Third-generation EGFR-TKI Research Articles

Exploring practical experience with different treatments in NSCLC patients with MET-deregulated: a retrospective analysis from the real world

BackgroundMesenchymal to epithelial transition factor (MET) dysregulation in non-small-cell-lung-cancer (NSCLC) is understudied, with scant data on treatment outcomes.MethodsWe retrospectively examined 160 NSCLC patients: 125 with primary MET mutations (further classified into MET exon 14 (METex14) skipping mutations and primary MET amplifications) and 35 with secondary MET amplifications. Patients underwent varied treatments: Chemotherapy, Immune monotherapy, Crizotinib, or Savolitinib. Secondary MET amplification patients were grouped by treatment: Group A (Class Ib MET-TKI with third-generation EGFR-TKI), Group B (Crizotinib with first-generation EGFR-TKI), and Group C (Crizotinib alone). One hundred and thirty patients have completed the whole treatment process. Their data were included in the study's survival analysis (included 95 patients with primary MET mutations and 35 patients with secondary MET amplifications).ResultsAmong METex14 skipping mutations patients (n = 57), median progression free survival (PFS) was: Chemotherapy 7.64 m, Crizotinib 8.5 m, Savolitinib 9.3 m, and Immunotherapy 3.87 m. Targeted therapies and chemotherapy significantly outperformed Immunotherapy. Sub-group analysis indicated splice donor region mutations benefited more than those at the polypyrimidine tract (9.23 m vs. 4.03 m, P = 0.038). For primary MET amplifications (n = 38), PFS was: Chemotherapy 2.84 m, Crizotinib 3.80 m, Savolitinib 5.23 m, and Immunotherapy 3.30 m. Patients with copy number (CN) > 5 had longer PFS than CN ≤ 5 (5.17 m vs. 3.44 m, P = 0.039). In secondary MET amplifications (n = 35), Group A and B had similar PFS (6.77 m and 6.57 m) versus Group C (3.13 m). Dual-target therapy PFS showed no difference between CN ≤ 5 and CN > 5 (8.63 m vs. 6.27 m, P = 0.29).ConclusionNSCLC patients with METex14 skipping mutations benefit more from targeted therapies, especially those with splice donor mutations. MET amplification patients benefit universally from targeted therapies; primary MET amplifications show higher benefits with increased copy numbers. For secondary MET amplifications post-EGFR-TKI resistance, dual-target therapy surpasses Crizotinib monotherapy, independent of MET copy number.

The effectiveness of sequential afatinib and furmonertinib in an advanced lung adenocarcinoma with rare compound EGFR mutation (L833V/H835L).

Uncommon atypical mutations account for 10-15% of all epidermal growth factor receptor (EGFR) activating mutations in nonsmall-cell lung cancer (NSCLC). Tumors harboring rare EGFR mutations show highly heterogeneous responses to EGFR tyrosine kinase inhibitors (TKIs). There is insufficient clinical evidence for uncommon types of EGFR mutations, especially those with compound EGFR mutations. In addition, for those with uncommon compound EGFR mutations, few studies have focused on acquired resistance mechanisms and subsequent treatment strategies after disease progression on EGFR-TKIs. Here, a 66-year-old smoking male was diagnosed with lung adenocarcinoma accompanied by pleural metastasis. A rare L833V/H835L compound mutation in exon 21 of EGFR was detected in tumor biopsy by next-generation sequencing. Afatinib was used as first-line therapy and showed favorable efficacy. The patient continued afatinib treatment for a duration of 24 months. A new T790M mutation was detected with a rebiopsy after progression on afatinib. Then the patient received cryoablation therapy and a third-generation EGFR-TKI, furmonertinib. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before and during treatment in clinical practice, and afatinib and furmonertinib could be first- and second-line treatment options in NSCLC patients harboring EGFR L833V/H835L mutations.

Cancer-associated fibroblasts induce almonertinib resistance in non-small cell lung cancer

BackgroundAlmonertinib is the initial third-generation EGFR-TKI in China, but its resistance mechanism is unknown. Cancer-associated fibroblasts (CAFs) are essential matrix components in the tumor microenvironment, but their impact on almonertinib resistance is unknown. This study aimed to explore the correlation between CAFs and almonertinib resistance in non-small cell lung cancer (NSCLC).MethodsThe anti-cancer effects of almonertinib on NSCLC cells, as well as the reversal of these effects mediated by CAFs, were validated through phenotypic experiments. Differential gene expression analysis, along with GO and KEGG enrichment analyses, was performed to predict the potential mechanisms underlying resistance to third-generation EGFR-TKIs. Finally, qPCR and Western blot analyses were used to explore the signaling pathways by which CAFs induce resistance to almonertinib in NSCLC cells.ResultsOur findings revealed that almonertinib significantly suppressed the invasion, migration, and proliferation of EGFR T790M-mutant NSCLC cells. TGF-β1 successfully induced the differentiation of CAFs and upregulated the expression of CAF markers, including α-SMA and fibroblast activation protein (FAP). Exposure of H1975 cells to almonertinib increased TGF-β1 secretion. Additionally, CAFs enhanced the survival of almonertinib-treated NSCLC cells, whereas normal fibroblasts (NFs) exerted the opposite effect. qPCR analysis demonstrated that the expression of the core molecules of the Hippo pathway, YAP and TAZ, was lower in A549 cells than in H1975 cells, and CAF intervention further reduced YAP/TAZ expression in H1975 cells. Western blot analysis confirmed a significant reduction in YAP/TAZ protein levels in cancer cells treated with CAF-conditioned medium (CAF-CM) compared to those treated with normal control-conditioned medium (NC-CM). Finally, we demonstrated that CAFs induced resistance to almonertinib in NSCLC cells, potentially through a mechanism involving YAP/TAZ.ConclusionThis study demonstrated that H1975 cells stimulated by almonertinib promoted the accumulation of CAFs in NSCLC cells, likely through increased secretion of TGF-β1. The accumulation of CAFs enhanced the survival of NSCLC cells undergoing almonertinib treatment and induced drug resistance. Additionally, the mechanism underlying CAF-induced drug resistance in NSCLC cells was potentially linked to the activation of the YAP/TAZ signaling pathway.

The potential of lazertinib and amivantamab combination therapy as a treatment strategy for uncommon EGFR-mutated NSCLC.

Uncommon epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) pose therapeutic challenge due to limited response to EGFR tyrosine kinase inhibitors (TKIs). This study presents preclinical evidence and mechanistic insights into the combination of lazertinib, a third-generation EGFR-TKI; and amivantamab, an EGFR-MET bispecific antibody, for treating NSCLC with uncommon EGFR mutations. The lazertinib-amivantamab combination demonstrates significant antitumor activity in patient-derived models with uncommon EGFR mutations either before treatment or after progressing on EGFR-TKIs. Lazertinib enhances the inhibitory capacity of amivantamab by increasing its on-target expression. Notably, the combination surpasses afatinib, a first-line treatment for uncommon EGFR mutations in NSCLC, in terms of invivo efficacy. Promising clinical activity is also observed in two case studies of patients treated with this combination (NCT04077463). Our findings highlight the potential of the lazertinib-amivantamab combination as a therapeutic strategy for uncommon EGFR mutations, an area of unmet medical need, and support further clinical investigation.

Successful treatment of epidermal growth factor receptor exon 19 deletion non-small cell lung cancer with almonertinib after osimertinib-induced interstitial lung disease: A case report.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has revolutionized one of the standard most efficient treatments for EGFR mutation-positive non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently one of most efficient treatments in clinical practice. However, it has a potentially fatal side effect: interstitial lung disease (ILD). When severe ILD occurs, a drug substitution is often required, and there is a rising concern about which drug to choose to inhibit the progression of NSCLC and avoid aggravating while alleviating ILD. Herein, we report an NSCLC case with osimertinib-induced ILD successfully rechallenged by almonertinib. In addition, we conducted a literature review on the clinical efficacy and adverse effects of almonertinib, hoping to provide insight into NSCLC treatment.

Non-small Cell Lung Cancer Cell Line PC-9 Drug-resistant Mutant Cell Line Establishment and Validation of Their Sensitivity to EGFR Inhibitors

Mutations in the structural domain of the epidermal growth factor receptor (EGFR) kinase represent a critical pathogenetic factor in non-small cell lung cancer (NSCLC). Small-molecule EGFR-tyrosine kinase inhibitors (TKIs) serve as first-line therapeutic agents for the treatment of EGFR-mutated NSCLC. But the resistance mutations of EGFR restrict the clinical application of EGFR-TKIs. In this study, we constructed a clinically relevant PC-9 EGFRD19/T790M/C797S cellular model featuring the mutation type within the EGFRD19/T790M/C797S. This model aims to investigate the inhibitory effects of small-molecule EGFR-TKIs and to provide a cellular platform for developing a new generation of innovative drugs that target resistance associated with EGFR mutations. Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR/Cas9) technology was employed to knock in the EGFRT790M/C797S mutant fragment into NSCLC PC-9 cells, originally harboring the EGFRD19 mutation, to generate the PC-9 EGFRD19/T790M/C797S cell model. This model, with the EGFRD19/T790M/C797S mutant, was used to investigate the inhibitory effects of EGFR-TKIs on cell proliferation through MTS assay. Additionally, Western blot analysis was conducted to assess the regulation of EGFR protein expression and the phosphorylation levels of downstream signaling molecules, including protein kinase B (AKT) and mitogen-activated protein kinase (MAPK). PC-9 EGFRD19/T790M/C797S cells, with the EGFRD19/T790M/C797S mutation, were successfully generated using CRISPR/Cas9 technology. In terms of proliferation inhibition, the marketed first-, second-, and third-generation EGFR-TKIs that were ineffective against the EGFRD19/T790M/C797S mutation showed weak proliferation inhibitory activity against this cell line, and the proliferation inhibition (half maximal inhibitory concentration, IC50)>1000 nmol/L; in contrast, the fourth-generation EGFR-TKIs in development, which have better efficacy against the EGFRD19/T790M/C797S mutation, showed strong proliferation inhibition in this cell model. On mechanistic validation, the first-, second-, and third-generation EGFR-TKIs had weak inhibitory activity on the phosphorylation of EGFR and the downstream AKT/MAPK signaling pathway in this cell line, whereas the fourth generation of EGFR-TKIs under development significantly inhibited the phosphorylation of EGFR and the downstream AKT/MAPK signaling pathway in this cell line. Using CRISPR/Cas9 technology, the EGFRT790M/C797S mutant fragment was successfully knocked into PC-9 cells to create cell lines harboring the EGFRD19/T790M/C797S mutation. The study demonstrated that the EGFR-TKIs showed different sensitivities to whether the EGFRD19/T790M/C797S mutation was effective or not and different inhibitory effects on the phosphorylation of EGFR and downstream pathways, which demonstrated that this cell line depended on the activation of the EGFRD19/T790M/C797S mutation and EGFR/AKT/MAPK signaling pathway for proliferation. This study provides a clinically relevant cellular evaluation and mechanism validation system for the development of a new generation of innovative drugs targeting EGFR mutation resistance.

Aberrant expression of MRAS and HEG1 as the biomarkers for osimertinib resistance in LUAD

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most applied targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, osimertinib, is widely used throughout lung cancer treatment, with single or combination modes. One of the main barriers in osimertinib treatment is the acquired resistance and mechanisms are not fully understood. Gene expression other than genetic mutations might predict drug response and mediate resistance occurrence. We analyzed six datasets of osimertinib-resistant LUAD cells from the Gene Expression Omnibus (GEO) database and identified two hub genes, named MRAS and HEG1. We found that the expression mode of MRAS/HEG1 in LUAD was osimertinib-dependent and contributed to drug resistance. We also explored potential mechanisms of hub genes related osimertinib resistance and emphasized the M2 infiltration involved. Moreover, potential therapeutic agents conquering MRAS/HEG1-related resistance were also identified. In conclusion, MRAS and HEG1 might be responsible for osimertinib resistance and could be promising prognostic biomarkers for osimertinib response in LUAD, which might provide insights into therapeutic strategies.

EGFR-TKIs or EGFR-TKIs combination treatments for untreated advanced EGFR-mutated NSCLC: a network meta-analysis

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC.MethodsWe searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach.ResultsWe identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events.ConclusionThese results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates.

EP.12A.43 Savolitinib and Third-Generation EGFR-TKI Therapy in EGFRm, MET-Altered NSCLC Patients: A Case Series

EP.12A.43 Savolitinib and Third-Generation EGFR-TKI Therapy in EGFRm, MET-Altered NSCLC Patients: A Case Series

Evidence from resected early-stage non-small cell lung cancer with EGFR mutation: a literature review.

Non-small cell lung cancer (NSCLC) in early-stages (I-IIIA) with epidermal growth factor receptor (EGFR) mutation may have specific epidemiological, clinical characteristics and treatment implications. This review aims to summarise the available evidence on these particularities, especially focusing on patient characteristics, treatment outcomes and safety with EGFR-tyrosine-kinase inhibitor (TKI). An exhaustive search of international bibliographic databases, as well as in abstracts of communications from major international congresses was performed for evidence related to EGFR-mutated NSCLC or early-stage NSCLC published in English before December 31st, 2023. Early-stage NSCLC with EGFR mutation presents with a variable incidence depending on geographical aspects. The clinical, radiological and molecular features differ slightly from both early-stage NSCLC without EGFR mutation and advanced NSCLC with EGFR mutation. Adjuvant treatment with the third-generation EGFR-TKI osimertinib has led to improvements in disease-free survival and overall survival (OS) in these patients, representing a practice changing and a new standard of care in clinical practice. No new safety signals have been reported with EGFR-TKI in the adjuvant setting. Clinical trials are ongoing to explore new therapeutic options in the adjuvant and neoadjuvant setting as well as the optimal duration of adjuvant osimertinib. Detection of EGFR mutation in early-stage NSCLC is an important goal due to the different characteristics and additional therapeutic options that improve patient outcomes and follow-up.

EGFR mutations in patients with lung adenocarcinoma and malignant pleural effusion: a propensity score-matched analysis of a single-center database.

Malignant pleural effusion (MPE) is associated with poor prognosis in patients with advanced lung adenocarcinoma (LUAD), and abnormal activation of epidermal growth factor receptor (EGFR) plays a crucial role in the development of LUAD. This study aimed to investigate the correlation between EGFR mutations and the occurrence of MPE in patients with LUAD and evaluate the effect of EGFR mutations on the prognosis of patients with LUAD with MPE. A case-control study design was adopted that included patients pathologically diagnosed with LUAD. Clinical data were collected, and patients were divided into the MPE group and the non-MPE (N-MPE) group based on the presence of MPE. Propensity score matching (PSM) was used to control for confounding factors. The correlation between EGFR mutations and the occurrence of MPE in LUAD was initially examined. Additionally, various factors affecting the overall survival (OS) of patients with LUAD and MPE were evaluated. A total of 849 patients were included in the study. After 1:2 PSM, there were 180 patients in the MPE group and 360 in the N-MPE group. The EGFR mutation rate was significantly higher in the MPE group compared to the N-MPE group [62.7% vs. 50.2%; odds ratio (OR) =1.668; P=0.006]. This difference was primarily attributed to the T790M mutation (8.3% vs. 1.3%; OR =8.015; P<0.001), but no significant differences observed in other mutation sites between the groups. Further evaluation of factors affecting OS in patients with LUAD and MPE revealed that EGFR mutation was an independent protective factor for OS [hazard ratio (HR) 0.662, 95% CI: 0.456-0.962; P=0.03]. For patients with LUAD, MPE, and EGFR mutations, treatment with third-generation EGFR-tyrosine kinase inhibitors (TKIs) alone (HR 0.466, 95% CI: 0.233-0.930; P=0.03) or sequential first- and third-generation EGFR-TKIs (HR 0.385, 95% CI: 0.219-0.676; P=0.001) was associated with better median OS compared to first-generation EGFR-TKIs alone (first-generation EGFR-TKIs: 35 months, 95% CI: 28.4-41.6; third-generation EGFR-TKIs: 50 months, 95% CI: 37.3-62.7; sequential first- and third-generation EGFR-TKIs: 51 months, 95% CI: 45.6-56.4; P<0.001). This study found there to be a positive correlation between EGFR mutations, particularly the T790M mutation, and MPE in patients with LUAD. EGFR mutation was associated with improved OS in patients with LUAD and MPE. For patients with LUAD, MPE, and EGFR mutations, sequential treatment with first- and third-generation EGFR-TKIs or third-generation EGFR-TKIs alone is recommended, as these regimens provide significant benefit to OS.

Safety and efficacy of consolidative stereotactic radiotherapy for oligo-residual EGFR-mutant non-small cell lung cancer after first-line third-generation EGFR-tyrosine kinase inhibitors: a single-arm, phase 2 trial

Prospective data is limited on the efficacy and safety of consolidative stereotactic radiotherapy (SRT) in metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients harboring oligo-residual disease (ORD) after first-line third-generation EGFR-tyrosine kinase inhibitors (TKIs). In this single-arm, phase II trial, 61 patients from two academic centers were enrolled from March 2021 to March 2023. All these patients had metastatic EGFR-mutant NSCLC and harbored ORD after first-line third-generation EGFR-TKIs. Consolidative SRT was performed and EGFR-TKIs were not held during SRT. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival and treatment-related adverse events (TRAEs). A prespecified propensity score matched (PSM) comparison was conducted with a contemporary cohort of patients who developed ORD but received EGFR-TKIs alone. This trial was registered with ClinicalTrails.gov, NCT04764214. All patients received consolidative SRT. With a median follow-up of 21.1 months, the median PFS was 29.9 (80% CI 22.4-32.4) months and the lower boundary exceeded the predefined threshold, meeting the primary endpoint. TRAEs occurred in 43 (70%) patients, with pneumonitis (27.9%) and esophagitis (26.2%) being the most common toxicities. Four patients (6.6%) reported grade ≥3 TRAEs, each for pneumonitis, esophagitis, leukopenia, and cranial radiation necrosis. PSM analysis showed significantly prolonged PFS in EGFR-TKI+SRT group compared to EGFR-TKI group (HR 0.46, 80% CI 0.20-0.61; p=0.002). Consolidative SRT is associated with an encouraging PFS in first-line third-generation EGFR-TKI-treated metastatic NSCLC patients harboring ORD, with generally acceptable toxicities. Further confirmatory studies are warranted. Hui Lan Public Welfare and the Chinese Society of Clinical Oncology Foundation.

Novel Combination of Therapeutic Approaches in Advanced NSCLC with EGFR Activating Mutations

The vast majority of advanced NSCLC cases are histologically represented by adenocarcinomas. EGFR activating mutations (exon 19 deletions, exon 21 L858R substitutions, exon 20 insertions) represent one of the most common druggable alterations. Since erlotinib’s FDA approval in 2013, EGFR-TKIs have represented a staple of EGFR+ advanced NSCLC treatment, with osimertinib representing the latest major FDA-approved third-generation EGFR-TKI. In recent years, however, several preclinical data have highlighted promising results regarding combination therapies involving EGFR-TKIs plus chemotherapy, and various recent clinical trials have confirmed these results. In addition, in 2021, amivantamab was the first FDA-approved mAb for the treatment of EGFR+ advanced NSCLC patients; according to some extremely up-to-date clinical trials, the combination of amivantamab plus chemotherapy is also associated with superior results. Therefore, this paper aims to provide a comprehensive review of both the bases and the latest evidence of the combination therapies involving EGFR+ advanced NSCLC patients.

1386P Prognostic value of EGFR A859S alteration in advanced NSCLC patients treated with third-generation EGFR-TKI

1386P Prognostic value of EGFR A859S alteration in advanced NSCLC patients treated with third-generation EGFR-TKI

Befotertinib in first-line treatment for Chinese non-small cell lung cancer patients harboring common EGFR-mutations reveals similar efficacy to other third-generation EGFR-TKIs but somewhat different safety profile.

Befotertinib in first-line treatment for Chinese non-small cell lung cancer patients harboring common EGFR-mutations reveals similar efficacy to other third-generation EGFR-TKIs but somewhat different safety profile.

Strong PD-L1 affect clinical outcomes in advanced NSCLC treated with third-generation EGFR-TKIs.

Background: In first/second generation EGFR-TKIs, strong PD-L1 expression contributes to primary resistance, significantly affecting patient prognosis. The relationship between PD-L1 expression levels and third-generation TKIs remains unclear.Methods: This study analyzed advanced NSCLC who received third-generation EGFR-TKIs as first-line systemic therapy from March 2019 to June 2022. The EGFR and PD-L1 status of the patients was also assessed.Results: Overall, 150 patients were included in this study. PD-L1 expression was negative (PD-L1 tumor proportion score <1%) in 89 cases, weak (1-49%) in 42 cases, and strong (≥50%) in 19 cases. mPFS for patients with negative, weak and strong PD-L1 expressions was 23.60, 26.12 and 16.60months, respectively. The mPFS for strong PD-L1 expression was significantly shorter than that for with weak PD-L1 expression but was not associated with negativity. The same conclusions were shown in subgroup analyses of mutation types and TKI kinds. In addition, Relative to PD-L1-negative patients, resistance to TKIs may be associated with early progression for patients with strong PD-L1 expression.Conclusion: PD-L1 expression in tumor cells influenced the clinical outcomes of patients with advanced NSCLC treated with third-generation EGFR-TKIs. Stronger PD-L1 expression in TKIs-treated patients with advanced first-line EGFR-mutated NSCLC was associated with worse PFS.

Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer.

Histologic transformation from EGFR-mutant non-small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored. We conducted whole-transcriptome analysis of 59 regions of interest through the spatial profiling of formalin-fixed, paraffin-embedded tissues obtained from 10 patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; and t-SCLC, 30 regions of interests). Transcriptomic profiles and differentially expressed genes were compared between pre- and post-transformed tumors. Following EGFR-TKI treatment, 93.7% (15/16) of t-SCLC components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, histone deacetylase inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the histone deacetylase inhibitor fimepinostat were validated in both in vitro and in vivo models. Our study demonstrated that most t-SCLC cases showed neuronal subtypes with low EGFR expression. Differentially expressed gene analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

SUCCESSFUL TREATMENT OF METASTATIC LUNG ADENOCARCINOMA WITH LAZERTINIB: A CASE REPORT

Lung cancer is one of the most common social diseases affecting the quality and length of life. A feature of lung cancer is the high frequency of genetic mutations. EGFR mutation is the most common among them. The prognosis for patients, especially with advanced stages, remains unfavorable since this type of tumor is resistant to chemotherapy. Tyrosine kinase inhibitors (TKIs) are considered the promising direction of targeted therapy. Gefitinib, afatinib, and erlotinib are TKIs widely used to treat patients. However, the significant problem remains the acquired resistance, which is most often associated with the additional mutation T790M. Lazertinib is a new and most promising third-generation EGFR-TKI.The study aimed to investigate the indications for lazertinib and to report the results of the successful treatment of a patient with metastatic lung adenocarcinoma with a follow-up period of 35 months.Case report and discussion. Lazertinib is used to treat patients with single (L858R, Ex19del, or T790M) or combined mutations (L858R and T790M, Ex19del and T790). This drug is effective for the first, second, and third lines of therapy, as it can block the T790M mutation, penetrate the blood-brain barrier, and counteract the emergence of acquired resistance. Lazertinib is used as monotherapy, but treatment effectiveness increases if combined with chemotherapy and/or amivantamab (a bispecific antibody against EGFR and MET). Our case report demonstrates that progression-free survival in patients receiving lazertinib can be very high. In patients taking tyrosine kinase inhibitors of the first generation, disease progression occurs after about 12 months. In our case, the patient has no progression within 35 months of treatment. Skin dryness and grade 1 thrombocytopenia have been reported as side effects. The high efficiency of lazertinib in the presented case report can be explained by the presence of the most sensitive to EGFR-TKI mutation - Ex19del, and the absence of uncommon mutations such as Ex20ins, G719X, L861Q, S768I, and T790M.Conclusions. Lazertinib is a highly effective EGFR-TKI with a low toxicity profile that may significantly improve the treatment outcomes of EGFR-mutated patients.

The efficacy of almonertinib and anlotinib combination therapy for advanced non-small-cell lung cancer patients who continued to experience cancer progression during third-generation EGFR-TKI treatment: a retrospective study.

Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non-small-cell lung cancer (NSCLC) patients. While third-generation EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third-generation EGFR-TKI therapy. In this retrospective analysis, we included EGFR-mutated NSCLC patients who were resistant to third-generation EGFR-TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well-tolerated, with manageable adverse events. Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR-mutated NSCLC patients who have progressed on third-generation EGFR-TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines.