CDx, including 361 (84%) patients with at least one EGFR mutation in NCCN Guidelines. Among patients with available PD-L1 status (n=254, 59%), PD-L1 positivity (≥1% tumor proportion score) was more common among patients who received 2L C-IO (88%) compared to patients overall (59%). 30 (7%) of 428 patients had high TMB (≥10 mut/Mb); prevalence of high TMB was similar regardless of 2L therapy choice. Conclusions:This real-world data analysis confirmed that among patients with aNSCLC treated with EGFR TKIs, the vast majority received 1L osimertinib. Among 2L treatment options, additional EGFR TKI use was the most common and patients in this cohort had robust outcomes, with a median rwOS of 21 mos. Further analyses will describe the clinical characteristics of patients receiving different 2L treatment strategies and evaluate the association of PD-L1 status and select EGFR mutations with outcomes across therapeutic classes. Citation Format: Ericka Ebot, Jie He, David Fabrizio, Ivy Altomare, Neha Jain, Davey Daniel, Thomas Stricker, Edward Arrowsmith. Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 933.

Oncogenic epidermal growth factor receptor signal-induced histone deacetylation suppresses chemokine gene expression in human lung adenocarcinoma

Epidermal growth factor receptor (EGFR)-mutated (mt) lung adenocarcinoma (LA) is refractory to immune checkpoint inhibitors (ICIs). However, the mechanisms have not been fully elucidated. CD8+ T cell infiltration was significantly lower in EGFR-mt than in EGFR-wild-type LA, which was associated with suppression of chemokine expression. Since this T cell-deserted tumor microenvironment may lead to the refractoriness of ICIs against EGFR-mt LA, we investigated the mechanism by focusing on the regulation of chemokine expression. The expression of C-X-C motif ligand (CXCL) 9, 10 and 11, which constitute a gene cluster on chromosome 4, was suppressed under EGFR signaling. The assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) revealed open chromatin peaks near this gene cluster following EGFR-tyrosine kinase inhibitor (TKI) treatment. The histone deacetylase (HDAC) inhibitor recovered the expression of CXCL9, 10 and 11 in EGFR-mt LA. Nuclear HDAC activity, as well as histone H3 deacetylation, were dependent on oncogenic EGFR signaling. Furthermore, the Cleavage Under Targets and Tagmentation (CUT & Tag) assay revealed a histone H3K27 acetylation peak at 15 kb upstream of CXCL11 after treatment with EGFR-TKI, which corresponded to one of the open chromatin peaks detected by ATAC-seq. The data suggest that EGFR-HDAC axis mediates silencing of the chemokine gene cluster through chromatin conformational change, which might be relevant to the ICI resistance by creating T cell-deserted tumor microenvironment. Targeting this axis may develop a new therapeutic strategy to overcome the ICI resistance of EGFR-mt LA.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

Evaluation of combination treatment with DS-1205c, an AXL kinase inhibitor, and osimertinib in metastatic or unresectable EGFR-mutant non-small cell lung cancer: results from a multicenter, open-label phase 1 study

SummaryThe objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov; NCT03255083.

Discontinuation of Immune Checkpoint Inhibitor due to irAEs in NSCLC Patients With EGFR Mutation.

Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small cell lung cancer (NSCLC) treatment. Even patients with epidermal growth factor receptor (EGFR)-mutated NSCLC may choose an ICI after failure of EGFR-tyrosine kinase inhibitor treatment. ICI-mediated immune-related adverse events (irAEs) may prompt NSCLC patients to discontinue their treatment. This study evaluated the effect of ICI treatment discontinuation on the prognosis of patients with EGFR-mutated NSCLC. We performed a retrospective study that reviewed the clinical courses of patients with EGFR-mutated NSCLC treated with ICI therapy from February 2016 to February 2022. 'Discontinuation' was defined as failure to receive at least two treatment courses of ICI due to grade 2 irAEs (grade 1 in the lung) or higher in patients responding to ICI. During the study period, 13 of 31 patients discontinued ICI therapy due to irAEs. Survival from the initiation of ICI therapy was significantly longer in patients who discontinued ICI therapy compared with those who did not discontinue. In uni- and multivariate analyses, 'discontinuation' was a favourable factor. There was no significant difference in survival from ICI initiation between patients with grade 3 or higher irAEs and those with grade 2 or lower irAEs. In this patient cohort, discontinuation of ICI therapy due to irAEs did not adversely affect prognosis in patients with EGFR-mutant NSCLC. Our results suggest that when treating patients with EGFR-mutant NSCLC with ICIs, chest physicians should consider discontinuing ICI with close monitoring.

HER3-targeted therapeutic antibodies and antibody–drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors

Human epidermal growth factor receptor 3 (HER3) is a unique member of the human epidermal growth factor receptor (HER/EGFR) family, since it has negligible kinase activity. Therefore, HER3 must interact with a kinase-proficient receptor to form a heterodimer, leading to the activation of signaling cascades. Overexpression of HER3 is observed in various human cancers, including non-small cell lung cancer (NSCLC), and correlates with poor clinical outcomes in patients. Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers. Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs). Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate “bypass signaling pathways”, thereby resulting in resistance to EGFR-TKIs. To date, no HER3-targeted therapy has been approved for cancer treatment. In both preclinical and clinical studies, targeting HER3 with a blocking antibody (Ab) is the only strategy being examined. Recent evaluations of an anti-HER3 Ab-drug conjugate (ADC) show promising results in patients with EGFR-TKI-resistant NSCLC. Herein, we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs, with a focus on its dimerization partners and subsequent activation of signaling pathways. We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.

Healthcare coverage affects survival of EGFR-mutant Thai lung cancer patients.

Despite significant benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with EGFR-mutated NSCLC, access remains limited in Thailand and elsewhere. Retrospective analysis of patients with locally advanced/recurrent NSCLC and known EGFR mutation (EGFRm) status treated at Ramathibodi Hospital (2012-2017). Prognostic factors for overall survival (OS), including treatment type and healthcare coverage, were analyzed using Cox regression. Of 750 patients, 56.3% were EGFRm-positive. After first-line therapy (n=646), 29.4% received no subsequent (second-line) treatment. EGFR-TKI-treated EGFRm-positive patients survived significantly longer than EGFRm-negative patients without EGFR-TKIs (median OS [mOS] 36.4 vs. 11.9 months; hazard ratio HR=0.38 [95%CI 0.32-0.46], P<0.001). Cox regression indicated significantly longer OS in patients with comprehensive healthcare coverage that included reimbursement of EGFR-TKIs, versus basic coverage (mOS 27.2 vs. 18.3 months; adjusted HR=0.73 [95%CI 0.59-0.90]). Compared with best supportive care (BSC; reference), EGFR-TKI-treated patients survived significantly longer (mOS 36.5 months; adjusted HR (aHR)=0.26 [95%CI 0.19-0.34]), and versus chemotherapy alone (14.5 months; aHR=0.60 [95%CI 0.47-0.78]). In EGFRm-positive patients (n=422), relative survival benefit of EGFR-TKI treatment remained highly significant (aHR[EGFR-TKI]=0.19 [95%CI 0.12-0.29]; aHR(chemotherapy only)=0.50 [95%CI 0.30-0.85]; reference:BSC), indicating that healthcare coverage (reimbursement) affected treatment choice and survival. Our analysis describes EGFRm prevalence and survival benefit of EGFR-TKI therapy for EGFRm-positive NSCLC patients treated from 2012-2017, one of the largest such Thai datasets. Together with research by others, these findings contributed evidence supporting the decision to broaden erlotinib access on healthcare schemes in Thailand from 2021, demonstrating the value of local real-world outcome data for healthcare policy decision-making.

Comprehensive Kinase Activity Profiling Revealed the Kinase Activity Patterns Associated with the Effects of EGFR Tyrosine Kinase Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients with Sensitizing EGFR Mutations

EGFR mutations are strong predictive markers for EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with non-small-cell lung cancer (NSCLC). Although NSCLC patients with sensitizing EGFR mutations have better prognoses, some patients exhibit worse prognoses. We hypothesized that various activities of kinases could be potential predictive biomarkers for EGFR-TKI treatment among NSCLC patients with sensitizing EGFR mutations. In 18 patients with stage IV NSCLC, EGFR mutations were detected and comprehensive kinase activity profiling was performed using the peptide array PamStation12 for 100 tyrosine kinases. Prognoses were observed prospectively after the administration of EGFR-TKIs. Finally, the kinase profiles were analyzed in combination with the prognoses of the patients. Comprehensive kinase activity analysis identified specific kinase features, consisting of 102 peptides and 35 kinases, in NSCLC patients with sensitizing EGFR mutations. Network analysis revealed seven highly phosphorylated kinases: CTNNB1, CRK, EGFR, ERBB2, PIK3R1, PLCG1, and PTPN11. Pathway analysis and Reactome analysis revealed that the PI3K-AKT and RAF/ MAPK pathways were significantly enriched in the poor prognosis group, being consistent with the outcome of the network analysis. Patients with poor prognoses exhibited high activation of EGFR, PIK3R1, and ERBB2. Comprehensive kinase activity profiles may provide predictive biomarker candidates for screening patients with advanced NSCLC harboring sensitizing EGFR mutations.

Profile of Exon 20 T790M Mutation Incidence Rate with Plasma ctDNA in Lung Adenocarcinoma Patients Receiving EGFR-TKI Treatment

Introduction: Patients with lung adenocarcinoma following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment will develop acquired resistance after 7 to 16 months of starting the medication, indicated by the emergence of exon 20 T790M mutations. This study aimed to identify the clinical and demographical profile of acquired resistance in patients with lung adenocarcinoma receiving EGFR-TKI therapy through plasma circulating tumor deoxyribonucleic acid (ctDNA) examination. Methods: This was a descriptive study with a retrospective cross-sectional design involving 108 lung adenocarcinoma patients who received EGFR-TKI for more than six months. Exon 20 T790M EGFR mutations were identified as a sign of acquired resistance using the digital droplet polymerase chain reaction (ddPCR) approach to examine plasma ctDNA Utilizing the Statistical Package for the Social Sciences, statistical tests were used to examine the data (SPSS). The data were analyzed by statistical tests using the Statistical Package for the Social Sciences (SPSS). Results: A total of 31 patients were recruited as study participants. The majority of the research subjects were female (64.5%), aged 20-69 years old (58%), and non-smokers (67.7%). Exon 19 deletions were the most prevalent EGFR mutation (58.1%). The incidence of acquired resistance was found in 10 subjects (32.3%). Patients with acquired resistance were predominately female (70%), non-smokers (80%), and with gefitinib therapy (90%). The average time for EGFR-TKI treatment until acquired resistance occurred was 12.6 months. Conclusion: The incidence of acquired resistance was mainly found in women without a smoking history after 12.6 months of treatment with EGFR-TKI.

CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene BIRC5 (survivin). This E2F1-mediated upregulation of BIRC5 in CBX5-knockdown LUAD cells attenuates apoptosis induction following EGFRi treatment. Consistent with these results, knockdown of E2F1 or BIRC5 partly rescues CBX5-knockdown-induced EGFRi resistance in cell culture and mice. EGFRi-resistant LUAD cell lines show reduced CBX5 expression compared to parental lines; however, bromo- and extra-terminal (BET)-domain inhibitors (BETi) restore CBX5 expression in these cells and sensitize them to EGFRi/BETi combination therapy. Similarly, treatment with a BIRC5 inhibitor suppresses growth of EGFRi-resistant LUAD cells. Collectively, these studies identify CBX5 loss as a driver of EGFRi resistance and reveal therapeutic opportunities for treating EGFRi-resistant LUAD.

Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Novel systemic therapies in the management of tyrosine kinase inhibitor-pretreated patients with epidermal growth factor receptor-mutant non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line option for non-small-cell lung cancer (NSCLC) harboring active EGFR mutations. The overall survival of patients with advanced NSCLC has improved dramatically with the development of comprehensive genetic profiles and targeted therapies. However, resistance inevitably occurs, leading to disease progression after approximately 10-18 months of EGFR-TKI treatment. Platinum-based chemotherapy is the standard treatment for patients who have experienced disease progression while undergoing EGFR-TKI treatment, but its efficacy is limited. The management of extensively pretreated patients with EGFR-mutant NSCLC is becoming increasingly concerning. New agents have shown encouraging efficacy in clinical trials for this patient population, including fourth-generation EGFR-TKIs, EGFR-TKIs combined with counterpart targeted drugs, and novel agents such as antibody-drug conjugates. We review current efforts to manage extensively pretreated patients with EGFR-mutant NSCLC.

Effects of targeted lung cancer drugs on cardiomyocytes studied by atomic force microscopy.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has become one of the important targeted drugs for the treatment of non-small cell lung cancer (NSCLC). But the cardiac adverse events (AEs) related to the EGFR-TKI treatment occur frequently. And the cases of TKI-associated cardiac AEs remain poorly understood. In order to study the effects of EGFR-TKIs on cardiomyocytes, atomic force microscopy (AFM) was used to measure and analyze the physical properties of cardiomyocytes under the actions of three drugs (gefitinib, afatinib and osimertinib) with different concentrations. By comparing the height, adhesion, Young's modulus, the amplitude and the time of the contraction and relaxation process, it was found that the changes of the mechanical properties of cells were well correlated with the symptoms of AEs, such as cardiomyocyte hypertrophy, QT prolongation, atrial fibrillation, ejection fraction reductions, and cardiac failure. In addition, osimertinib has the most obvious effect on cardiomyocytes at a low concentration, and gefitinib has the greatest effect with the increase of concentration, while afatinib has the least effect on cardiomyocytes. This provides a new method for screening drugs and exploring the principle of action in the process of cancer treatment at the cellular level.

Influence of Smoking Habits on the Efficacy of EGFR-TKI Therapy in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to analyze the efficacy of EGFR-TKIs treatment in patients with advanced NSCLC of different smoking habits. Methods: We conducted a search for meta-analyses and systematic reviews on the PubMed, MEDLINE, Embase, and the Cochrane Library to address this knowledge gap. Patients were divided into 2 groups: (1) experimental group: treated with EGFR-TKIs or EGFR-TKIs combined with chemotherapy, immunotherapy, antiangiogenesis, radiotherapy and (2) control group: treated with chemotherapy. Progressive-free survival (PFS) and total survival (OS) were adopted for evaluating the efficacy of EGFR-TKIs between experimental group and control group. Results: Eleven studies including 6760 patients were included in the meta-analysis. The results showed that smoking (including previous and current smoking) significantly reduces the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs. In addition, EGFR-TKIs combined with anti-vascular endothelial growth factor therapy can reduce the risk of disease progression in smokers. Conclusions: Our study indicated that smoking significantly reduced the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs.

Osteosclerotic change as a therapeutic response to gefitinib in symptomatic non-small cell lung cancer bone metastasis

BackgroundDespite improvement in the overall survival of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, the effects of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment on bone metastasis remain unclear. This study investigated radiological responses to gefitinib regarding bone metastasis in patients.MethodsWe treated 260 patients with NSCLC and symptomatic bone metastasis. Thirty-seven patients harboring EGFR mutation were treated with gefitinib for more than 30 days and followed up for more than 3 months (GEF group). We performed a retrospective observational study by selecting 36 cases without EGFR-TKI treatment, at least 3 months of follow-up, and at least two radiological evaluations as the control group. We assessed the best overall radiological response, interval from treatment initiation to appearance of a radiological response, and the local response maintenance rate.ResultsThe best effect in the GEF group was 98% partial response or better, which was significantly higher than the 57% observed in the control group (p < 0.001). The GEF and control groups maintained 83% and 42% local response maintenance rates at one year, respectively (p < 0.001). In the GEF with radiotherapy group, the local response maintenance rate was maintained at 92% at 1 year, while in the GEF without RT group, there was a decrease in the local response maintenance rate from 270 days.ConclusionGefitinib treatment for bone metastases in patients harboring EGFR mutation resulted in a beneficial osteosclerotic change in most patients. Combined gefitinib and radiotherapy provide long-lasting local control of bone metastases.

Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell Lung Cancer Patients with Acquired EGFR T790M Mutation

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.