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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present study investigated real-world EGFR TKI use and patient outcomes in NSCLC. We collected all the patients who had reimbursement for EGFR TKIs in Finland 2011–2020 and had data available at Finnish Cancer Registry. Survival and time-on-treatment (ToT) were analyzed from the first EGFR TKI purchase and patients were stratified according to the TKIs. Whole patient cohort consisted of 1498 individuals who were treated with erlotinib (n = 998), afatinib (n = 258), or gefitinib (n = 238). In the EGFR mutant cohort (all gefitinib users and afatinib users with non-squamous histology; n = 466), survival was comparable to registrational trials while patients treated with afatinib had improved survival (HR 0.67 CI 95% 0.53–0.85) and longer ToT (13.9 vs 11.9 months, NS) compared to those treated with gefitinib. Females treated with afatinib had improved survival (HR 0.61 CI 95% 0.44–0.83) and longer ToT (15.1 vs 12.5 months, NS) compared to gefitinib while similar was not observed in males. Later line osimertinib treatment was applied for 78 patients. Approximately 20% of the individuals treated with previous gefitinib or afatinib had later line osimertinib treatment. Efficacy analysis of osimertinib treated showed similar ToT and survival regardless of the first line EGFR TKI. EGFR mutants treated with afatinib have improved outcomes compared to gefitinib while later-line osimertinib was applied only for around 20% of the individuals. The study further highlights the good real-world performance of EGFR TKIs and sheds light on therapy sequencing. [ABSTRACT FROM AUTHOR]

The majority of malignant tumors exhibit an altered metabolic phenotype that ultimately provides the required energy and molecular precursors necessary for unregulated cell division. Within this, phosphoserine aminotransferase 1 (PSAT1) is involved in de novo serine biosynthesis and its activity promotes various biochemical processes, including one-carbon metabolism. It also directly generates α-ketoglutarate (α-KG), a Kreb cycle intermediate and epigenetic-regulating metabolite. Prior studies examining PSAT1 depletion have identified individual affected downstream pathways, such as GSK3β and E2F, in several cancer types, including non-small-cell lung cancer (NSCLC). However, global gene expression examination in response to PSAT1 loss, particularly in EGFR mutant NSCLC, has not been unexplored. Transcriptional profiling of EGFR mutant NSCLC cells with or without stable knock-down of PSAT1 identified differentially expressed genes (DEGs) enriched in several metabolic pathways required for cell division, including amino acid and nucleotide biosynthesis. Supplementation studies involving non-essential amino acids, nucleosides and α-KG partially restored defects in anchorage-independent growth due to the knockdown of PSAT1. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis identified potential impacts on actin cytoskeleton arrangement and β-catenin activity, which were rescued by PSAT1 re-expression. Finally, a comparative analysis of PSAT1 DEGs against transcripts enriched in patient EGFR mutant lung tumors identified a gene signature that is associated with overall and relapse-free survival (RFS) and was able to distinguish low or high-risk populations for RFS in early-stage EGFR mutant NSCLC. Overall, investigating genes altered by PSAT1 loss confirmed known PSAT1-regulated cellular pathways, identified a previously unknown role in the mediation of cytoskeleton arrangement in EGFR mutant NSCLC cells and allowed for the characterization of a gene signature with putative predictive potential for RFS in early-stage disease. [ABSTRACT FROM AUTHOR]

Background Studies regarding the outcomes of salvage lung resections of epidermal growth factor receptor (EGFR)‐mutant advanced lung adenocarcinomas (ALAs) following treatment with EGFR tyrosine kinase inhibitors (TKIs) are limited, hence the objective of this study was to investigate such outcomes. Methods A total of 29 patients with EGFR‐mutant ALA who underwent salvage surgery after EGFR‐TKI treatment from October 2013 through January 2019 were enrolled. The patients were divided into two groups according to the surgical indications. Their perioperative parameters and surgical outcomes, including progression‐free survival (PFS) and overall survival (OS), were then analyzed. Results The initial stages of the patients were stage IIIB (seven patients), IVA (17 patients), and IVB (five patients). Their surgical indications included residual tumor (25 patients) and progressive disease (PD) (four patients). They all underwent surgery via minimally invasive approaches and the median follow‐up was 33.9 months. Within that follow‐up duration, the median PFS after surgery was 36.4 months, and the median OS was still not reached. There were no significant differences in PFS or OS according to the different EGFR‐TKIs used, the different durations of EGFR‐TKI treatment before surgery, or the different surgical indications. However, the patients presenting with pleural seeding before EGFR‐TKI treatment had significantly poorer PFS and OS than the other patients (P

BackgroundAlthough the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non-small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET. We sought to demonstrate the activity of INC-280 on select NSCLC cell lines both as a single agent and in combination with erlotinib using exogenous HGF to simulate MET up-regulation.MethodsFour NSCLC cell lines (HCC827, PC9, H1666, and H358) were treated with either single-agent INC-280 or in combination with erlotinib with or without HGF. The activity of the drug treatments was measured by cell viability assays. Immunoblotting was used to monitor expression of EGFR/pEGFR, MET/pMET, GAB1/pGAB1, AKT/pAKT, and ERK/pERK as well as markers of apoptosis (PARP and capase-3 cleavage) in H1666, HCC827, and PC9.ResultsAs a single agent, INC-280 showed minimal cytotoxicity despite potent inhibition of MET kinase activity at concentrations as low as 10 nM. Addition of HGF prevented erlotinib-induced cell death. The addition of INC280 to HGF-mediated erlotinib-resistant models restored erlotinib sensitivity for all cell lines tested, associated with cleavage of both PARP and caspase-3. In these models, INC-280 treatment was sufficient to restore erlotinib-induced inhibition of MET, GAB1, AKT, and ERK in the presence of HGF.ConclusionAlthough the MET inhibitor INC-280 alone had no discernible effect on cell growth, it was able to restore sensitivity to erlotinib and promote apoptosis in NSCLC models rendered erlotinib resistant by HGF. These data provide a preclinical rationale for an ongoing phase 1 clinical trial of erlotinib plus INC-280 in EGFR-mutated NSCLC.

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.

Anticancer therapy targets Tyrosine kinase (TK) to inhibit signal transduction pathway that regulate various physiological and biochemical processes. Mutation in and around the catalytic domain may lead to conformational changes and activity. The first identified mutation leading to resistance against tyrosine kinase inhibitor (TKI) was observed when Thr at 790 replaced to Met in Epidermal Growth Factor Receptor (EGFR). Third generation EGFR-TKIs bind irreversibly to the Cysteine 797, (ATP-binding pocket). Mutation of Cys 797 to Ser residue (EGFRC797S) causes resistance to third generation TKI. The present study explores allosteric inhibitor of EGFRT790M+C797S mutant TK by molecular modelling techniques using 3,92,945 compounds of Zinc database. Molecular docking study revealed that ZINC000072404720 have similar binding pattern and MM/GBSA free energy as known allosteric inhibitor EAI045. RMSD of EGFRT790M+C797S bound to EAI045 and ZINC000072404720 were quite similar and in acceptable range. Hydrogen bonds after 150ns simulation was observed between Lys 745 and Asp 855 with EAI045 and novel inhibitor showed hydrogen bonding with Lys 745, Leu 788, Thr 854, Asp 855, Phe 856. MM/GBSA free energy was better (-84.09 Kcal/mol) known inhibitor EAI045b (-65.95 Kcal/mol). ZINC000072404720 fulfils drug likeliness property and did not violate Lipinski's rule of five. [ABSTRACT FROM AUTHOR]

Simple Summary: Osimertinib has become the standard of care for the first-line treatment of EGFR-mutant NSCLC patients. The aim of this current translational research study was to assess the clinical relevance of liquid biopsy in 47 patients receiving osimertinib. Effects on circulating tumor cells (CTCs) and plasma-DNA (ctDNA) were investigated before, after one treatment cycle, and at the end of treatment. ctDNA and CTCs decreased after one treatment cycle, but increased at the end of treatment. The detection of ctDNA before and after one treatment cycle was associated with shorter progression-free and overall survivals (PFS and OS), whereas ctDNA clearance after one treatment cycle resulted in a significantly longer PFS and OS. ctDNA at baseline emerged as an independent predictor of shorter PFS. Thus, changes in liquid biopsy status (CTCs, ctDNA) during osimertinib treatment can be used as a tool for treatment efficacy. Introduction: Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib. Methods: Forty-seven EGFR-mutant NSCLC patients who had progressed on prior first- or second-generation EGFR inhibitors were enrolled in the study and treated with osimertinib, irrespective of the presence of the T790M mutation in the primary tumor or the plasma. Peripheral blood was collected at baseline (n = 47), post-Cycle 1 (n = 47), and at the end of treatment (EOT; n = 39). CTCs were evaluated in 32 patients at the same time points (n = 32, n = 27, and n = 21, respectively) and phenotypic characterization was performed using triple immunofluorescence staining (CK/VIM/CD45). Results: Osimertinib resulted in an ORR of 34% (2 CR) and a DCR of 76.6%. The median PFS and OS values were 7.5 (range, 0.8–52.8) and 15.1 (range, 2.1–52.8) months, respectively. ctDNA was detected in 61.7%, 27.7%, and 61.5% of patients at baseline, post-Cycle 1, and EOT, respectively. CTCs (CK+/CD45-) were detected in 68.8%, 48.1%, and 61.9% of patients at the three time points, respectively. CTCs expressing both epithelial and mesenchymal markers (CK+/VIM+/CD45-) were detected in 56.3% and 29.6% of patients at baseline and post-Cycle 1, respectively. The detection of ctDNA at baseline and post-Cycle 1 was associated with shorter PFS and OS, whereas the ctDNA clearance post-Cycle 1 resulted in a significantly longer PFS and OS. Multivariate analysis revealed that male sex and the detection of ctDNA at baseline were independent predictors of shorter PFS (HR: 2.6, 95% C.I.: 1.2–5.5, p = 0.015 and HR: 3.0, 95% C.I.: 1.3–6.9; p = 0.009, respectively). Conclusions: The decrease in both CTCs and ctDNA occurring early during osimertinib treatment is predictive of better outcome, implying that liquid biopsy monitoring may be a valuable tool for the assessment of treatment efficacy. [ABSTRACT FROM AUTHOR]

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2-5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wildtype (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5mg/kg via IV-delivery. AUCs (h-ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-aweek 5mg/kg IV topotecan. [ABSTRACT FROM AUTHOR]

Background: Studies regarding the outcomes of salvage lung resections of epidermal growth factor receptor (EGFR)‐mutant advanced lung adenocarcinomas (ALAs) following treatment with EGFR tyrosine kinase inhibitors (TKIs) are limited, hence the objective of this study was to investigate such outcomes. Methods: A total of 29 patients with EGFR‐mutant ALA who underwent salvage surgery after EGFR‐TKI treatment from October 2013 through January 2019 were enrolled. The patients were divided into two groups according to the surgical indications. Their perioperative parameters and surgical outcomes, including progression‐free survival (PFS) and overall survival (OS), were then analyzed. Results: The initial stages of the patients were stage IIIB (seven patients), IVA (17 patients), and IVB (five patients). Their surgical indications included residual tumor (25 patients) and progressive disease (PD) (four patients). They all underwent surgery via minimally invasive approaches and the median follow‐up was 33.9 months. Within that follow‐up duration, the median PFS after surgery was 36.4 months, and the median OS was still not reached. There were no significant differences in PFS or OS according to the different EGFR‐TKIs used, the different durations of EGFR‐TKI treatment before surgery, or the different surgical indications. However, the patients presenting with pleural seeding before EGFR‐TKI treatment had significantly poorer PFS and OS than the other patients (P < 0.001). Conclusions: Salvage surgery following EGFR‐TKI treatment of ALAs is a safe procedure with acceptable intra‐ and postoperative results. However, studies involving more cases and longer follow‐up periods are needed to clarify its benefits. Key points: Salvage surgery following EGFR‐TKI treatment of ALAs is a safe procedure with acceptable intra‐ and postoperative results.Our results support the use of surgery following treatment with EGFR‐TKIs such as afatinib in advanced lung cancer. [ABSTRACT FROM AUTHOR]

• This real-world study evaluated the outcomes of patients treated with first line osimertinib who would/would not have been eligible for the original FLAURA clinical trial. • Nearly half of real-world patients would have been ineligible for FLAURA, predominantly due to poor performance status. • Patients who would have been ineligible for FLAURA had a median overall survival that was 18 months shorter than FLAURA eligible patients. • FLAURA ineligible patients had a higher burden of disease at baseline. Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8–30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients. [ABSTRACT FROM AUTHOR]

Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through β-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer. • ALDOA/PDE3A were found to be upregulated in human lung cancer tissues and to be associated with a poor prognosis. • ALDOA/PDE3A was found to reflect the EGFR mutant events in lung cancer cell lines and specimens. • The activation of the β-catenin/ID3 axis was shown to respond to the overexpression of ALDOA/PDE3A in lung cancer. • The β-catenin/ID3 pathway fosters M2 macrophage polarization. • Treatment with Trequinsin was found to reverse the series of phenotypes induced by ALDOA/PDE3A. [ABSTRACT FROM AUTHOR]

Abstract Objectives The aim of this study was whether quercetin induces cell death by caspase and MAPK signaling pathway in EGFR mutant lung cancer cells Methods PC-9 cells, EGFR mutant lung cancer cells, were treated various times and concentrations of quercetin and harvested and measured using MTT assay, DNA fragmentation, Western blotting, and FACS analysis. Results Treatment with quercetin in PC-9 cells resulted in inhibition of cell growth through apoptosis. Quercetin-induced apoptosis was associated with caspase-dependent manner. Quercetin also significantly increased levels of phosphor-p38 and decreased levels of phosphor-ERK, indicating that quercetin induces p38 MAPK signaling pathway in PC-9 cells. Quecetin treatment also generated the release of cytochrome c in PC-9 cells; however, pretreatment with rotenone or z-LEHD-fmk, significantly attenuated quercetin-induced apoptosis. Conclusions Our data indicate that quercetin exhibits EGFR mutant lung cancer effects through apoptosis by caspase dependent and mitochondrial pathway.

Circulating tumor cells (CTCs) have become an important biomarker for liquid biopsy to monitor tumor progression and indicate response to therapies. Many epithelial cellular adhesion molecule (EpCAM) dependent CTC isolation methods have been developed, which have a limitation for low EpCAM expressed tumor cells. In an effort to overcome these drawbacks, we developed combined immunomagnetic beads (EpCAM, Mucin1 and epidermal growth factor receptor) to sensitively isolate CTCs for immunofluorescence analysis and genetic characterization. With this combined immunomagnetic beads, 93.35% H446 cells from spiked blood sample can be recovered. We were able to detect CTCs in 127 among 143 patients included in the study (88.8%). Some CTC clusters were captured with the combined magnetic beads system. In 17 of them, CTCs after chemotherapy significantly decreased compared to that before chemotherapy (4.42 (± 3.94) vs. 12 (± 7)/mL, P  = 0.002). For subsequent genetic characterization of CTCs, 2 of 6 samples, using a droplet digital PCR (ddPCR) chip, have detectable EGFR L858R mutation in the cells enriched with the combined immunomagnetic beads. In conclusion, this method integrating the combined immunomagnetic beads and the ddPCR chip for CTCs detection can be of potential application in terms of diagnosis, therapeutic evaluation and personalized medicine in lung cancer. [ABSTRACT FROM AUTHOR]

Background: The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. Methods: WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor ( EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. Results: From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. Conclusion: Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported. [ABSTRACT FROM AUTHOR]

Highlights • De novo MET amplification is believed to promote primary resistance to EGFR tyrosine kinase inhibitors in the non-small cell lung cancer. • Treatment of patients with EGFR mutant and de novo MET amplification is unknown. • We report the progress free survival of the patient harboring the rare mutations for the first time. • The combination of EGFR- and MET- tyrosine kinase inhibitors may be an effective treatment for the rare mutations. Abstract Objective De novo mesenchymal-epithelial transition (MET) amplification is believed to promote primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the non-squamous non-small cell lung cancer (NSCLC). We sought to seek the treatment of a patient with EGFR-mutant NSCLC harboring de novo MET amplification. Materials and methods After clinical diagnosis, tissue and plasma samples were obtained from the patient and subjected to next-generation sequencing to identify and dynamic monitor the mutations. Results The patient was treated with gefitinib monotherapy in the beginning and experienced primary resistance to gefitinib but achieved a good response to the combination therapy of gefitinib and crizotinib. He achieved a 16.8-month progress free survival with the combination therapy. NGS of plasma circulating cell-free tumor DNA shown that L858R mutation was no longer detectable and the copy number of MET dropped when the patient got remission. Conclusions The combination of EGFR- and MET- tyrosine kinase inhibitors may be an effective treatment for the rare mutations. [ABSTRACT FROM AUTHOR]

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI., Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed., Results: Of 193 evaluable patients, 151 (78.2%) were T790M+ (T790M positive) with 96 (49.2%) tissue confirmed; 52% of patients received osimertinib in the second line setting. After median follow up of 37 months, median progression-free survival (PFS) of the entire cohort was 10.3 [95% confidence interval (CI): 8.64-11.50] months and median overall survival (OS) was 20 (95% CI: 15.61-23.13) months. Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs . 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs . 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs . 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027)., Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-661/coif). JM reports travel support for meetings from AstraZeneca. GGYL reports honoraria from Amgen and consulting/advisory role for Merck, AstraZeneca, Pfizer, Bristol Myers Squibb and Roche. MKA reports support for meetings from AstraZeneca, Boehringer Ingelheim, Ipsen; honoraria from Boston Scientific and consulting/advisory role for Merck. RK reports research funding support from Sanofi (Inst), Janssen Pharmaceuticals (Inst); honoraria from Astellas Pharma, Novartis, Janssen Pharmaceuticals, MSD Oncology, Bristol-Myers Squibb, consulting/advisory role for Pfizer, Astellas Pharma, Novartis, Mundipharma. TR reports honoraria and Speakers’ Bureau from Novartis, consulting/advisory role for Ipsen and Eisai. TKHL reports honoraria for AstraZeneca and consulting/advisory role for MSD. DSWT reports research funding from Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst); honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, Novartis, Roche and Pfizer; consulting/advisory role for Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer. DWTL reports research funding from Bristol-Myers Squibb (Inst), honoraria from Boehringer Ingelheim, consulting/advisory role for Roche, AstraZeneca, MSD Oncology, Novartis and Boehringer Ingelheim and stock ownership from Clearbridge Biomedics. QSN reports research funding from Novartis, MSD Oncology and Bayer; honoraria from MSD Oncology, AstraZeneca and Pierre Fabre and consulting/advisory role for Boehringer Ingelheim. WLT reports educational grant support from AstraZeneca; honoraria from Novartis, Merck, and Amgen; support for meetings from AstraZeneca, Ipsen, Boehringer Ingelheim, Bristol-Myers Squibb (Inst), and DKSH. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Introduction: The prognostic value of EGFR mutation in lung cancer patients with brain metastases is uncertain and therapeutic efficacy with EGFR TKI is limited. Looking for biomarkers closely related with early tumor changes and brain metastases in non-small cell lung cancer is warranted. MicroRNAs (miRNAs) are frequently deregulated in lung cancer. The objective of this study was to investigate whether some miRNAs are related with brain metastasis risk in EGFR-mutant non-small cell lung cancer patients. Materials and methods: miRNA quantification was retrospectively performed in formalin-fixed, extracranial paraffin-embedded adenocarcinoma tumor tissue available from 17 human samples of advanced non-small cell lung cancer patients. Samples were classified as brain metastasis group (5 EGFR-mutant patients with initial BM, EGFRm-BM+; and 6 EGFR wild-type patients with initial BM) and the control group (6 EGFR-mutant NSCLC patients without BM). The RNA obtained was preamplified and retro-transcribed, and the miRNA was quantified with the TaqMan OpenArray Human MiRNA Panel in the QuantStudio™ 12 K Flex Real-Time PCR system. Results: miRNA-197 and miRNA-184 showed a significant higher expression in EGFRm-BM+ group than in the control group ( p = 0.017 and p = 0.01, for miRNA-197 and miRNA-184, respectively), with a trend toward overexpression in BM group compared with the control group ( p = 0.08 and p = 0.065, for miRNA-197 and miRNA-184, respectively), without differences in expression in BM group according to EGFR mutational status (EGFR wild type vs. EGFR-mutant: p = 0.175 and p = 0.117, for miRNA-197, miRNA-184 respectively). Conclusions: miRNA-197 and miRNA-184 are overexpressed in EGFR-mutant patients with BM and they might be a new biomarker for stratifying the risk of BM in this subpopulation. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) patients whose tumors have an EGFR-activating mutation develop acquired resistance after a median of 9-11 months from the beginning of treatment with erlotinib, gefitinib and afatinib. T790M mutation is the cause of this resistance in approximately 60% of cases. AZD9291 is an oral, irreversible, mutant-selective EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) developed to have potency against EGFR mutations, including T790M mutation, while sparing wild-type EGFR. A Phase I trial of AZD9291 in EGFR-mutant NSCLC patients, demonstrated high activity, essentially among T790M-mutant tumors, with a manageable tolerability profile. Ongoing Phase III trials are evaluating AZD9291 in EGFR-mutant patients as first-line treatment compared with erlotinib and gefitinib; and as second-line treatment compared with chemotherapy after progression on EGFR TKI in T790M-mutant tumors. Better identification of T790M-mutant tumors post EGFR TKI relapse and mechanisms of resistance to AZD9291 are the future challenges. This article reviews the emerging data regarding AZD9291 in the treatment of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial. [ABSTRACT FROM AUTHOR]

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.