Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Efficacy and safety of EGFR-TKIs for non-small cell lung cancer: A meta-analysis of randomized controlled clinical trials.

We conducted this meta-analysis based on updated literature and research to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as treatments for patients with non-small cell lung cancer (NSCLC). A literature search was conducted using PubMed, Embase, Medline and Web of Science databases to perform a systematic literature search based on random control trials. In these articles, EGFR-TKIs were compared with placebos, chemotherapy, or whole-brain irradiation as treatments for NSCLC. In this research, a meta-analysis of the literature was performed to produce a combined risk ratio (RR) with a 95% confidence interval (CI) for progression-free survival (PFS), overall survival (OS), and adverse events. The data were synthesized with Review Manager 5.3 software, which was used to manage the process. There were 15 random control trials included in the study, involving 4249 patients in total. There was evidence that EGFR-TKIs can significantly prolong OS (RR: 0.87, 95% CI: 0.75-1) and PFS (RR: 0.75, 95% CI: 0.66-0.86) in NSCLC patients. There was an increase in the incidence of adverse events after treatment with EGFR-TKI, including diarrhea (RR: 0.18, 95% CI: 0.10-0.26), infection (RR: 0.09, 95% CI: 0.02-0.16), and rash (RR: 0.37, 95% CI: 0.22-0.51). It has been shown that EGFR-TKIs prolong OS and PFS in patients with NSCLC. NSCLC patients may benefit from EGFR-TKIs as an important treatment option in order to prolong their survival.

Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.

Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

Multinational proficiency tests for EGFR exon 20 insertions reveal that the assay design matters

Insertion mutations in exon 20 of the epidermal growth factor receptor gene (EGFR exon20ins) are rare, heterogeneous alterations observed in non-small cell lung cancer (NSCLC). With a few exceptions, they are associated with primary resistance to established EGFR tyrosine kinase inhibitors (TKIs). As patients carrying EGFR exon20ins may be eligible for treatment with novel therapeutics—the bispecific antibody amivantamab, the TKI mobocertinib, or potential future innovations—they need to be identified reliably in clinical practice for which quality-based routine genetic testing is crucial. Spearheaded by the German Quality Assurance Initiative Pathology two international proficiency tests were run, assessing the performance of 104 participating institutes detecting EGFR exon20ins in tissue and/or plasma samples. EGFR exon20ins were most reliably identified using next-generation sequencing (NGS). Interestingly, success rates of institutes using commercially available mutation-/allele-specific quantitative (q)PCR were below 30% for tissue samples and 0% for plasma samples. Most of these mutation-/allele-specific (q)PCR assays are not designed to detect the whole spectrum of EGFR exon20ins mutations leading to false negative results. These data suggest that NGS is a suitable method to detect EGFR exon20ins in various types of patient samples and is superior to the detection spectrum of commercially available assays.

Custom-Designed Probes for the Accurate Determination of Epidermal Growth Factor Receptor Mutations and Their Allelic Configuration.

The identification of single nucleotide polymorphisms (SNPs) is of paramount importance for disease diagnosis and clinical prognostication. In the context of nonsmall cell lung cancer (NSCLC), the emergence of resistance mutations, exemplified by the epidermal growth factor receptor (EGFR) T790 M and C797S, is intricately linked to the therapeutic efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Herein, a highly efficient and specific SNP detection platform for T790 M and C797S mutations has been engineered through the integration of an asymmetric polymerase chain reaction (PCR) and an ingeniously tailored four-way junction (4WJ) probe. Notably, a molecular beacon (MB) probe was judiciously designed to discern the allelic configuration of these mutations. The administration of first- and third-generation EGFR-TKIs demonstrates therapeutic efficacy solely when the mutations are in the trans configuration, characterized by a low fluorescence signal. In contrast, significant fluorescence by the MB probe is indicative of the C797S mutation being in a cis arrangement with T790M, thereby rendering the cells refractory to the therapeutic interventions of both first- and third-generation EGFR-TKIs. The assay is capable of concurrently detecting two point-mutations and ascertaining their allelic positions in a single test within 1.5 h, enhancing both efficiency and simplicity. It also exhibits high accuracy in the identification of clinical samples, offering promising implications for therapeutic guidelines. By enabling tailored treatment plans based on specific genetic profiles, our approach not only advances the precision of NSCLC treatment strategies but also marks a significant contribution to personalized medicine.

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

GLUT1 promotes cell proliferation via binds and stabilizes phosphorylated EGFR in lung adenocarcinoma

BackgroundWhile previous studies have primarily focused on Glucose transporter type 1 (GLUT1) related glucose metabolism signaling, we aim to discover if GLUT1 promotes tumor progression through a non-metabolic pathway.MethodsThe RNA-seq and microarray data were comprehensively analyzed to evaluate the significance of GLUT1 expression in lung adenocarcinoma (LUAD). The cell proliferation, colony formation, invasion, and migration were used to test GLUT1 ‘s oncogenic function. Co-immunoprecipitation and mass spectrum (MS) were used to uncover potential GLUT1 interacting proteins. RNA-seq, DIA-MS, western blot, and qRT-PCR to probe the change of gene and cell signaling pathways.ResultsWe found that GLUT1 is highly expressed in LUAD, and higher expression is related to poor patient survival. GLUT1 knockdown caused a decrease in cell proliferation, colony formation, migration, invasion, and induced apoptosis in LUAD cells. Mechanistically, GLUT1 directly interacted with phosphor-epidermal growth factor receptor (p-EGFR) and prevented EGFR protein degradation via ubiquitin-mediated proteolysis. The GLUT1 inhibitor WZB117 can increase the sensitivity of LUAD cells to EGFR-tyrosine kinase inhibitors (TKIs) Gefitinib.ConclusionsGLUT1 expression is higher in LUAD and plays an oncogenic role in lung cancer progression. Combining GLUT1 inhibitors and EGFR-TKIs could be a potential therapeutic option for LUAD treatment.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

BackgroundOsimertinib is a recommended treatment for advanced non–small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC.MethodsIn this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review.ResultsA total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged.ConclusionsTreatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.)

The association between osimertinib and nutritional deficiency among patients with non-small cell lung cancer.

8031 Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the standard-of-care in EGFR mutation-positive non-small-cell lung cancer (NSCLC) in various settings. Osimertinib commonly causes gastrointestinal adverse effects thereby potentially leading to nutritional deficiencies. Therefore, we aim to evaluate the association between the use of osimertinib and nutritional deficiencies among patients with NSCLC. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with NSCLC who received either osimertinib or other EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib). The outcomes of interest included vitamin B deficiency, vitamin D deficiency, iron deficiency as well as associated anemia including vitamin B12 deficiency anemia, folate deficiency anemia, and iron deficiency anemia within 5 years of EGFR-TKI initiation. Results: We matched 4264 patients who received osimertinib to patients who received other EGFR-TKIs. In Cox proportional hazard analysis, osimertinib was associated with a 50% higher risk of vitamin B deficiency (Hazard ratio, 1.52 [95% CI: 1.07-2.16]) compared to other EGFR-TKIs. Consistent with this observation, osimertinib was associated with an increased risk of vitamin B12 deficiency anemia and a tendency towards folate deficiency anemia. We also noted a 2-fold higher risk of vitamin D and 5-fold higher risk of iron deficiency in the osimertinib cohort. Consistent with this observation, osimertinib was associated with an increased risk of iron deficiency anemia compared to other EGFR-TKIs. Conclusions: The use of osimertinib is associated with a higher risk of nutritional deficiencies and associated anemias compared to other EGFR-TKIs. One potential explanation is the extended duration of osimertinib therapy, driven by its potent anti-cancer effects. Therefore, it is advisable to consider screening for specific nutritional deficiencies in individuals receiving osimertinib therapy. [Table: see text]

Dermatologic adverse events in EGFR-TKIs: A real-world analysis.

e20572 Background: Dermatologic adverse events (DAEs) affect a significant number of patients with non-small cell lung cancer (NSCLC) who are treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While many DAEs have been identified during clinical trials and included in FDA drug labels, patients have raised concerns about experiencing unexpected DAEs. This study reviews the FDA Adverse Events Reporting System (FAERS) to identify DAEs in EGFR TKIs approved in NSCLC that are not included in drug labels. Methods: FAERS was queried for DAEs between 2003 – 2023 for osimertinib, afatinib, ertlotinib, gefitinib and mobocertinib. The reporting odds ratio (ROR) was calculated to compare DAEs between these EGFR-TKIs and all other drugs in the database. DAEs were considered statistically significant if the lower limit of the ROR 95% confidence interval (CI) was &gt; 1 and if there were ≥ 3 reported adverse reactions. Results: 67,480 adverse events were reported for the 5 EGFR-TKIs studied. DAEs constituted 30.3% (20,426) of all adverse event reports. We identified skin (skin fissures, eczema, lip swelling, and skin infection), nail (onychalgia and onychomadesis), and hair (abnormal hair growth and hair disorder) DAEs not previously included in EGFR-TKI drug labels. RORs with 95% CIs are summarized in the table. Conclusions: Real-world FAERS data complements clinical trial data in identifying specific DAEs affecting NSCLC patients treated with EGFR TKIs. Our findings highlight DAEs that were previously not described, aiding clinicians in educating patients about side effects and giving patients a more nuanced understanding of what to expect before undergoing treatment. [Table: see text]

EGFR-TKI as neoadjuvant treatment in patients with NSCLC with EGFR sensitive mutation: A retrospective real-world analysis.

8081 Background: This study aimed to evaluate the efficacy and outcome of Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as preoperative neoadjuvant treatment in patients with NSCLC and EGFR sensitive mutation. Methods: A retrospective analysis was conducted. Patients with resectable stage I-III NSCLCs and received neoadjuvant treatment with any generation of EGFR-TKI before surgical resection were enrolled. The primary endpoint were major pathological response (MPR) and objective response rate (ORR), the second endpoints included diseases down staging, surgical outcomes, disease-free survival (DFS) and overall survival (OS). Results: A total of 58 patients were enrolled. Female accounted for 62.1% and most of them (77.6%) were never-smoker. Forty-five (77.6%) patients received the first generation of EGFR-TKI and 11 received the third. The median duration of EGFR-TKI before surgery was 3.6 months (0.7-19.5m). Nine (15.5%) patients achieved MPR and one patient (1.71%) achieved pathological complete response (pCR). The ORR was 60.3% (35/58) according to RECIST v1.1. Eighteen patients achieved TNM downstaging with T downstaging occurred in 44.8% of patients and N downstaging was about 32.8%. Majority of patients (96.6%) underwent thoracoscopic surgery and the rate of R0 resection was 82.8% (48/58). The DFS and OS of the whole cohort was 25.7months and not reached respectively. Patients with MPR had statistically improved outcomes than those without. What noticeable was that patients with tumor regression grade 3 (13/58) (residual viable tumor cells counts for 10% to 50%) also demonstrated a significant benefit from EGFR-TKI preoperative treatment than those with TRG4 or 5 (residual viable tumor cells&gt;50%) (p = 0.01). We define patients with TRG1 to TRG3 as deep pathological regression (DPR) and the rest as non-DPR, and the DPR cohort showed significantly prolonged DFS than those with non-DPR (median DFS, 60.9 vs 16.7 months; HR, 0.29 (95%CI: 0.11-0.74), p = 0.006), the data of OS was not mature. Subgroup analysis validated DPR was an independent predictive factor for DFS. Conclusions: EGFR-TKI as neoadjuvant therapy had good effect on tumor pathological regression and disease downstaging, DPR patients were more likely to achieve long-term disease-free survival. Patients with NDPR should be closely followed up and appropriate adjuvant therapy was necessary after surgery due to the high risk of reccurence.

IGF-1R, E-cadherin, N-cadherin, and occludin gene expression and resistance to EGFR tyrosine-kinase inhibitors in patients with lung adenocarcinoma in Serbia.

8524 Background: Mutations in epidermal growth factor-receptor ( EGFR) are found in approximately 10% of patients with lung adenocarcinoma in Serbia. EGFR tyrosine-kinase inhibitors ( EGFR-TKIs) is a safe and effective targeted therapy. However, most patients develop resistance. Acquired resistance to EGFR-TKI is defined as disease progression after achieving response or stable disease and there is a possible molecular association with epithelial-mesenchymal transition (EMT), particularly N-cadherin, E-cadherin, occludin and insulin-like growth factor-1 receptor (IGF-1R). We assessed the gene expression levels of IGF-1R, E-cadherin, N-cadherin, and occludin as predictive factors of resistance to EGFR-TKIs and survival outcomes in patients with advanced EGFR mutation-positive lung adenocarcinoma in Serbia. Methods: 101 patients with stage IIIB/IV EGFR mutation positive lung adenocarcinoma treated with EGFR-TKIs were included in the study. Quantitative RT-PCR was performed to determine mutations in EGFR, and expression of N-cadherin, E-cadherin, occludin and IGF-1R. Kaplan-Meier method was employed to estimate overall-survival (OS) and progression-free survival (PFS), with significance set at p&lt;0.05. Results: Median age of patients was 61.7 (39 - 81) years, 65.3% were females and 91% were diagnosed with metastatic lung adenocarcinoma. EGFR mutations were more frequently detected in females (p &lt;0.001). Median overall survival (OS) was 21 months (15.2–26.7 CI 95%) and progression-free survival (PFS) was 10 months (7.4-12.5 CI 95%). Patients whose tumors had lower levels of IGF-1R, and N-cadherin expression had statistically significantly longer PFS (p &lt;0.001). Patients with lower levels of IGF-1R and higher levels of E-cadherin gene expression were more likely to have a complete or partial response to therapy (p = 0.04). There was a statistically significant association between elevated IGF-1R expression and the occurrence of EGFR-TKI resistance in patients (p &lt;0.001). There was a statistically significant association between increased N-cadherin expression and reduced E-cadherin expression with EGFR-TKI resistance in patients. Conclusions: The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin. In this group of patients, higher levels of IGF-1R and N-cadherin gene expression were associated with shorter PFS and resistance to EGFR TKI, compared to higher levels of expression of E-cadherin, which may indicate potential value of expression of these genes in predicting acquired resistance to EGFR-TKI. Therefore, more research is needed to prove the potential predictive value of E-cadherin, N-cadherin and IFG-1R in acquired resistance to EGFR-TKI and developing novel therapeutic options with anti-EMT properties that can overcome this problem.

Genomic profiling of non-small cell lung cancer with rare aberrations in EGFR codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic EGFRL858R.

8596 Background: Rare genomic aberrations in EGFR codon L858 causing L858R (rare EGFRL858R) or non-L858R mutations have been reported, besides the predominant c.2573T&gt;G genomic mutation leading to classic EGFRL858R. However, molecular features, survival benefit under EGFR tyrosine kinase inhibitors (TKIs), and resistance mechanisms of these rare mutations lack comprehensive investigation in non-small cell lung cancer (NSCLC). Methods: We retrospectively included 489 NSCLCs with treatment-naive tumor tissues/plasma biopsies harboring rare EGFRL858R (N=124), EGFRL858Q/M (N=17), or classic EGFRL858R mutations (N=348). Mutational landscapes, tumor mutation burden (TMB), and chromosome instability (CIN) scores, were investigated using tissue samples subject to a targeted next-generation sequencing panel covering 437 cancer-related genes. Advanced NSCLCs receiving EGFR TKIs as first-line therapy were sub-grouped to study survival benefit and resistance mechanisms. Results: NSCLCs with rare EGFRL858R had less-frequently mutated TP53 (59% vs. 72%, P=0.04) and lower CIN scores (0.29 vs. 0.23, P=0.02) than those with classic EGFRL858R, while age, sex, stage at diagnosis, histology subtype, and TMB were comparable. We also detected the cooccurrence of EGFRL858Q/M with EGFRL861Q ( P&lt;0.01), particularly in patients carrying EGFRL858M (100%). Compared to 233 advanced NSCLCs harboring classic EGFRL858R, 58 patients with rare EGFRL858R exhibited superior first-line progression-free survival (PFS) [median: 13.0 vs. 10.0 months, hazard ratio (HR): 0. 57, 95% confidence interval (CI): 0.41–0.80], with a similar association observed in approximately 80% of included patients who received first-generation EGFR TKIs (median: 12.0 vs. 10.0 months, HR: 0.64, 95% CI: 0.45–0.92). After controlling for age, sex, histological subtype, EGFR TKI category, and anti-vascular therapy, rare EGFRL858R remained associated with improved PFS (adjusted HR: 0.55, 95% CI: 0.39–0.77). Patients with EGFRL858Q/M also had better PFS than those with classic EGFRL858R (adjusted HR: 0.26, 95% CI: 0.10–0.67). Of note, NSCLCs with combined EGFRL858M and EGFRL861Q appeared to have lower progression risks when receiving afatinib than using gefitinib/icotinib as first-line therapy. Furthermore, matched samples at baseline and progression revealed similar resistance mechanisms between NSCLCs with rare and classic EGFRL858R. Conclusions: NSCLCs carrying rare genomic aberrations in EGFR codon L858 were likely to get more survival benefits from first-line EGFR TKI treatment than those with classic EGFRL858R, giving scientific evidence supporting the clinical application of EGFR TKIs in these patients.

Efficacy and safety of aumolertinib combined with or without chemotherapy as an adjuvant treatment for stage II-IIIA non-small cell lung cancer following complete tumour resection: The first third-generation EGFR-TKI versus chemotherapy phase III clinical study (APEX).

TPS8117 Background: Patients with stage II-III A non-small cell lung cancer (NSCLC) can benefit from adjuvant targeted therapy. ADAURA study shows a remarkable advantage of disease-free survival (DFS). However, there are still unresolved clinical issues. Firstly, the control group in the trial is received placebo, making it impossible to directly compare the efficacy of adjuvant targeted therapy with the traditionally recommended adjuvant chemotherapy in guidelines. Thus, it cannot address the direct comparison of third-generation TKIs with the current standard therapy (chemotherapy). Secondly, the necessity of combining chemotherapy with adjuvant targeted therapy need to explored. Aumolertinib is a third-generation epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR sensitizing and EGFR T790M resistance mutations. This study aims to evaluate the efficacy and safety of aumolertinib combined with or without chemotherapy as adjuvant treatment for EGFR-sensitive mutations stage II-III A non-squamous NSCLC patients. Methods: This is a multicenter, randomized, open label, phase III study. Patients with histologically confirmed stage II-III A non-squamous NSCLC harboring EGFR mutations without prior EGFR TKI treatment and R0 resection are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 606 patients, will be randomized (3:2:1) to receive either aumolertinib alone (110mg, po, once daily) or aumolertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv). The first patient was enrolled on August 2, 2021. The primary end point is DFS, The secondary endpoints include 2, 3, 4, 5-year DFS rates, 5-year overall survival (OS), OS, safety and quality of life. Adverse effects were graded per CTCAE v.4.0. This trial is registered as NCT04762459. Clinical trial information: NCT04762459 .

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC.

Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs. Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes. The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies. This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.

Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC).

TPS8658 Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Clinical trial information: NCT05394831 .

REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (EGFR) mutations.

TPS8670 Background: Patients with NSCLC harboring uncommon EGFR mutations, including ex20ins, have limited treatment options. Zipalertinib (CLN-081/TAS6417) is an oral tyrosine kinase inhibitor of EGFR with broad activity against EGFRmutations (including ex20ins) and increased selectivity for ex20ins versus wild-type EGFR. Zipalertinib has shown preclinical activity against a wide spectrum of EGFR ex20ins mutations and other uncommon EGFR mutations. In a phase 1/2a study (REZILIENT1), encouraging antitumor activity and an acceptable safety profile were observed in heavily pretreated patients with EGFRex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation from the U.S. Food and Drug Administration. The aim of REZILIENT2 is to evaluate the efficacy and safety of zipalertinib in patients with NSCLC harboring EGFRex20ins and other uncommon single or compound EGFR mutations, including patients with brain metastases and leptomeningeal disease (LMD). Methods: In this global, phase 2b, open-label, multicohort study (NCT05967689), adult patients with locally advanced or metastatic NSCLC will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation: A) patients with EGFR ex20ins mutations who have progressed on or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins (administered together or separately) for advanced disease; B) patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease; C) patients with ex20ins or other uncommon single or compound EGFR mutations and active central nervous system metastases (including LMD) who may or may not have received prior treatment for advanced disease; and D) patients harboring other uncommon non-ex20ins single or compound EGFR mutations who have progressed on or after standard systemic therapy. Patients will receive zipalertinib at a starting dose of 100 mg orally twice daily, which will continue on a 21-day cycle until progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumours, version 1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (cohort C), safety and tolerability, and pharmacokinetics. Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023. Clinical trial information: NCT05967689 .

First-line treatment of EGFR mutation adenosquamous carcinoma of the lung with aumolertinib: A multicenter, single-arm, prospective study (ARISE Study).

e20541 Background: Adenosquamous carcinoma of the lung (ASC), which composed of squamous cell carcinoma and adenocarcinoma, is a rare lung cancer. In Asian population, the mutation rate of epidermal growth factor receptor (EGFR) in ASC is approximately 15.4% to 44%. There were no large prospective clinical studies using EGFR tyrosine kinase inhibitors (TKI) to treat ASC. Methods: We conducted a prospective, multicenter, single-arm clinical trial, designed to evaluate the efficacy and safety of Aumolertinib for ASC patients with EGFR mutations without prior systemic therapy (originally designed as a randomized controlled study versus chemotherapy; the protocol was revised to single-arm study due to insufficient enrollment; Clinical Trial Registry No. NCT04354961). Eligible participants of stage IIIB/IV ASC with EGFR mutations from six Chinese medical centers received Aumolertinib 110mg orally once daily. Follow-up were performed every 6 weeks conducted by independent central review (ICR), based on the RECIST 1.1 criteria. Primary endpoints was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: Of the 18 patients recruited, 12 were evaluated for efficacy and safety. The median follow-up was 13.3 months, with 17 (range 4-26) doses of Aumolertinib treatment. The median PFS was 6.2 months (95% CI 5.0-8.2), while the median OS has not been reached. Of the 12 patients, 7 (58.3%) achieved PR, 3 (25.0%) achieved SD, and 2 (16.7%) were PD. The ICR-confirmed ORR and DCR were 58.3% (95% CI: 62.6%-74.6%) and 83.3% (95% CI: 89.6%-96.2%), respectively. A total of 9 patients (75%) experienced at least one treatment-related adverse events (TRAEs). the most common TRAEs were anemia (27.3%) and elevated aminotransferase (18.2%). three patients (25%) experienced grade 3-4 TRAEs in the form of paralysis, neutropenia and hypokalemia. No treatment-related deaths occurred. Conclusions: This is the first prospective clinical study showing that Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for ASC with EGFR mutations, with favorable ORR and general PFS. In future, head-to-head comparisons of EGFR TKI with chemotherapy and combination therapy would be needed to be explored. Clinical trial information: NCT04354961 .

Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.

3143 Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify &gt;20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.

Cancer mutational signatures identification in clinical assays using neural embedding-based representations

While mutational signatures provide a plethora of prognostic and therapeutic insights, their application in clinical-setting, targeted gene panels is extremely limited. We develop a mutational representation model (which learns and embeds specific mutation signature connections) that enables prediction of dominant signatures with only a few mutations. We predict the dominant signatures across more than 60,000 tumors with gene panels, delineating their landscape across different cancers. Dominant signature predictions in gene panels are of clinical importance. These included UV, tobacco, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures that are associated with better survival, independently from mutational burden. Further analyses reveal gene and mutation associations with signatures, such as SBS5 with TP53 and APOBEC with FGFR3S249C. In a clinical use case, APOBEC signature is a robust and specific predictor for resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Our model provides an easy-to-use way to detect signatures in clinical setting assays with many possible clinical implications for an unprecedented number of cancer patients.

Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p=0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p=0.048] and OS [HR 3.62(1.60-8.17), p=0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.