CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer / 医学前沿

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Lnc-TMEM132D-AS1 overexpression reduces sensitivity of non-small cell lung cancer cells to osimertinib / 南方医科大学学报

OBJECTIVE@#To screen the differentially expressed long non-coding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) cells with acquired resistance to osimertinib and explore their roles in drug resistance of the cells.@*METHODS@#The cell lines H1975_OR and HCC827_OR with acquired osimertinib resistance were derived from their osimertinib-sensitive parental NSCLC cell lines H1975 and HCC827, respectively, and their sensitivity to osimertinib was assessed with CCK-8 assay, clone formation assay and flow cytometry. RNA sequencing (RNA-seq) and real-time quantitative PCR (qPCR) were used to screen the differentially expressed lncRNAs in osimertinib-resistant cells. The role of the identified lncRNA in osimertinib resistance was explored using CCK-8, clone formation and Transwell assays, and its subcellular localization and downstream targets were analyzed by nucleoplasmic separation, bioinformatics analysis and qPCR.@*RESULTS@#The resistance index of H1975_OR and HCC827_OR cells to osimertinib was 598.70 and 428.82, respectively (P < 0.001), and the two cell lines showed significantly increased proliferation and colony-forming abilities with decreased apoptosis (P < 0.01). RNA-seq identified 34 differentially expressed lncRNAs in osimertinib-resistant cells, and among them lnc-TMEM132D-AS1 showed the highest increase of expression after acquired osimertinib resistance (P < 0.01). Analysis of the TCGA database suggested that the level of lnc-TMEM132D-AS1 was significantly higher in NSCLC than in adjacent tissues (P < 0.001), and its high expression was associated with a poor prognosis of the patients. In osimertinib-sensitive cells, overexpression of Lnc-TMEM132D-AS1 obviously promoted cell proliferation, colony formation and migration (P < 0.05), while Lnc-TMEM132D-AS1 knockdown partially restored osimertinib sensitivity of the resistant cells (P < 0.01). Lnc-TMEM132D-AS1 was localized mainly in the cytoplasm, and bioinformatics analysis suggested that hsa-miR-766-5p was its candidate target, and their expression levels were inversely correlated. The target mRNAs of hsa-miR-766-5p were mainly enriched in the Ras signaling pathway.@*CONCLUSION@#The expression of lnc-TMEM132D-AS1 is significantly upregulated in NSCLC cells with acquired osimertinib resistance, and may serve as a potential biomarker and therapeutic target for osimertinibresistant NSCLC.

Clinical efficacy of osimertinib and icotinib in first-line treatment of EGFR-positive metastatic NSCLC / 国际肿瘤学杂志

Objective:To investigate the real-world efficacy of osimertinib and icotinib in metastatic non-small cell lung carcinoma (NSCLC) patients.Methods:A retrospective analysis was performed on clinical data of 151 newly-diagnosed patients with epidermal growth factor receptor (EGFR) -positive advanced NSCLC in Renmin Hospital of Wuhan University from March 2018 to May 2022. The patients were divided into osimertinib group ( n=53) and icotinib group ( n=98) according to treatment method. The objective response rate (ORR) , disease control rate (DCR) , progression-free survival (PFS) and overall survival (OS) were compared between the two groups. The factors influencing prognosis were analyzed by using Cox regression models. Subgroup analysis was performed according to metastatic site and EGFR mutation type. Results:ORR was 56.6% (30/53) and 59.2% (58/98) for patients in the osimertinib group and icotinib group, respectively, with no statistically significant difference ( χ2=0.09, P=0.759) . DCR was 83.0% (44/53) and 91.8% (90/98) for patients in the osimertinib group and icotinib group, respectively, with no statistically significant difference ( χ2=2.68, P=0.102) . The median PFS was 11.7 months and 11.8 months for patients in the osimertinib group and icotinib group, respectively, with no statistically significant difference ( χ2=0.06, P=0.802) . The median OS was not reached for patients in both the osimertinib group and icotinib group, with no statistically significant difference ( χ2<0.01, P=0.969) . The results of multivariate analysis showed that adrenal metastases ( HR=1.89, 95% CI: 1.04-3.41, P=0.036) was an independent prognostic factor for PFS. Gender ( HR=2.22, 95% CI: 1.08-4.58, P=0.031) and adrenal metastases ( HR=4.87, 95% CI: 1.76-13.46, P=0.002) were independent prognostic factors for OS. The results of the subgroup analysis showed that in patients with pleural metastases (median PFS: 11.7 months vs. 9.3 months, median OS: not reached vs. not reached) , adrenal metastases (median PFS: 8.7 months vs. 5.6 months, median OS: 20.0 months vs. 15.3 months) , 19DEL mutations (median PFS: 14.5 months vs. 13.3 months, median OS: not reached vs. 40.7 months) , the osimertinib group tended to have better survival outcomes. Conversely, in patients with contralateral lung metastases (median PFS: 8.3 months vs. 11.2 months, median OS: not reached vs. 40.7 months) , bone metastases (median PFS: 11.7 months vs. 11.8 months, median OS: not reached vs. 34.5 months) , liver metastases (median PFS: 8.7 months vs. 9.1 months, median OS: not reached vs. 23.8 months) , brain metastases (median PFS: 11.7 months vs. 15.3 months, median OS: 22.4 months vs. 35.3 months) and 21L858R mutations (median PFS: 9.5 months vs. 10.0 months, median OS: 22.4 months vs. not reached) , the icotinib group tended to have better survival outcomes, but with no statistically significant differences (all P>0.05) . Conclusion:Both osimertinib and icotinib have good therapeutic efficacy in patients with EGFR-positive advanced NSCLC, thus can be used as first-line treatment options.

Osimertinibe comparado a Erlotinibe Gefitinibe ou quimioterapia para tratamento de carcinoma pulmonar de células não pequenas com mutação do gene do receptor do fator de crescimento epidérmico (EFGR): revisão rápida / Osimertinib compared to erlotinib, gefitinib or chemotherapy for the treatment of non-small cell pumonary carcinoma with epidermal growth factor receptor (EFGR) gene mutation: rapid review

Mesilato de osimertinibe, gefitinibe, erlotinibe, quimioterapia padrão. Indicação: Câncer de pulmão de células não pequenas com mutação do receptor do fator de crescimento epidérmico (EGFR). Pergunta: Mesilato de osimertinibe é mais eficaz e seguro que gefitinibe, erlotinibe ou quimioterapia para os desfechos de sobrevida global, sobrevida livre de progressão e de segurança no tratamento de carcinoma pulmonar de células não pequenas com mutação do EGFR? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED e EPISTEMONIKOS, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Resultados: Foram selecionadas duas revisões sistemáticas que atenderam aos critérios de elegibilidade. Conclusão: Mesilato de osimertinibe é mais eficaz do que gefitinibe ou erlotinibe na melhora da sobrevida global e da sobrevida livre de progressão em pacientes virgens de tratamento. Em pacientes previamente tratados, o mesilato de osimertinibe não é superior à quimioterapia padrão à base de platina no prolongamento da sobrevida global, mas é mais eficaz no aumento da sobrevida livre de progressão. Para câncer avançado, mesilato de osimertinibe não é mais eficaz do que a quimioterapia com ou sem pemetrexede para prolongar a sobrevida global, mas é mais eficaz em melhorar a sobrevida livre de progressão. Gefitinibe combinado com quimioterapia à base de pemetrexede foi superior à quimioterapia com ou sem pemetrexede na melhora da sobrevida global e da sobrevida livre de progressão

Osimertinib mesylate, gefitinib, erlotinib, standard chemotherapy. Indication: Non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. Question: Is osimertinib mesylate more effective and safer than gefitinib, erlotinib or chemotherapy for overall survival, progression-free survival and safety outcomes in the treatment of non-small cell lung cancer with EGFR mutation? Methods: A bibliographic search was done in the PUBMED and EPISTEMONIKOS database, following predefined search strategies. The methodological quality of systematic reviews was evaluated using the Assessing the Methodological Quality of Systematic Reviews Version 2 tool. Results: Two systematic reviews were selected because they met the eligibility criteria. Conclusion: Osimertinib mesylate is more effective than gefitinib or erlotinib in improving overall survival and progression-free survival in treatment-naive patients. In previously treated patients, osimertinib mesylate is not superior to standard platinum-based chemotherapy in prolonging overall survival, but it is more effective in increasing progression-free survival. For advanced cancer, osimertinib mesylate is not more effective than chemotherapy with or without pemetrexed in prolonging overall survival, but it is more effective in improving progression-free survival. Gefitinib combined with pemetrexed-based chemotherapy was superior to chemotherapy with or without pemetrexed in improving overall survival and progression-free survival

Case analysis of a patient with osimertinib-induced interstitial pneumonia who re-used EGFR-TKI therapy / 中国药房

OBJECTIVE To explore the way to re-use epidermal growth factor receptor-tyrosine kinase inhibitors （EGFR-TKI） in patients with EGFR-TKI-induced interstitial pneumonia （IP）， using osimertinib as an example. METHODS The IP treatment regimen and re-use of EGFR-TKI regimen in a patient who developed IP after the use of osimertinib were analyzed. And a literature review was made by combining the characteristics of the cases which reported in the literature and the characteristics of this case. RESULTS The patient’s IP symptoms due to treatment with osimertinib had resolved after treatment. The patient’s IP symptoms also did not worsen after using almonertinib in combination with hormones as re-use of EGFR-TKI regimen. However， almonertinib was discontinued as the patient experienced disease progression. The adverse reactions of IP needed to be dealt with in time， the EGFR-TKI should be discontinued and symptomatic treatment should be given. CONCLUSIONS EGFR-TKI targeted therapy could be re-selected by replacing EGFR-TKI， adjusting the dose of EGFR-TKI， and using hormones in combination. EGFR-TKI-induced adverse drug reactions of IP are rare， but need to be observed closely. If other EGFR-TKI is used， close monitoring of adverse reactions and curative effects are also required in order to adjust the patient’s treatment plan in time.

Relationship of EGFR-TKI Targeted Therapy and Pyroptosis in Non-small Cell Lung Cancer / 肿瘤防治研究

Objective To explore the relationship between pyroptosis and treatment in non-small cell lung cancer patients treated with tyrosine kinase inhibitors targeted therapy. Methods Stable transfection strains with common EGFR mutations found in clinical practice were constructed through lentiviral transfection. LDH and Western blot experiments were conducted to determine the degree and mechanism of pyroptosis after osimertinib treatment. Animal experiments verified the effect of pyroptosis on treatment efficacy. ELISA was used to explore the potential connection between pyroptosis and tumor immunotherapy. Results After osimertinib treatment on stable lines, the EGFR-L858R mutation had obvious pyroptosis at the morphology and protein levels. Western blot experiment confirmed that pyroptosis was mediated by GSDME (P < 0.0001). Experiments through the overexpression of GSDME and corresponding animal studies discovered that the degree of pyroptosis affected the treatment outcome. Blood analysis revealed that the level of IL-1β secreted by EGFR-L858R and EGFR-L858R-GSDME-OE mice after treatment was higher than that of the control group (P < 0.0001), and it may regulate tumor immunity to a certain extent. Conclusion Osimertinib can induce pyroptosis in EGFR-L858R mutant strains mediated by GSDME, and the level of pyroptosis in cell lines is positively correlated with therapeutic effect to a certain extent.

Ligustroflavone mediates the resistance of non-small cell lung cancer to osimertinib by arresting G1/S phase / 药学学报

Natural products are an important source for the development of antitumor lead compounds, but the pharmacological effects and regulatory mechanisms of natural products in osimertinib resistance in non-small cell lung cancer (NSCLC) are not well understood. The natural product ligustroflavone was used as the research object to analyze its efficacy in osimertinib-resistant NSCLC cells by cell proliferation assay and cell cycle detection. The potential targets of ligustroflavone in osimertinib-resistant NSCLC cells were screened by public databases and bioinformatics, molecular docking and microscale thermophoresis were used to identify the interaction between privet and target molecules. Western blot was used to detect the effect of privet on the target molecules and their downstream pathways. Ligustroflavone reduced the proliferation of osimertinib-resistant NSCLC cells, and could arrest the cell cycle. Cyclin-dependent kinase 6 (CDK6) was the potential target of ligustroflavone in osimertinib-resistant NSCLC cells. Ligustroflavone inhibited the activation of CDK6-Rb axis. Together, ligustroflavone could regulate osimertinib resistance in NSCLC cells by binding cell cyclin-related molecules. This study provides a theoretical basis for the targeted drug resistance of NSCLC with natural products, and also provides a new idea for the development of clinical drug combination.

Clinical observation on osimertinib combined with bevacizumab in treatment of advanced non-small cell lung cancer with epidermal growth factor receptor T790M positive / 肿瘤研究与临床

Objective:To explore the clinical effect of osimertinib combined with bevacizumab in treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) T790M positive.Methods:A prospective study was conducted on 83 EGFR T790M-positive advanced NSCLC patients who were admitted to Anhui Chest Hospital from April 2018 to December 2020. The patients were randomly divided into the observation group and the control group using random number table method. Among them, 41 cases in the control group were treated with osimertinib, while 42 cases in the observation group were treated with osimertinib combined with bevacizumab. The clinical efficacy, tumor markers [carcinoembryonic antigen (CEA), serum neuron specific enolase (NSE)] levels, tumor vascular associated protein factor (S100β protein) level and adverse reactions between the two groups after 3 months of treatment were compared. Kaplan-Meier method was used to draw survival curves, and the 1-year survival status of patients in the two groups was compared.Results:The disease control rate in the observation group was 69.05% (29/42), which was higher than that in the control group [43.90% (18/41)] ( χ2 = 5.34, P = 0.021), but there was no statistical difference in the objective response rate between the two groups [33.33% (14/42) vs. 21.95% (9/41)] ( χ2 = 1.34, P = 0.247). After treatment, the serum levels of CEA [(19.9±3.6) μg/ml vs. (79.3±7.9) μg/ml, (27.8±4.8) μg/ml vs. (78.6±8.1) μg/ml] and NSE [(18.9±3.2) ng/ml vs. (27.2±5.0) ng/ml, (22.0±3.3) ng/ml vs. (26.1±4.8) ng/ml] in the observation group and control group were lower than those before treatment (all P < 0.05). There was no statistical difference in CEA and NSE levels between the two groups before treatment (both P > 0.05), and after treatment, the observation group was lower than the control group (both P < 0.001). The serum S100β levels of patients in the observation and control groups after treatment were all higher than those before treatment [(50±5) μg/ml vs.(44±5) μg/ml, (55±4) μg/ml vs. (45±6) μg/ml, both P = 0.001), and the difference in S100β level between the two groups before treatment was not statistically significant ( P > 0.05), and after treatment, the observation group was lower than the control group ( P < 0.001). Both groups of patients did not experience acute severe adverse reactions during the medication period. There were no statistical differences between the observation group and the control group in the incidence rates of nausea and vomiting [9.52% (4/42) vs. 7.32% (3/41)], constipation and diarrhea [4.76% (2/42) vs. 4.88% (2/41)], thrombocytopenia [9.52% (4/42) vs. 4.88% (2/41)], and liver function damage [7.14% (3/42) vs. 2.44% (1/41)] (all P > 0.05). The 1-year overall survival rate of the observation group was higher than that of the control group [68.3% (95% CI 47.9%-86.1%) vs. 41.0% (95% CI 22.4%-65.3%)], and the overall survival of the observation group was better than that of the control group ( χ2 = 2.60, P = 0.037). Conclusions:The combination of osimertinib and bevacizumab in treatment of EGFR T790M-positive advanced NSCLC can effectively regulate the levels of tumor related factors, with good efficacy and safety.

A retrospective analysis of Osimertinib in treatment of elderly patients with advanced lung adenocarcinoma with epidermal growth factor receptor mutation / 中华老年医学杂志

Objective:To evaluate the efficacy and safety of Osimertinib in the second-line and above treatment of elderly patients with advanced lung adenocarcinoma with epidermal grouth factor receptor(EGFR)mutation.Methods:A retrospective analysis of 51 elderly patients with advanced lung adenocarcinoma aged 65 years and over was performed.EGFR gene mutations were detected at baseline.The patients were treated with Osimertinib as second or later-line treatment after disease progression on prior epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)therapy.Results:The median age of the patients was 72 years old, and the median progression-free survival(PFS)with Osimertinib was 13 months(95% CI: 10.8-15.2 months). Patients with exon 19 deletion(19del)treated with Osimertinib had longer PFS than patients with EGFR 21 exon L858R mutation(12 vs.24 month, P=0.028). In patients with EGFR resistance mutation T790M(T790M-positive), the PFS of patients with 19del combined with T790M(19del / T790M-positive)was better than that of patients with L858R combined with T790M(L858R / T790M-positive)(10 vs.28 months, P=0.029). After Osimertinib treatment, 43.8% of patients had brain or meningeal progression.The most commonly used agents for treatment after resistance to Osimertinib are antiangiogenic drugs.The common adverse reactions of Osimertinib were diarrhea(31.4 %), followed by dry skin with itching(29.4%)and rash(25.5 %). Most adverse reactions were grade 1 to 2, and one patient discontinued the drug intermittently due to grade 3 hematological adverse reactions. Conclusions:Osimertinib is effective and well tolerated in elderly patients with advanced EGFR-mutant lung adenocarcinoma.

Ideal sequencing in Stage IV epidermal growth factor receptor mutant Non朣mall?Cell Lung Cancer

Evidence from several studies has shown improved progression?free survival (PFS) with first? or second?generation epidermal growth factor receptor (EGFR)杢yrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second?generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third?generation, irreversible, oral EGFR?TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first?generation EGFR?TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first?line treatment. Because EGFR?mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs � erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib � is necessary. The sequencing of EGFR?TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third?generation TKI may be the preferred first?line treatment because patients may not opt for or die before the start of second?line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first?line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR?TKI, recent updates recommend osimertinib as a first?line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR?TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Safety of osimertinib in adult patients with metastatic epidermal growth factor receptor T790M mutation?positive non?small cell lung cancer: Results from a Phase IV study in India

Background: A Phase IV, single?arm study was conducted to assess the safety of osimertinib in Indian patients with epidermal growth factor receptor (EGFR) T790M mutation?positive stage IV non?small cell lung cancer (NSCLC). Methods: Enrolled patients received 80 mg osimertinib for six cycles or until disease progression or unacceptable toxicity or withdrawal. Primary safety variables included treatment?emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation/interruption/change (D/I/C) of drug dose, and AEs of special interest (AESIs). AEs were summarized by the percentage of patients experiencing at least one occurrence of each event. Results: Of the 60 enrolled patients (median age 58 [range: 34�] years; 51.7% women) at eight sites, nine patients were discontinued prematurely due to disease progression (n = 7) and death (n = 2); median (range) duration of treatment was 126 (1�4) days. Median age of patients was 58 (34�) years; 51.7% (n = 31) were women; 86.7% (n = 52) were nonsmokers; and most of them (98.3%) had adenocarcinoma. About 75% (n = 45) of patients experienced any of the TEAEs, with the most frequent being fatigue and creatine phosphokinase (CPK) increase (n = 6, 10% each). TEAEs in 11 (18.3%) patients were judged as study treatment related, with CPK increase being the most common (n = 4, 6.7%). TEAEs led to D/I/C of drug dose in eight (13.3%) patients, with one being study treatment related. Nine (15%) patients had AESIs of dyspnea (n = 6), chest pain (n = 2), and cardiorespiratory arrest (n = 1); two of them had a fatal outcome. One AESI (mild dyspnea) was considered study drug related. TEAEs of grade ?3 were reported in seven (11.7%) patients, including dyspnea in two (3.3%), followed by diarrhea, mucosal inflammation, cardiorespiratory arrest, and others (n = 1,1.7% each). None of the SAEs and fatal events were considered as study treatment related. Seven (11.7%) patients had abnormal electrocardiogram (ECG; not clinically significant) at the end of the study. Conclusion: Our study confirms the favorable safety profile of osimertinib without any new safety concerns in Indian patients with EGFR T790M mutation?positive stage IV NSCLC. ClinicalTrials.gov Identifier: NCT03853551 CTRI registration no. CTRI/2018/10/015941

Application of MIDD in Clinical Research of Antitumor Drugs / 中国肺癌杂志

The antitumor drug has become one of the focused areas in new drug research and development. Their clinical research generally consumes a long period of time, with high cost and high risk. Model-informed drug development (MIDD) integrates and quantitatively analyzes physiological, pharmacological, and disease progression information through modeling and simulation, which can reduce the cost of drug development and improve the efficiency of clinical research. In this essay, Osimertinib and Pembrolizumab are given as examples to illustrate the specific application of MIDD in different phases of clinical research, aiming to provide references for the application of MIDD to guide the clinical research of antitumor drugs.
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Progress of osimertinib in epidermal growth factor receptor mutant non-small cell lung cancer / 肿瘤研究与临床

As an important tumor driver gene, epidermal growth factor receptor (EGFR) gene plays an important role in the development and progression of non-small cell lung cancer (NSCLC). As the latest generation of EGFR-tyrosine kinase inhibitor (TKI) drugs, osimertinib has brought significant therapeutic efficacies and encouraging results both in patients with sensitive EGFR mutations and patients with rare EGFR mutations. Compared with previous EGFR-TKI drugs, osimertinib has strong blood-brain barrier penetration, which can effectively prevent the occurrence of lung cancer brain metastasis. After the resistance of first and second generation of targeted drugs, osimertinib is still effective in the follow-up treatment process. This article reviews the characteristics of EGFR mutation, the action mechanism of osimertinib, and the latest progress of osimertinib in treatment of EGFR mutations in NSCLC.

Application of Third-generation TKIs in EGFR-mutated Non-small Cell Lung Cancer / 肿瘤防治研究

The individualization of cancer treatment has brought about revolution in clinical practice. In recent years, EGFR-TKI has shown good anti-tumor activity in non-small cell lung cancer with EGFR positive mutation. Compared with the first-generation EGFR-TKI, the third-generation EGFR-TKI significantly increased the effective rate, progression-free survival and overall survival of advanced non-small cell lung cancer with EGFR mutation, especially the brain metastases. And the third-generation EGFR-TKI also showed the benefits of disease-free survival as the post-operative adjuvant therapy for operable EGFR-mutated non-small cell lung cancer. Moreover, the third-generation EGFR-TKI in combination with radiotherapy showed obvious advantages in the treatment of locally advanced and advanced oligometastatic EGFR-mutated non-small cell lung cancer.

Cost-utility Analysis of Osimertinib in the First-line Treatment of EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer / 中国药房

OBJECTIVE：To evaluate the economic s of osimertinib versus first-generation EGFR-TKIs in the first-line treatment of EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer （NSCLC），and to provide evidence-based reference for medical and healthy decision-making in China. METHODS ：From respective of health care system ，Markov model was developed by using patientsurvival data and published literature datato simulate 10 years of direct medical costs and quality-adjusted life years （QALY）for EGFR mutation-positive locally advanced or metastatic NSCLC patients ，with a model cycle length of 3 weeks，and the discount rate of 5％. One-way sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the effects of parameter changes on the stability of the model results. RESULTS ：In the base-case analysis ，compared with the first-generation EGFR-TKIs ，osimertinib could obtain 0.40 QALYs more ，with an incremental cost of 163 531.55 yuan and an incremental cost-utility ratio （ICER）of 409 321.54 yuan/QALY，which was higher than the willingness-to-pay （WTP）threshold in China（3 times per capita GDP in China in 2019 of 212 676 yuan/QALY）. The results of one-way sensitivity analysis showed that the utility value of progression-free survival status and the price of osimertinib had the greatest impact on ICER. The results of probability sensitivity analysis showed that the probability of osimertinib to be cost-effective was 11.00％ at the WTP threshold in China. When the price of osimertinib decreased by 30％，50％ and 70％，the probability of osimertinib to be cost-effective was 26.20％，47.40％，and 74.30％ at the WTP threshold of 212 676 yuan/QALY，respectively. CONCLUSIONS ：When Chinese 3 times per capita GDP in 2019 is used as the criterion for judgment ，osimertinib is not economical compared with the first-generation EGFR-TKIs in first-line treatment of locally advanced or metastatic NSCLC with EGFR mutation-positive. Appropriate price reduction can improve its economy.

Pharmacoeconomic Systematic Review of Osimertinib for Advanced Non-small Cell Lung Cancer / 中国药房

OBJECTIVE：To s ystematically review the economics of osimertinib for advanced non-small cell lung cancer （NSCLC），and to provide the reference for clinical application and healthcare decision makers. METHODS ：Retrieved from PubMed，Embase，the Cochrane L ibrary，Health Technology Assessment ，CNKI，Wanfang database ，VIP，CBM，etc.， pharmacoeconomic studies on osimertinib in the treatment of advanced NSCLC were collected from the inception to Apr. 2020. After screening and extracting relevant data ，the quality of the included studies was evaluated by using the Quality of Health Economics Studies （QHES），and the economic research results of the included literatures were systematically evaluated by using descriptive analysis method. RESULTS & CONCLUSIONS ：A total of 10 studies from 7 different countries were included ；QHES scores of the included literatures were 73-93，with an average of 86.8，and the quality of the researches was generally high. All the 10 studies were cost-effectiveness analysis ，including 6 first-line treatment ，4 second-line treatment. Six studies reported the cost discount rate ；only one study used the cost of osimertinib after price reduction for evaluation and analysis. Compared with other epidermal growth factor receptor-tyrosine kinase inhibitors （EGFR-TKI），six studies from different countries showed that osimertinib as the first-line treatment drug had no cost-effectiveness advantage ；cost-effectiveness of second-line treatment of osimertinib was controversial ，compared to chemotherapy. For advanced NSCLC patients ，the second-line treatment of osimertinib after the national centralized negotiation of price reduction has a more cost-effectiveness advantage in China ’s medical service system，while the first-line treatment of osimertinib before price reduction does not have this advantage compared with other EGFR-TKI drugs.

Osimertinib Re-challenge for EGFR-mutant NSCLC after Osimertinib-induced Interstitial Lung Disease: A Case Report / 中国肺癌杂志

Osimertinib-induced interstitial lung disease (ILD) is an uncommon, but fatal pulmonary toxicity in some patients. We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy. On day 60 after initiating treatment of osimertinib, the patient developed ILD. Osimertinib was discontinued immediately and oral prednisone 60 mg/d was initiated, ILD improved within 13 d. After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.
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Epidermal growth factor receptor-activating mutation(E746_T751>VP) in pancreatic ductal adenocarcinoma responds to erlotinib, followed by epidermal growth factor receptor resistance-mediating mutation (A647T): A case report and literature review

Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in personalized medicine. Here, we describe an epidermal growth factor receptor (EGFR)-activating mutation (E746_T751>VP) to erlotinib, a first-generation tyrosine kinase inhibitor (TKI), in a patient with metastatic PDAC. After an initial partial response to erlotinib for 12 months, the patient's disease progressed with emergence of the EGFR A647T mutation. Certainly, the patient also progressed after switching therapy to a third-generation EGFR TKI (osimertinib). This case illustrates the posttreatment evolution of EGFR A647T-mediated resistance to the first- and third-generation TKIs. To our knowledge, this is the first case to report the aforementioned activating and resistance-mediated mutations. In summary, genomic analysis performed in this patient with PDAC on the tumor biopsy and peripheral blood provided tools to understand mechanisms of response and resistance to targeted therapy with EFGR TKIs

Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer / 中国肺癌杂志

While treating cancer, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) still faces inevitable drug resistance. Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKI, and is a standard-of-care predictive biomarker used in therapeutic stratification. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR-TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs, and envisions future directions in translational and clinical research.

Case Report of Non-small Cell Lung Cancer Patient with EGFR T790M Mutation Treated with Th ird Generation Inhibitor

Lung cancer treatment based on the molecular classifi cation of the tumor has paved the way for multiple lines of targeted treatment, even though the development of resistance remains a major cause of concern. Epidermal growth factor receptor (EGFR) remains the poster boy for the use of targeted therapy, and the presence/absence of mutations in this gene has led to the development of inhibitors targeting specifi c mutations. We present the case of an advanced non-small cell lung cancer patient with EGFR T790M mutation treated with Osimertinib, a third-generation inhibitor.