EGFR-mutant Patients Research Articles

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

Pericytes Modulate Third-Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR-Mutated Lung Cancer Cells Through IL32-β5-Integrin Paracrine Signaling.

EGFR-mutated lung cancer patients sometimes display restricted responses to third-generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR-mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single-cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32-expressing pericytes closely interacting with β5-integrin-expressing cancer cells in EGFR-mutated patients, impacting therapeutic response and prognosis. Co-culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR-mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5-integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5-integrin-Src-Akt pathway in EGFR-mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co-injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5-integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32-β5-integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR-mutated patients.

Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study

IntroductionMany clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms. MethodsEGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30–40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. ResultsBetween January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2–22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease. ConclusionsSelected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.

EP.01D.02 Heterogeneous Germline Variants Detected in EGFR-Mutant Familial Lung Cancer Patients and Family Members

EP.01D.02 Heterogeneous Germline Variants Detected in EGFR-Mutant Familial Lung Cancer Patients and Family Members

EP.12A.46 Age, Health Utility Scores (HUS), and Survival Outcomes in EGFR-Mutated Lung Cancer Patients Receiving 1L TKI Treatment

EP.12A.46 Age, Health Utility Scores (HUS), and Survival Outcomes in EGFR-Mutated Lung Cancer Patients Receiving 1L TKI Treatment

EP.12A.10 Multi-Omics Uncovers Signatures Associated with Resistance to Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer Patients

EP.12A.10 Multi-Omics Uncovers Signatures Associated with Resistance to Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer Patients

P2.07A.04 Clinical Relevance of PD-L1 Expression Levels in Surgically Resected EGFR-Mutant Lung Adenocarcinoma Patients (CReGYT-01 Study)

P2.07A.04 Clinical Relevance of PD-L1 Expression Levels in Surgically Resected EGFR-Mutant Lung Adenocarcinoma Patients (CReGYT-01 Study)

P3.03H.04 Molecular and Clonal Evolution of Primary Lesions vs Brain Metastasis and Progressive Disease of EGFR Mutated Patients

P3.03H.04 Molecular and Clonal Evolution of Primary Lesions vs Brain Metastasis and Progressive Disease of EGFR Mutated Patients

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

BackgroundMicropapillary (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 methodsWe 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.ResultsOverall, 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.ConclusionMPP 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.

Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer

In EGFR-mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including BCL-2 and IAP family members, using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR-mutated lung cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR-mutated lung cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1/BCL-XL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1/BCL-XL expression is important for tumor cell survival as EGFR-TKI resistance emerges.

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.

EGFR Mutation and TKI Treatment Promote Secretion of Small Extracellular Vesicle PD-L1 and Contribute to Immunosuppression in NSCLC.

In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8+ T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8+ T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR-mutant patients and patients who have received TKI treatment.

Ileal perforation at the site of peritoneal metastasis with intestinal infiltration by dual EGFR-VEGF pathway inhibition in an EGFR-mutant non-small cell lung cancer patient.

Gastrointestinal (GI) perforation including ileal perforation is a rare complication of antivascular endothelial growth factor (anti-VEGF) therapy. Risk factors of GI perforation have not been fully understood. This report highlights the case of a patient who experienced GI perforation at the site of peritoneal metastasis with intestinal infiltration immediately after treatment with dual epidermal growth factor receptor (EGFR)-VEGF pathway inhibition agents for EGFR-mutant non-small cell lung cancer (NSCLC). The administration of dual EGFR-VEGF pathway inhibition agents in EGFR mutant NSCLC patients appears to elevate the risk of GI perforation. This report provides insights into the association between EGFR mutant NSCLC and the susceptibility to GI perforation following treatment with dual EGFR-VEGF pathway inhibition agents.

Heterogeneity in PD-L1 expression between primary and metastatic lymph nodes: a predictor of EGFR-TKI therapy response in non-small cell lung cancer

BackgroundThere is inconclusive evidence to suggest that the expression of programmed cell death ligand 1 (PD-L1) is a putative predictor of response to EGFR-TKI therapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC). We evaluated the heterogeneity in PD-L1 expression in the primary lung site and metastatic lymph nodes to analyze the association between PD-L1 expression and response for patients treated with EGFR-TKI.MethodsThis study reviewed 184 advanced NSCLC patients with EGFR mutations who received first-generation EGFR-TKI as first-line treatment from 2020 to 2021 at Shanghai Chest Hospital. The patients were divided into the primary lung site group (n = 100) and the metastatic lymph nodes group (n = 84) according to the biopsy site. The patients in each group were divided into TPS < 1%, TPS 1–49%, and TPS ≥ 50% groups according to PD-L1 expression.ResultsThe median PFS was 7 (95% CI: 5.7–8.3) months, and the median OS was 26 (95% CI: 23.5–28.5) months for all patients. No correlation existed between PFS or OS and PD-L1 expression. The median PFS in the primary lung site group was 11 months (95% CI: 9.6–12.4) in the TPS < 1% group, 8 months (95% CI: 6.6–9.4) in TPS 1–49% group, and 4 months (95% CI: 3.2–4.8) in TPS ≥ 50% group, with statistically significant differences (p = 0.000). The median OS of the TPS < 1% group and TPS ≥ 50% group showed a statistically significant difference (p = 0.008) in the primary lung site group. In contrast, PD-L1 expression in the lymph nodes of EGFR-mutant patients was unrelated to PFS or OS after EGFR-TKI therapy.ConclusionPD-L1 expression from the primary lung site might predict clinical benefit from EGFR-TKI, whereas PD-L1 from metastatic lymph nodes did not.Trial registration: This retrospective study was approved by the Ethics Committee of Shanghai Chest Hospital (ID: IS23060) and performed following the Helsinki Declaration of 1964 (revised 2008).

Prevalence of EGFR Mutations in Patients With Resected Stages I to III NSCLC: Results From the EARLY-EGFR Study

IntroductionThere is limited literature on the prevalence of EGFR mutations in early stage NSCLC. EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early stage NSCLC. MethodsThis noninterventional, real-world study enrolled consecutive patients with resected stages IA to IIIB (American Joint Committee on Cancer eighth edition) NSCLC from 14 countries across Asia, Latin America, and the Middle East and Africa. The primary end point was prevalence of EGFR mutations and secondary end points included prevalence of EGFR mutation subtypes and treatment patterns. ResultsOf 601 patients (median [range] age: 62.0 [30.0–86.0] y) enrolled, 52.7% were females and 64.2% were nonsmokers. Most had stages IA to IB NSCLC (64.1%) and adenocarcinoma (98.7%). Overall prevalence of EGFR mutations was 51.0%; most reported exon 19 deletions (48.5%) followed by exon 21 L858R mutations (34.0%). Women had a higher EGFR mutation rate than men (64.0% versus 36.4%). Compared with no EGFR mutations, patients with EGFR mutations were more likely to be nonsmokers (35.1% versus 60.9%) and have stage I NSCLC than stages II and III NSCLC (54.8% versus 47.3% and 35.6%). Systemic adjuvant therapy was planned in 33.8% of the patients with stages IB to IIIB disease and adjuvant chemoradiotherapy in 6.8%. Age above or equal to 60 years, females, and Asians were found to have a significantly (p < 0.05) higher odds of EGFR mutations, whereas smoking history and stage III disease had lower odds of EGFR mutations. ConclusionsThe EARLY-EGFR study provides an overview of EGFR mutations and subtype prevalence in patients with early stage NSCLC. The study highlights the limited adherence to treatment guidelines suggesting an unmet need for improved adjuvant therapy.

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.

Comparing the efficacy of two generations of EGFR-TKIs: An integrated drug-disease mechanistic model approach in EGFR-mutant lung adenocarcinoma.

e20578 Background: The epidermal growth factor receptor (EGFR) is frequently mutated in patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) targeting EGFR have been developed. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. Methods: We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, two EGFR TKIs, to accurately simulate the drugs' distribution within the primary tumor and metastatic sites following administration. These models were integrated with a mechanistic model of EGFR-mutant LUAD, enabling the representation of the mechanism of action of gefitinib and osimertinib. This model outputs the evolutions of the primary tumor and each metastasis, facilitating the evaluation of patient progression following RECIST criteria. Notably, the model encapsulates the heterogeneity within the tumor, representing various subclones defined by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002, FLAURA and AURA3 clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. Results: The model adeptly replicated the time to progression in EGFR-mutant LUAD patients receiving gefitinib or osimertinib, whether as first-line or second-line therapy. Furthermore, it accurately mirrored the progression causes as per the RECIST criteria, including the emergence of new metastases in the lung, brain, liver, and bone. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. Conclusions: The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a promising tool for deriving pertinent insights and informing treatment strategies. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the requisite patient cohort size in such trials, optimizing resource utilization.

Identification of Potential Biomarkers of EGFR Mutation in Pleural Effusion of Non-Small Cell Lung Cancer Patients Based on Metabolomics.

Malignant pleural effusion (MPE) is a common complication of non-small cell lung cancer (NSCLC). Patients with NSCLC exhibit a high rate of epidermal growth factor receptor (EGFR) mutations. The detection of EGFR mutations is usually time-consuming and costly. This study aimed at identifying potential biomarkers of EGFR mutations in MPE of NSCLC patients by metabolomics. In total, 58 MPE samples from 30 EGFR mutant and from 28 wild-type NSCLC patients were collected and analyzed by using hydrogen nuclear magnetic resonance (1H NMR) based metabolomics and UPLC-MS/MS based amino acid analysis. Our 1H NMR study showed a significant increase in the lysine levels but a significant decrease in the alanine levels in MPE of NSCLC patients with EGFR-mutant. Twelve amino acids in MPE were further determined by UPLC-MS/MS. It showed that alanine in MPE (6.34 ± 1.88 vs. 8.73 ± 3.68) were significantly decreased and leucine (3.13 ± 0.57 vs. 2.22 ± 0.13), lysine (2.19 ± 0.50 vs. 1.53 ± 0.40), and tyrosine (2.69 ± 0.71 vs. 1.89 ± 0.46) were increased in the EGFR mutation group; leucine (2.19 ± 0.50 vs. 1.53 ± 0.40), methionine (2.19 ± 0.50 vs. 1.53 ± 0.40), and threonine (2.19 ± 0.50 vs. 1.53 ± 0.40) in MPE were significantly lower in the EGRF 19 mutation compared with 21 mutation patients. The area under the receiver operating characteristic curve of 0.851 and 0.931 would be achieved by the logistic model for classification of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients. Amino acids in MPE are significantly altered and helpful in the diagnosis of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients with high accuracy, which is worthy of further study.

The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study

BackgroundEffective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy.MethodsA total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR).ResultsThe median follow-up period was 28.6 months (range: 2.3–54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2–7.4 months), and the median OS was 17.1 months (95% CI 12.0–22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1–2, and no increase in adverse events was observed compared to monotherapy.ConclusionAnlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

Concomitant ALK translocation and EGFR C797S mutation as resistance mechanisms to osimertinib in an EGFR-mutant NSCLC patient

Concomitant ALK translocation and EGFR C797S mutation as resistance mechanisms to osimertinib in an EGFR-mutant NSCLC patient