Sensitive Mutant Research Articles

Prognosticators of osimertinib treatment outcomes in patients with EGFR-mutant non-small cell lung cancer and leptomeningeal metastasis.

Leptomeningeal metastasis (LM) is a serious complication of non-small cell lung cancer (NSCLC), particularly in patients with EGFR mutations. In this study, we investigated the survival outcomes of patients with EGFR-mutant NSCLC who have developed LM and explored the factors associated with their survival. From April 2018 to November 2021, patients with EGFR-mutant NSCLC who underwent cerebrospinal fluid (CSF) sampling under the clinical suspicion of LM were enrolled. The patients' clinicodemographic characteristics, treatment history including whole-brain radiation therapy (WBRT), overall survival (OS), and intracranial progression-free survival (icPFS) were measured. EGFR mutations in cell-free tumor DNA (ctDNA) of CSF, including T790M mutation, were analyzed. We enrolled 62 patients with NSCLC. The median time form diagnosis to LM was 23.1months and 16 (25.8%) patients had history of prior third-generation EGFR-TKI use. EGFR mutation in CSF ctDNA was detected in 53 patients (85.5%); of them, 10 (16.1%) had T790M mutation. The patients' icPFS and OS after osimertinib were 6.43 and 9.37months, respectively, and were comparable among patients with different sensitive EGFR mutations, indicating that EGFR mutation status did not affect osimertinib efficacy. Patients who received WBRT after LM had numerically higher icPFS and OS compared to those without. Multivariate analysis revealed that lack of prior exposure to third-generation EGFR-TKI was associated with better OS. Osimertinib is effective in patients with EGFR-mutant NSCLC who developed LM and prior third-generation EGFR-TKI use was associated with poor survival in these patients. The role of WBRT warrants further investigation.

380P Survival outcome and cost-effectiveness of tyrosine kinase inhibitor in EGFR sensitive mutation advanced-stage NSCLC in Thammasat university hospital

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first-line treatment of advanced-stage NSCLC with EGFR-sensitive mutation. We aimed to determine the efficacy and cost-effectiveness of each EGFR-TKI.

299P Furmonertinib as adjuvant therapy in EGFR-mutated non-small cell lung cancer following radical lung cancer surgery

Furmonertinib (AST2818) is a novel promising third-generation EGFR tyrosine kinase inhibitor (TKI) that targets both EGFR sensitive mutations and T790M mutation. Furmonertinib has shown encouraging efficacy and good tolerability in advanced Non–Small-Cell Lung Cancer (NSCLC) in previous clinical trials, especially in patients with CNS metastasis. Here, we investigated the efficacy and safety of furmonertinib as adjuvant therapy in postoperative EGFR-mutated NSCLC patients.

Quality of life assessment on non-small cell lung cancer patients treated by molecular targeted therapy

Introduction: Lung cancer is the leading cause of cancer death worldwide and in Vietnam. Among lung cancer cases, non-small cell lung cancer (NSCLC) accounts for approximately 85%. Most patients are diagnosed at the advanced stage, hence systemic therapy plays a crucial role to increase survival time. Targeted therapy is now the standard of care for NSCLC with TKIs sensitive mutations because of its efficacy and tolerability. The study of QoL in these groups of patients remains limited in Vietnam. Objectives: To evaluate the quality of life in patients with non-small cell lung cancer (NSCLC) being treated by targeted therapy and to determine the factors that affect the quality of life (QOL). Methodology: A descriptive study was conducted on 55 non-small cell lung cancer patients being treated at the Hue Central Hospital and the Hue University of Medicine and Pharmacy Hospital from 6/2021 to 8/2022. The EORTC QLQ-C30 was used to assess the quality of life. Evaluation of the quality of life by descriptive statistics. The linear regression test was used to determine the correlated factor. Results: The mean age of the group of patients was 66.6 ± 9.9. The global health scale was 55.8 ± 12.6 which was found to be related to the level of depression DASS21 (p < 0.01). In the functional scale, the cognitive function had the highest score (84.2 ± 14.8), and the lowest was social function items (42.4 ± 18.9). The function score was found to be correlated to the disease duration (p < 0.05) and DASS21 (p < 0.01) Less common symptoms were constipation and nausea. The most prominent symptoms were loss of appetite and fatigue. The symptom score was related to the disease duration (p = 0.02) and DASS21 (p < 0.01). In terms of financial impact, the mean score was 41.2 (± 38.5), related to the residence (p = 0.04), occupation (p = 0.04), and economic condition (p = 0.01). Conclusion: The global health QoL score was quite high in NSCLC patients treated with molecular targeted therapy. The residence, occupation, economic conditions, duration of illness, and DASS21 were associated with the QoL of patients. Key words: non-small cell lung cancer, quality of life, molecular targeted therapy, EORTC QLQ_C30, advanced stage.

Picropodophyllotoxin Inhibits Cell Growth and Induces Apoptosis in Gefitinib-Resistant Non-Small Lung Cancer Cells by Dual-Targeting EGFR and MET.

Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resistance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunction, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.

The Optimal Intervention Timing of Thoracic Radiotherapy in Patients with Late-Staged EGFR Mutant Lung Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Studies confirmed that thoracic radiotherapy combined with EGFR-TKIs (Epidermal Growth Factor Receptor -Tyrosine Kinase Inhibitors, EGFR-TKIs) can improve the prognosis of advanced non-small cell lung cancer patients with EGFR sensitive mutations. However, the optimal timing of radiotherapy intervention still needs to be clarified. This study aimed to investigate the effect of thoracic radiotherapy intervention on the prognosis of patients at different time points in the process of targeted therapy by analyzing the related clinical cases to provide evidence for determining the optimal therapy regimen of thoracic radiotherapy combined with EGFR TKIs. <h3>Materials/Methods</h3> Patients with EGFR mutant lung adenocarcinoma who received thoracic radiotherapy between March 2008 and June 2021 were included in present study. According to the intervention timing of thoracic radiotherapy during the course of targeted therapy, the patients were divided into two groups: radiotherapy before drug resistance and radiotherapy after drug resistance. Medical data were analyzed for thoracic progression-free survival (TPFS) and overall survival (OS). Survival curve for the two groups were determined using the Kaplan-Meier method. The hazard ratios were reported as relative risks with their corresponding 95% confidence intervals (CIs). <i>P</i> <0.05 was considered statistically significant. <h3>Results</h3> A total of 126 patients met the inclusion criteria in this retrospective study. 61 and 65 patients were divided in the groups of thoracic radiotherapy before drug resistance and after drug resistance respectively. The median TPFS and OS of the entire cohort were 16 months and 42.1 months. The median TPFS of patients with radiotherapy before EGFR-TKIs resistance was significantly longer than that of patients in another group (33.9 months vs 10.8 months, hazard ratio: 3.231, 95% confidence interval: 2.131–4.899, <i>P</i><0.05). The median OS of patients in thoracic radiotherapy before and after drug resistance groups were 53.3 and 34.4 months respectively (hazard ratio: 1.549, 95% confidence interval: 1.022–2.349, <i>P</i><0.05). <h3>Conclusion</h3> The early application of thoracic radiotherapy for the primary lesion may improve the survival of patients with advanced EGFR mutant lung adenocarcinoma.

Basement-Membrane-Related Gene Signature Predicts Prognosis in WHO Grade II/III Gliomas.

Gliomas that are classified as grade II or grade III lesions by the World Health Organization (WHO) are highly aggressive, and some may develop into glioblastomas within a short period, thus portending the conferral of a poor prognosis for patients. Previous studies have implicated basement membrane (BM)-related genes in glioma development. In this study, we constructed a prognostic model for WHO grade II/III gliomas in accordance with the risk scores of BM-related genes. Differentially expressed genes (DEGs) in the glioma samples relative to normal samples were screened from the GEO database, and five prognostically relevant BM-related genes, including NELL2, UNC5A, TNC, CSPG4, and SMOC1, were selected using Cox regression analyses for the risk score model. The median risk score was calculated, based on which high- and low-risk groups of patients were generated. The clinical information, pathological information, and risk group were combined to establish a prognostic nomogram. Both the nomogram and risk score model performed well in the independent CGGA cohort. Gene set enrichment analysis (GSEA) and immune profile, drug sensitivity, and tumor mutation burden (TMB) analyses were performed in the two risk groups. A significant enrichment of ‘Autophagy–other’, ‘Collecting duct acid secretion’, ‘Glycosphingolipid biosynthesis–lacto and neolacto series’, ‘Valine, leucine, and isoleucine degradation’, ‘Vibrio cholerae infection’, and other pathways were observed for patients with high risk. In addition, higher proportions of monocytes and resting CD4 memory T cells were observed in the low- and high-risk groups, respectively. In conclusion, the BM-related gene risk score model can guide the clinical management of WHO grade II and III gliomas.

Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy.

BackgroundFew treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients.MethodsNSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan−Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors.ResultsA total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy.ConclusionsOur results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed.

Efficacy Differences of First-line EGFR-TKIs Alone vs in Combination with Chemotherapy in Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutation and Concomitant Non-EGFR Genetic Alterations.

Background and objectiveEpidermal growth factor receptor (EGFR) mutations are often associated with non-EGFR genetic alterations, which may be a reason for the poor efficacy of EGFR tyrosine kinase inhibitors (TKIs). Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Materials and methodsCases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant non-EGFR genetic alterations were retrospectively collected. And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy. Demographic, clinical and pathological data were collected, and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression. Survival data were obtained through face-to-face or telephone follow-up. The differences between the two groups in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were investigated.Results107 patients were included, including 63 cases in the combination group and 44 cases in the monotherapy group. The ORR were 78% and 50% (P=0.003), and DCR were 97% and 77% (P=0.002), respectively. At a median follow-up of 13.7 mon, a PFS event occurred in 38.1% and 81.8% of patients in the two groups, with median PFS of 18.8 mon and 5.3 mon, respectively (P < 0.000, 1). Median OS was unreached in the combination group, and 27.8 mon in the monotherapy group (P=0.31). According to the Cox multivariate regression analysis, combination therapy was an independent prognostic factor of PFS.ConclusionIn patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations, combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy, which should be the preferred treatment option.

The efficacy of immune checkpoint inhibitors in advanced EGFR-Mutated non-small cell lung cancer after resistance to EGFR-TKIs: Real-World evidence from a multicenter retrospective study.

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting.Patients and methodsWe collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients’ objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed.ResultsThe ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009).ConclusionsOur study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.

948TiP Efficacy and safety of almonertinib in the adjuvant treatment of resectable stage I non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-sensitizing mutations in solid and/or micropapillary components

Pathological subtypes are prognostic indicators independent of TNM stage, and patients with micropapillary and solid components have poorer prognosis. Previous studies have found that the presence of a micropapillary component was significantly associated with worse recurrence-free survival in patients with stage I lung adenocarcinoma, even the components are less than 5%, and postoperative adjuvant chemotherapy can still bring benefit to those patients even with stage IA. Third-generation EGFR-TKI have recently shown striking benefit for postoperative adjuvant therapy in patients with EGFR-mutated NSCLC. At present, there is no systematic study on the efficacy and safety of third-generation EGFR-TKI in stage I NSCLC patients with high-risk recurrence factors, such as solid and micropapillarycomponents. The third-generation EGFR-TKI, aumolertinib(HS-10296), showed promising efficacy in advanced NSCLC patients with sensitive EGFR mutation. This is the first study to explore the efficacy and safety of aumolertinib as adjuvant therapy in patients with EGFR mutant stage I NSCLC with solid and/or micropapillary component. Approximately 52 stage I EGFR-mutated NSCLC patients with solid and/or micropapillary components ≥10% will be enrolled in this multicenter single-arm study. After radical lung cancer surgery, they will receive oral almonertinib 110 mg/d as adjuvant therapy for 3 years. The primary endpoint is 2-year disease free survival (DFS) rates, and secondary endpoints included the 3-, 4-, and 5-year DFS rates, 5-year overall survival rates, safety and quality of life, Circulating tumor DNA will also be monitored during the study. Recruitment of this study is ongoing, and the first patient had been enrolled in January 2022. The author.

EP08.02-001 Concurrent Aumolertinib and Cerebral Radiotherapy as First-Line Treatment for EGFR Mutated Non-small Cell Lung Cancer with Brain Metastases

Patients with non-small cell lung cancer (NSCLC) are accompanied by 25%-40% brain metastases, who have a dismal prognosis and quality of life. The current therapeutic regimens for the treatment of brain metastases are poor efficacy. Currently, brain metastasis of epidermal growth factor receptor (EGFR) sensitive mutations is a hot and difficult point in targeted era of NSCLC treatment, meanwhile it is also the central issue of controversy in the field of lung cancer treatment. EGFR-TKIs is recently shown to be a potential treatment option for brain metastases of NSCLC patients.

EP08.02-067 Concurrent Aumolertinib Plus Icotinib for First-Line Treatment of EGFR Mutated Non-small Cell Lung Cancer with Brain Metastases

Brain metastases are associated with significant morbidity and are found in up to 50% of patients with advanced non-small cell lung cancer (NSCLC), and seriously affect the prognosis of lung cancer patients. Currently, brain metastasis of epidermal growth factor receptor (EGFR) sensitive mutations is a hot and difficult point in targeted era of NSCLC treatment, meanwhile it is also the central issue of controversy in the field of lung cancer treatment. Additionally, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been recommended as standard therapy for asymptomatic NSCLC patients with EGFR mutations with brain metastases.

1188TiP ORCHARD platform study: Osimertinib + datopotamab deruxtecan (Dato-DXd) cohort in patients (pts) with advanced NSCLC (aNSCLC) who have progressed on first-line (1L) osimertinib

Osimertinib, a third-generation, irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M resistance mutations, with demonstrated efficacy in EGFRm NSCLC, including CNS metastases. Osimertinib is the preferred 1L treatment in EGFRm a NSCLC, with significant improvements in progression-free survival/overall survival vs comparators; however, pts may eventually develop disease progression. ORCHARD (NCT03944772) aims to identify mechanisms of resistance to 1L osimertinib and explore novel therapeutic options by allocating pts to biomarker/non-biomarker directed cohorts based on tumour molecular profile. Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC. Dato-DXd is a TROP2-directed antibody conjugated to a topoisomerase I inhibitor via a tumour-selective cleavable linker that has encouraging antitumour activity in a NSCLC. A new ORCHARD cohort will evaluate osimertinib + Dato-DXd in pts without identifiable, actionable resistance mechanisms. In the open-label, multicentre, multidrug, biomarker-directed, Phase II platform ORCHARD study, pts with EGFRm aNSCLC with progression on 1L osimertinib are allocated to treatment. Pts without a biomarker match (ALK, RET, BRAF) may enrol to receive oral osimertinib 80 mg once daily + intravenous Dato-DXd 4 mg/kg every 3 weeks (Q3W). If no dose-limiting toxicities occur in the first 3–4 pts, pts may enrol to receive osimertinib + 6mg/kg Dato-DXd. Safety/tolerability data will inform expansion of the 4 or 6 mg/kg Dato-DXd + osimertinib cohort to ∼16 pts. Tumour assessments (RECIST 1.1) will be performed Q6W for the first 24 weeks, then Q9W until disease progression. Primary outcome: investigator-assessed confirmed objective response rate. Secondary outcomes include safety/tolerability, duration of response, and pharmacokinetics; exploratory outcomes include change in tumour burden using circulating tumour DNA in plasma, and tumour/plasma biomarker analyses and their correlation with treatment effect. NCT03944772, 10 May 2019. The authors would like to acknowledge Bernadette Tynan, MSc, of Ashfield MedComms, Macclesfield, UK, part of UDG Healthcare for medical writing support that was funded by AstraZeneca. AstraZeneca.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001. We report updated exploratory analyses of DFS and recurrence patterns after 2 yrs added follow up. Eligible pts (aged ≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1, completely resected EGFRm stage IBꟷIIIA [AJCC 7th edition] NSCLC; adjuvant CT allowed) were randomised 1:1 to osimertinib 80 mg once daily or PBO for up to 3 yrs. Primary endpoint: investigator-assessed DFS in stage IIꟷIIIA. Secondary endpoints: DFS in stage IBꟷIIIA, overall survival and safety. Patterns of recurrence and CNS DFS were pre-specified exploratory endpoints. Data cut-off: 11 April 2022. Globally, 682 pts were randomised; osimertinib n=339, PBO n=343. In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO. CNS DFS HR was 0.24 (95% CI 0.14, 0.42; 63/470 events) in stage IIꟷIIIA. The long-term safety profile remains consistent with the known profile of osimertinib. With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

EP16.03-006 Genetic Characteristics of EGFR Concurrent Variants with RB1 and TP53 in NCSLC Patients

EGFR-TKIs (tyrosine kinase inhibitor) can effectively improve the survival rate of NSCLC patients with EGFR sensitive mutations. However, concomitant alterations along with EGFR mutations often affect the effect of EGFR-TKIs. The genome characteristic of EGFR co-mutation is of great significance for guiding clinical treatment. In this study, we first reported the genetic characteristics of EGFR/RB1/TP53 co-variation in the Chinese non-small cell lung cancer (NSCLC) cohort.

952P Effect of thoracic radiotherapy timing on prognosis for patients with late-staged lung adenocarcinoma harboring EGFR mutations

Studies confirmed that thoracic radiotherapy combined with EGFR-TKIs (EGFR-tyrosine kinase inhibitors, EGFR-TKIs) can improve the prognosis of advanced lung adenocarcinoma patients with EGFR sensitive mutations. However, the optimal timing of radiotherapy intervention still needs to be clarified. This study aimed to investigate the effect of thoracic radiotherapy intervention on the prognosis of patients at different time points in the process of targeted therapy by analyzing the related clinical cases to provide evidence for determining the optimal therapy regimen of thoracic radiotherapy combined with EGFR TKIs. Patients with EGFR mutant lung adenocarcinoma who received thoracic radiotherapy were included in present study. According to the timing of thoracic radiotherapy in the process of targeted therapy, the patients were divided into two groups: radiotherapy before drug resistance and radiotherapy after drug resistance. Medical data were analyzed for overall survival (OS) and thoracic progression-free survival (TPFS). Survival curve for the two groups were determined using the Kaplan-Meier method. the hazard ratios were reported as relative risks with their corresponding 95% confidence intervals (CIs). P <0.05 was considered statistically significant. A total of 129 patients met the inclusion criteria in this retrospective study, 66 and 63 patients respectively included in the groups of thoracic radiotherapy before drug resistance and after drug resistance. The median TPFS and OS of the entire cohort were 16.1 months and 42.1 months. The median OS of patients in thoracic radiotherapy before and after drug resistance groups were 52 and 34.5 months respectively (hazard ratio: 1.507, 95% confidence interval: 1.004–2.264, P<0.05). The median TPFS of patients with radiotherapy before EGFR-TKIs resistance was significantly longer than that of patients in another group (33.1 months vs 10.4 months, hazard ratio: 3.183, 95% confidence interval: 2.119–4.780, P<0.0001). The early application of thoracic radiotherapy, at least until EGFR-TKIs resistance, for the primary lesion may improve the survival of patients with advanced EGFR mutant lung adenocarcinoma.

EP08.02-095 Successful Treatment of EGFR Exon 19 Deletion with TP53 and ERBB2 20ins Mutation in Stage IVB NSCLC Patient with Aumolertinib

Based on BENEFIT study, EGFR sensitive mutation NSCLC patients could benefit from first-line EGFR-TKI treatment regardless of combination with tumor suppressor or driver gene mutation. However, for patients combined with both tumor suppressor and driver gene mutations, it is still an unresolved challenge for clinical practice. Herein, we reported a case happened to be this intractable situation.

EP08.02-169 Research of Aumolertinib Combined with Bevacizumab for Advanced NSCLC Lung Cancer with EGFR Sensitive Mutation

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR-TKI with proved efficiency and safety for untreated NSCLC patients with EGFR sensitizing mutations in China. The efficacy of the combination of first-generation EGFR-TKI and bevacizumab was confirmed by NEJ026, JO25567 ARTEMIS studies, but the effect of 3rd generation TKI plus bevacizumab is still under debate. This study was conducted to evaluate aumolertinib plus bevacizumab for untreated NS-NSCLC patients with EGFR sensitizing mutations.

1034P A phase II study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed prior EFGR-TKIs

KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. In the phase II study, promising anti-tumor activity was seen with KN046 in subjects with non-small cell lung cancer (NSCLC). Here, we reported the efficacy and safety results of KN046 combined with chemotherapy in treatment of advanced NSCLC with EGFR sensitivity mutation who failed prior tyrosine kinase inhibitors (TKIs) from Cohort D in this study.