Deciphering the Dynamics of EGFR-TKI Resistance in Lung Cancer: Insights from Bibliometric Analysis.

Background: EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct a bibliometric analysis to elucidate evolving research hotspots and trends in EGFR-TKI resistance, offering insights for clinical interventions and scientific inquiries. Methods: Publications spanning from 1996 to 2024, focusing on EGFR-TKI resistance in NSCLC, were sourced from the Web of Science Core Collection. Utilizing VOSviewer 1.6.19, CiteSpace 6.2. R2, and Scimago Graphica 1.0.35, we analyzed these articles to identify countries/regions and institutions, Journals, publications, key contributors, collaborations, and emerging topics. Results: An analysis of 8051 articles by 38,215 researchers from 86 countries shows growing interest in EGFR-TKI resistance mechanisms. Since 1996, publications have steadily increased, surpassing 500 per year after 2016, with a sharp rise in citations. Research articles make up 84% of publications, emphasizing scholarly focus. Global collaboration, especially among researchers in China, the US, and Japan, is strong. Leading institutions like Dana-Farber and Harvard, along with journals such as "Lung Cancer", are key in sharing findings. Professors Yi-Long Wu and William Pao are prominent contributors. Keyword analysis reveals core themes, including first-generation EGFR-TKIs, emerging agents like osimertinib, and research on the T790M mutation. Conclusion: EGFR-TKI resistance remains a critical issue in NSCLC treatment, driving ongoing research efforts worldwide. Focusing future research on clear identification of resistance mechanisms will guide post-resistance treatment strategies, necessitating further exploration, alongside the validation of emerging drugs through clinical trials. Moreover, "chemo+" treatments following EGFR-TKI resistance require more clinical data and real-world evidence for assessing safety and patient outcomes. As research advances, a multidisciplinary approach will be key to overcoming these challenges. Continued innovation in treatment could greatly enhance patient survival and quality of life.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433-0.973) and 0.682 (95% CI: 0.464-0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511-1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14-3.4) and PFS 2.13 (95% CI: 1.28-3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

BACKGROUND: Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. METHODS: Eligible patients were aged ≥ 20 years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240 mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. RESULTS: This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9 months; estimated survival rates at 12, 24, and 36 months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240 mg/day was consistent with previous findings. CONCLUSIONS: Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03046992.

A novel role for WZ3146 in the inhibition of cell proliferation via ERK and AKT pathway in the rare EGFR G719X mutant cells.

Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.

Harnessing molecular probes for imaging of human epidermal growth factor receptor (HER) family.

The human epidermal growth factor receptor (HER) family plays a critical role in the development, migration, and invasion of various cancers. Currently, the FDA has approved numerous targeting therapies for the HER family consist of small molecule drugs, monoclonal antibodies and antibody-drug conjugates. To facilitate precision therapy using currently approved targeted agents, early detection and quantification of each HER receptor are essential for assessment, treatment, and prognostic purposes. This study provides a comprehensive review of the latest advancements in detection and quantification of HER receptors, including traditional biopsies, liquid biopsies, and non-invasive detection methods. Although traditional histological methods, such as immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), have yielded valuable insights, advancements in real-time and non-invasive detection technologies necessitate improved methods for the dynamic evaluation of HER status. This article also reviews several emerging real-time techniques for detecting and quantifying HER status in circulating tumor cells (CTCs) extracted from blood samples, as well as in vivo assessments using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging. This review emphasizes the importance of continuous innovation in the application of HER receptor imaging technologies, with the goal of enhancing treatment outcomes and prognoses for cancer patients.

Design, synthesis, and antiproliferative activity of new indole/1,2,4-triazole/chalcone hybrids as EGFR and/or c-MET inhibitors.

A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.

The impact of postoperative adjuvant therapy on EGFR-mutated stage IA lung adenocarcinoma with micropapillary pathological subtypes.

BACKGROUND: Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components. MATERIALS AND METHODS: We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination. RESULTS: Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components. CONCLUSION: MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy.

Clinical observation of topical antipruritic spray acting on epidermal growth factor receptor tyrosine kinase inhibitor in the treatment of dermatitis.

To observe the efficacy of topical antipruritic spray (TAS) in the treatment of epidermal growth factor receptor (EGFR) tyrosine kinase-related rashes, and to evaluate its efficacy and safety. 120 malignant tumor patients with confirmed pathological diagnosis and rash after EGFR application were selected and randomly divided into an experimental group of 60 cases and a control group of 60 cases. The 2 groups were intervened with self-made antipruritic spray and erythromycin ointment for 14 consecutive days. To observe the changes in rash, itching degree, and quality of life index of skin diseases in both groups of patients before and after treatment. The decrease in the number of itching cases in the experimental group reached 53.84%, and after 7 weeks of intervention, the total effective rate of rash treatment in this group of patients (91.67%) was significantly better than that in the control group (36.67%); The symptoms of the dermatology life quality index (DLQI) scale in the experimental group patient table after intervention showed significant changes compared to before intervention. After statistical testing, there was a significant difference between the groups and outside the group (R < 0.05). And the comprehensive effect of the experimental patients with external spray after 14 weeks of intervention reached 93.16%. The self-made antipruritic spray has significant effect on improving EGFR rash and itching, and there is no obvious adverse reaction.

Supplementation with Fish Oil and Selenium Protects Lipolytic and Thermogenic Depletion of Adipose in Cachectic Mice Treated with an EGFR Inhibitor.

Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy.

Efficacy on symptoms and mortality day vs. night administration of EGFR-TKIs for advanced non-small cell lung cancer.

PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Natural killer cells: a future star for immunotherapy of head and neck squamous cell carcinoma.

The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti-EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC.

Association of mean platelet volume (MPV), MPV/PLATELET (PLT) ratio, and lymphocyte/monocyte ratio (LMR) as poor prognostic factor in EGFR-mutant lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor.

Introduction: Platelets (PLT) and host systemic inflammatory response (SIR) are known to be effective in the aggregation of cancer cells and the formation of metastasis. There are studies pointing out to the prognostic efficacy of lymphocyte-monocyte ratio (LMR) showing SIR activation and mean platelet volume (MPV) values indicating platelet activation in various cancer types. We predict that easy-to-access hemogram parameters such as MPV, MPV/PLT, and LMR can be guiding in the clinical follow-up period of patients with epidermal growth factor receptor (EGFR) positive mutation and who received EGFR, tyrosine kinase inhibitor (TKI) in the first-line treatment in predicting the progression of the disease, predicting the survival time of the patients, and evaluating the response to treatment. Materials and Methods: The study is retrospective and included patients with stage III and stage IV pulmonary adenocarcinoma with positive EGFR mutations and for whom TKI was used in the first-line treatment between January 2011 and January 2021. MPV, MPV/PLT, and LMR values of the patients were calculated before treatment. Age, sex, comorbidity, smoking history, TNM stage, metastasis localizations, EGFR mutation types, TKI treatments used in first-line treatment, and MPV, MPV/PLT, and LMR values at the 1st month of treatment were recorded. With Kaplan-Meier, six-month, one-year, three-year, and five-year survival rates, average life expectancy, and 95% confidence intervals for these periods were calculated. Variables that may affect progression and overall survival (OS) were determined by performing univariate and multivariate Cox regression analysis. Result: One hundred and two patients were included in the study. The mean age of the patients was 64.30 ± 12.6 years. Eighty-four patients were in stage IV at the time of diagnosis. The expected mean progression-free survival (PFS) period of the cases was found to be 13.3 months. The mean life expectancy of the cases was found to be 35.1 months. Web-based Cutoff Finder algorithm written in the R program (http://molpath.charite.de/cutoff) was used to determine the ideal cut points for MPV, MPV/PLT, and LMR. The cut-off values were found to be 7.55 fL for MPV, 0.251 for MPV/PLT, and 2.615 for LMR, respectively. In univariate Cox regression analysis, LMR level lower than 2.615 increased the rate of progression 1.747 times (95% confidence interval: 1.129-2.705) and the death rate 2.056 times (95% confidence interval: 1.217-3.475) (p= 0.012, p= 0.007). The mean PFS LMR cut-off value was 10.3 months, and 15.3 months, and mean OS durations were 25.1 months and 40.8 months for the groups with low and high cut-off values respectively (p= 0.011, p= 0.006 log-rank test). According to the results of multivariate Cox regression analysis, MPV/PLT < 0.251, smoking, presence of pleural and adrenal metastases, and gefitinib treatment were independent factors in determining PFS. The independent factors determining OS in multivariate Cox regression analysis were being male, platelet increase, MPV > 7.55, gefitinib treatment, and smoking. Conclusions: MPV, MPV/PLT, and LMR are potential biomarkers that can be used for the clinical follow-up of lung ADC patients receiving EGFR-TKI treatment.

Analysis of EGFR binding hotspots for design of new EGFR inhibitory biologics.

The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF-like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR-driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR-driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per-residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

EGFR-mutated NSCLC: A roadmap to treatment sequences.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for the management of EGFR-mutated non-small cell lung cancer. Recent results from the HARMONi-A trial lead to considering ivonescimab-a first-in-class, bispecific antibody targeting PD-1 and VEGF-plus chemotherapy as a new second-line option following third-generation TKIs.

Lactate-Induced HBEGF Shedding and EGFR Activation: Paving the Way to a New Anticancer Therapeutic Opportunity.

Cancer cells can release EGF-like peptides, acquiring the capacity of autocrine stimulation via EGFR-mediated signaling. One of these peptides (HBEGF) was found to be released from a membrane-bound precursor protein and is critically implicated in the proliferative potential of cancer cells. We observed that the increased lactate levels characterizing neoplastic tissues can induce the release of uPA, a protease promoting HBEGF shedding. This effect led to EGFR activation and increased ERK1/2 phosphorylation. Since EGFR-mediated signaling potentiates glycolytic metabolism, this phenomenon can induce a self-sustaining deleterious loop, favoring tumor growth. A well characterized HBEGF inhibitor is CRM197, a single-site variant of diphtheria toxin. We observed that, when administered individually, CRM197 did not trigger evident antineoplastic effects. However, its association with a uPA inhibitor caused dampening of EGFR-mediated signaling and apoptosis induction. Overall, our study highlights that the increased glycolytic metabolism and lactate production can foster the activated state of EGFR receptor and suggests that the inhibition of EGFR-mediated signaling can be attempted by means of CRM197 administered with an appropriate protease inhibitor. This attempt could help in overcoming the problem of the acquired resistance to the conventionally used EGFR inhibitors.

An "AND" logic gate-based supramolecular therapeutic nanoplatform for combatting drug-resistant non-small cell lung cancer.

Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non-small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an "AND" logic gate-based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli-responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.

[Advances in Diagnosis and Targeted Therapy of G719X/L861Q/S768I Mutant 
Non-small Cell Lung Cancer].

Lung cancer accounts for the highest proportion of cancer deaths in the world and poses a great threat to human health. About 30% to 40% of non-small cell lung cancer (NSCLC) is caused by point mutations, exon insertion and exon deletion of the epidermal growth factor receptor (EGFR). In addition to the common exon 19 deletion mutation and exon 21 L858R mutation, exon 18 G719X mutation, exon 21 L861Q mutation and exon 20 S768I mutation are the most important rare mutations. At present, the diagnostic methods for major rare mutations are mainly next-generation sequencing (NGS), digital polymerase chain reaction (dPCR), droplet digital PCR (ddPCR), etc. Regarding the targeted therapy of G719X/L861Q/S768I mutant NSCLC, the first generation EGFR-tyrosine kinase inhibitors (TKIs) have poor efficacy, while the second and third generation EGFR-TKIs have similar efficacy. The novel third generation EGFR-TKIs and combination therapy show a good therapeutic prospect. This article summarized the progress in the diagnosis and targeted therapy of G719X/L861Q/S768I mutant NSCLC, so as to provide reference for subsequent clinical drug use and research.
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[EGFR Exon 20 Insertion Mutation: Research Status and New Treatment Strategies].

In non-small cell lung cancer (NSCLC), as an improtant oncogenic driver gene, epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) has a unique protein structure and is primarily drug-resistant to traditional EGFR-tyrosine kinase inhibitors (EGFR-TKIs). In recent years, exploration of targeted therapy for EGFR ex20ins has never stopped. Firstly Mobocertinib and Amivantamab obtained approval from U.S. Food and Drug Administration (FDA) for EGFR ex20ins mutant NSCLC patients, then other drugs, such as Sunvozertinib, made breakthroughs and combination therapies also obtained gains. Multi-pronged measures are hopeful to overcome EGFR ex20ins drug resistance. As mentioned above, it's definitely important to gain deeper understanding of molecular mechanism of EGFR ex20ins and assess effect and difference between novel drugs. This review is devoted to make a summary about newest achievement so to provide valuable reference about precise therapy for patients with EGFR ex20ins.
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Successful rapid improvement of acute respiratory distress syndrome induced by EGFR-mutated non-small cell lung cancer with almonertinib: a case report.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition frequently encountered in critically ill patients, including those with advanced non-small cell lung cancer (NSCLC). Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promise as a first-line treatment for NSCLC with classical EGFR mutations. However, its efficacy in NSCLC patients suffering from ARDS has not been well-documented. CASE PRESENTATION: We report the case of a 63-year-old Chinese Han female with severe NSCLC complicated by ARDS. Upon hospital admission, the patient exhibited progressive dyspnea and required intubation to maintain oxygenation. Pathological analysis of bronchoalveolar lavage fluid sediment confirmed lung adenocarcinoma, and genetic testing of blood identified an EGFR E19 mutation. The patient was treated with almonertinib, resulting in significant clinical improvement and successful extubation after nine days. Radiographic imaging showed substantial reduction in pulmonary lesions, highlighting the efficacy of almonertinib. CONCLUSION: This case represents the first documented successful treatment of ARDS induced by EGFR E19 mutated NSCLC using almonertinib. The favorable clinical response observed in this critically ill patient suggests that almonertinib may be a viable therapeutic option for managing severe complications in NSCLC. Further research is necessary to corroborate these findings and optimize dosage and toxicity management strategies for broader clinical application.