Clinical observation of icotinib versus gefitinib in the treatment of EGFR-mutated advanced non-small cell lung cancer / 中国药房

OBJECTIVE To compare the efficacy and safety of icotinib and gefitinib in the treatment of epidermal growth factor receptor （EGFR）-mutated advanced non-small cell lung cancer （NSCLC）. METHODS The data of 146 patients with EGFR- mutant advanced NSCLC of our Hospital from December 2015 to September 2021 were retrospectively analyzed and divided into the gefitinib group （73 cases） and the icotinib group （73 cases） according to the drug use. Patients in the gefitinib group were given 0.25 g of gefitinib tablets once a day orally by single drug or combined with conventional chemotherapy， while patients in the icotinib group were given 125 mg of icotinib hydrochloride tablets three times a day orally by single drug or combined with conventional chemotherapy. Short-term efficacy， progression-free survival （PFS） were observed； Cox regression model was used to analyze the factors affecting the prognosis of patients； the occurrence of ADR were observed in the two groups. RESULTS There was no statistically significant difference in the objective remission rate， disease control rate， and the incidence of grade 1-2 and grade 3-4 adverse drug reactions between the two groups （P＞0.05）； median PFS was significantly better in the icotinib group than in the gefitinib group （P＝0.048）. Results of subgroup analysis based on patients basic information showed that compared with the gefitinib group， PFS of female [HR＝0.57，95%CI（0.34，0.96），P＝0.031] and non-brain metastatic patients [HR＝0.58，95%CI（0.36，0.91），P＝0.017] in icotinib group were prolonged significantly. Results of regression model analysis showed that EGFR19 exon Del mutation [HR＝0.50， 95%CI（0.25，1.00）， P＝0.049]， EGFR21 exon L858R mutation [HR＝0.44， 95%CI（0.21，0.89）， P＝0.022] and icotinib treatment [HR＝0.65， 95%CI （0.44，0.96）， P＝0.030] were influential factors for prognosis. CONCLUSIONS The short-term efficacy and safety of icotinib and gefitinib in the treatment of EGFR- mutant advanced NSCLC are comparable， but icotinib can significantly prolong the patients’ PFS； EGFR19 exon Del， EGFR21 exon L858R mutations and icotinib treatment are factors affecting patients’ prognosis.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Advances in the Treatment of EGFR Exon 20ins Mutant NSCLC / 中国肺癌杂志

Lung cancer has become one of the most dangerous cancers to human health and the mortality rate is the highest among all the causes of cancer death. Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of lung cancer. Chemotherapy is the main treatment for advanced NSCLC, but the 5-year survival rate is low. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in lung cancer, but EGFR exon 20 insertions (EGFR ex20ins) mutation belongs to one of the rare mutations, accounting for about 4%-10% of overall EGFR mutations, thus around 1.8% of advanced NSCLC patients. In recent years, targeted therapies represented by EGFR tyrosine kinase inhibitors (TKIs) have become an important treatment option for patients with advanced NSCLC, however, NSCLC patients with EGFR ex20ins mutation are not sensitive to most of EGFR-TKIs treatments. Currently, some of the targeted drugs for EGFR ex20ins mutation have achieved significant efficacy, while some of them are still under clinical investigation. In this article, we will describe various treatment methods for EGFR ex20ins mutation and their efficacy.
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CONCORDANCE: A real?world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non?small cell lung cancer

Background: Molecular tissue testing in non?small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients. Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next?generation sequencing (NGS) method and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients. Results: Out of the total patients enrolled (N = 245) the majority (64.5% n = 158) were men. The median age of patients was 58.0 (range: 26�) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92 78.37) and 90.1% [95% CI: 84.36 94.21) respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled 25 were tissue positive and plasma negative while 16 were plasma positive and tissue negative. Conclusions: This real?world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient抯 tumor mutation status. ClinicalTrials.gov Identifier: NCT03562819

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor

The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy and/or EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, and/or the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy and/or EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.

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.

A retrospective study on the efficacy of different chemotherapy regimens in lung adenocarcinoma patients harboring common EGFR mutations / 中国肿瘤临床

Objective: To investigate an optimal chemotherapy regimen for patients diagnosed with lung adenocarcinoma harboring common EGFR mutations. Methods: Clinical data of 4,021 patients diagnosed with advanced primary lung adenocarcinoma who were admitted to Guangdong Lung Cancer Institute from June 2007 to June 2014 were retrospectively collected. The efficacy of the standard chemotherapy regimen in patients diagnosed with luny adenocarcinoma harboring common EGFR mutations was analyzed. Results: In total, 205 patients were included in the study, and 119, 60 and 81 patients received gemcitabine plus platinum, pemetrexed plus platinum, and paclitaxel plus platinum regimens, respectively. Statistical difference was not observed in the objective response rate (ORR,25.2%, 25.0%, 30.8%, respectively) and progression free survival (PFS, 5.5, 5.2, 6.2 months, respectively) between these three treatment regimens (P=0.979, P=0.811). Conclusions: Platinum-based chemotherapy regimens based on gemcitabine, pemetrexed, and paclitaxel have similar efficacy in patients diagnosed with advanced primary lung adenocarcinoma harboring common EGFR mutations.

Metástasis cerebrales en cáncer de pulmón de células no pequeñas con mutación EGFR / Cerebral metastases in lung cancer of non-small cells with egfr mutation

El cáncer de pulmón es uno de los tumores que tienen la capacidad de metastatizarse en el cerebro y tienen la capacidad de penetrar la barrera hematoencefálica, la clínica es variada dependiendo del sitio afectado, así como los riesgos asociados de convulsión. Por lo tanto, la elección del tratamiento es compleja, considerando el primario, el número de metástasis y los sitios afectados. La radioterapia ha sido durante mucho tiempo la elección de los pacientes que no son candidatos a la cirugía, La presencia de mutaciones han permitido brindar terapias dirigidas como los inhibidores tirosin kinasas que penetran la barrera hematoencefálica y han sido clave para el manejo terapéutico.

Lung cancer is one of the tumors that have the ability to metastasize in the brain and have the ability to penetrate the blood-brain barrier, the clinic is varied depending on the affected site, as well as the associated risks of seizure. Therefore, the choice of treatment is complex, considering the primary, the number of metastases and the affected sites. Radiotherapy has long been the choice of patients who are not candidates for surgery. The presence of mutations have allowed targeted therapies such as tyrosine kinase inhibitors that penetrate the blood-brain barrier and have been key to therapeutic management.

Application of SM-PCR to detect plasma ctDNA in the treatment of patients with ad-vanced lung adenocarcinoma / 中国肿瘤临床

Objective: To investigate the application of single-molecule PCR (SM-PCR) in the detection of plasma ctDNA for the treat-ment of patients with advanced lung adenocarcinoma. Methods: In total, 30 patients diagnosed with advanced lung adenocarcinoma were enrolled between June 2017 and May 2018. ctDNA fragments of the target genes (EGFR, KRAS, BRAF, ALK, HER2, and TP53) from the blood samples were enriched by SM-PCR, and DNA libraries were prepared. Finally, a high-throughput sequencing was performed. The EGFR detection of tumor tissue samples was performed using real-time fluorescence PCR based on the amplification refractory mutation system (ARMS) and consistency in the results of EGFR mutation detection in the plasma and tissue was compared. Results:The results of both the methods were consistent (Kappa=0.867, P<0.001). The McNemar's test also indicated that the results are not statistically different (P=0.500). Conclusions: SM-PCR can be used for the detection of plasma EGFR mutations. The target detection sites are more comprehensive and multiple mutations can be detected at the same time. Results of the analysis are more precise and can be absolutely quantified.

Comparison of cobas EGFR Mutation Test v2 and PANAMutyper-R-EGFR for Detection and Semi-Quantification of Epidermal Growth Factor Receptor Mutations in Plasma and Pleural Effusion Supernatant

BACKGROUND: Plasma epidermal growth factor receptor (EGFR) mutation tests are less invasive than tissue EGFR mutation tests. We determined which of two kits is more efficient: cobas EGFR Mutation test v2 (cobasv2; Roche Molecular Systems, Pleasanton, CA, USA) or PANAMutyper-R-EGFR (Mutyper; Panagene, Daejeon, Korea). We also evaluated whether pleural effusion supernatant (PE-SUP) samples are assayable, similar to plasma samples, using these two kits. METHODS: We analyzed 156 plasma and PE-SUP samples (31 paired samples) from 116 individuals. We compared the kits in terms of accuracy, assessed genotype concordance (weighted κ with 95% confidence intervals), and calculated Spearman's rho between semi-quantitatively measured EGFR-mutant levels (SQIs) measured by each kit. We also compared sensitivity using 47 EGFR-mutant harboring samples divided into more-dilute and less-dilute samples (dilution ratio: ≥ or <1:1,000). RESULTS: cobasv2 tended to have higher accuracy than Mutyper (73% vs 69%, P=0.53), and PE-SUP samples had significantly higher accuracy than plasma samples (97% vs 55–71%) for both kits. Genotype concordance was 98% (κ=0.92, 0.88–0.96). SQIs showed strong positive correlations (P<0.0001). In less-dilute samples, accuracy and sensitivity did not differ significantly between kits. In more-dilute samples, cobasv2 tended to have higher sensitivity than Mutyper (43% vs 20%, P=0.07). CONCLUSIONS: The kits have similar performance in terms of EGFR mutation detection and semi-quantification in plasma and PE-SUP samples. cobasv2 tends to outperform Mutyper in detecting less-abundant EGFR-mutants. PE-SUP samples are assayable using either kit.

EGFR Mutation Is Associated with Short Progression-Free Survival in Patients with Stage III Non-squamous Cell Lung Cancer Treated with Concurrent Chemoradiotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to evaluate the relationship between epidermal growth factor receptor (EGFR) mutation and clinical outcomes in patients with stage III non-squamous cell lung cancer treated with definitive concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: From January 2008 to December 2013, the medical records of 197 patients with stage III non- squamous non-small cell lung cancer treated with definitive CCRT were analyzed to determine progression-free survival (PFS) and overall survival (OS) according to EGFR mutation status. RESULTS: Among 197 eligible patients, 81 patients were EGFR wild type, 36 patients had an EGFR mutation (exon 19 Del, n=18; L858R, n=9, uncommon [G719X, L868, T790M], n=9), and 80 patients had unknown EGFR status. The median age was 59 years (range, 28 to 80 years) and 136 patients (69.0%) were male. The median follow-up duration was 66.5 months (range, 1.9 to 114.5 months). One hundred sixty-four patients (83.2%) experienced disease progression. Median PFS was 8.9 months for the EGFR mutation group, 11.8 months for EGFR wild type, and 10.5 months for the unknown EGFR group (p=0.013 and p=0.042, respectively). The most common site of metastasis in the EGFR mutant group was the brain. However, there was no significant difference in OS among the three groups (34.6 months for EGFR mutant group vs. 31.9 months for EGFR wild type vs. 22.6 months for EGFR unknown group; p=0.792 and p=0.284). A total of 29 patients (80.6%) with EGFR mutation were treated with EGFR tyrosine kinase inhibitor (gefitinib, n=24; erlotinib, n=3; afatinib, n=2) upon progression. CONCLUSION: EGFR mutation is associatedwith short PFS and the brain is the most common site of distant metastasis in patients with stage III non- squamous cell lung cancer treated with CCRT.

Investigation on the Possibility of EGFR Mutation Testing on DNA Extracted from Fixation Liquid of Lung Cancer Biopsy / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR) mutation is the most common gene mutation in patients with non-small cell lung cancer (NSCLC). Many international guidelines are recommended to detected the EGFR mutation before the treatment of advanced non-small cell lung cancer. To investigate the possibility of EGFR mutation testing on DNA extracted from fixation liquid of lung cancer biopsy.@*METHODS@#Fixation liquid of lung cancer biopsy was collected and stored at -80 oC after centrifugal. DNA was extracted and EGFR gene mutation was detected by ARMS. Compared with EGFR mutation status of paraffin-embedded tissues, the consistency, the sensitivity and specificity of EGFR mutation testing were analyzed.@*RESULTS@#Among the 28 cases of EGFR mutation positive and 20 cases of EGFR mutation negative previously tested on paraffin-embedded tissue by clinic test, 20 cases with EGFR mutation positive and 20 cases with negative were detected by matched fixation liquid of lung cancer biopsy, respectively. The sensitivity and specificity were 71.4% and 100%. Moreover, 52 paraffin-embedded tissues and matched fixation liquid of lung cancer biopsy with unknown EGFR mutation status were detected, and the EGFR mutation positive rate were 36.5% and 28.8% respectively. The sensitivity and specificity of fixation liquid of lung cancer biopsy were 78.9% and 100.0%.@*CONCLUSIONS@#Extracting the DNA from fixation liquid of lung cancer biopsy may be a kind of feasible way to detect EGFR mutation.

Comparison of Effectiveness of Gefitinib, Erlotinib, and Afatinib in Advanced Non-small Cell Lung Cancer Patients with EGFR Mutation Positive in Indonesian Population / 中国肺癌杂志

BACKGROUND@#EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were used to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs; gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population.@*METHODS@#A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib (n=59), erlotinib (n=22), and afatinib (n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival (PFS), and mortality rate.@*RESULTS@#Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months (95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.
 CONCLUSIONS: Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.

Advances in the Influence of EGFR Mutation on the PD-L1 Expression in Non-small Cell Lung Cancer / 中国肺癌杂志

Researches on the inhibitors of programmed death-1 (PD-1) and programmed death-1 ligand (PD-L1) enjoy considerable breakthroughs in recent years, which has brought relative changes in the therapeutic model of non-small cell lung cancer (NSCLC) at an unexpected speed. However, it seems that PD-1/PD-L1 inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) mutation than those without. Previous studies have shown that the expression rate of PD-L1 on tumor cells is correlated with the therapeutic effect of PD-1/PD-L1 inhibitors. Yet, there is no complete agreement on the effect of EGFR mutation on PD-L1 expression. In this review, relevant studies will be summarized with an expectation of making some contributions to basic researches and to the clinical treatment.

Determinación de mutaciones (del E746-A750 exón 19 y L858R exón 21) en el gen receptor del factor de crecimiento epidérmico (EGFR) en muestras de suero y biopsia de carcinoma pulmonar no microcítico (CPNM) / Determination of mutations (del E746-A750 exon 19 and L858R exon 21) in the epidermal growth factor receptor (EGFR) gene in serum samples and in biopsys of non-microcytic lung carcinoma (NMLC)

Resumen Introducción Las mutaciones, del E746-A750 exón 19 y L858R exón 21 del gen EGFR en células tumorales de CPNM representan biomarcadores de respuesta a fármacos inhibidores de tirosina cinasa (ITK). Pacientes con tumores positivos a mutaciones EGFR muestran mejor respuesta y mayor sobrevivencia. Estas mutaciones ocupan el 90% de las mutaciones en cáncer de pulmón. Objetivo Evaluar la frecuencia de las mutaciones del E746-A750 exón 19 y L858R exón 21 del EGFR en muestras de biopsia de CPNM y en muestras de suero de población abierta de Yucatán. Material y métodos Se seleccionaron 19 muestras de biopsia de CNPM tipo adeconocarcinoma y 101 sueros de sujetos sanos. Las mutaciones del E746-A750 y L858R en EGFR se determinaron mediante amplificación por PCR oligo-alelo específica (PCR-ASO). Se calcularon las frecuencias genotípicas y alélicas y su distribución según Hardy Weinberg, utilizando la plataforma SNPstats. Resultados En muestras de suero se determinó el genotipo homocigoto (1/1) en 26.58%, 73.42% el heterocigoto (1/0) y ausencia del genotipo mutante con deleción (0/0) para del E746-A750; en tanto que, para L858R, 21.78% resultó homocigoto (TT), 54.46% heterocigoto (T/G) y 23.76% mutantes GG. En las biopsias, el heterocigoto fue más frecuente en ambas mutaciones 63.16% y 73.68% para del E746-A750 y L858R, respectivamente. Conclusión. La frecuencia de las mutaciones del gen EGFR en las muestras de sueros fue de 36.71% para la deleción del E746-A750 en exón 19 y 50.99% para L858R en exón 21. La distribución de las mutaciones en muestras de biopsia CPNM resultó en 42.11% para cada mutación estudiada.

Abstract Introduction EGFR mutations, del E746-A750 in exon 19 and L858R in exon 21 in tumor cells of NMLC represent biomarkers of response to tyrosine kinase inhibitors (TKI) therapy. Patients with tumors positive for EGFR mutations show better response and greater survival. These mutations occupy 90% of mutations in lung cancer. Objective To evaluate the frequency of mutations del E746-A750-exon 19 and L858R-exon 21 of EGFR gene in NMLC biopsy samples and in serum samples of the general population from Yucatán. Material and methods 19 NMLC biopsy samples of adenocarcinoma type and 101 serum samples from healthy subjects were selected. EGFR mutations del E746-A750 and L858R were determined by allele-specific PCR amplification (PCR-ASO). The genotypic and allelic frequencies; and their distribution according to Hardy Weinberg expectations were calculated using the SNPstats software. Results For serum, EGFR del E746-A750 mutation, homozygous genotype (1/1) was present in 26.58%, heterozygote (1/0) in 73.42% and absence of mutant genotype with deletion (0/0); whereas for L858R mutation, 21.78% were homozygous (TT), 54.46% heterozygous (T/G) and 23.76% GG mutants. For the NMLC biopsies, the heterozygote was the most frequent genotype for both mutations, 63.16% and 73.68% for del E746-A750 and L858R, respectively. Conclusion The frequency of mutations of EGFR gene in serum samples was 36.71% for deletion delE746-A750 in exon 19 and 50.99% for L858R in exon 21. Distribution of mutations in biopsy samples NMLC resulted in 42.11% for each EGFR mutation.

Application of PAP PCR to monitor plasma cfDNA in advanced non-small cell lung can-cer / 中国肿瘤临床

Objective:To explore the application of pyrophosphorolysis-activated polymerization(PAP)to monitor plasma cfDNA in ad-vanced non-small cell lung cancer(NSCLC).Methods:A total of 85 patients diagnosed with advanced NSCLC between March 2016 and June 2017 were enrolled in the present study. EGFR mutations in cfDNA extracted from the plasma were detected using PAP and ARMS-PCR technology.The concordance analysis of EGFR mutations involved plasma vs.tumor tissue and PAP vs.ARMS-PCR.Further-more,38 EGFR-positive patients were selected to monitor EGFR mutations with PAP.Results:No statistical differences in EGFR muta-tions were observed between plasma and tumor tissue(P=0.092),as well as PAP and ARMS-PCR(P=0.210).The detection rate of EGFR mutations in cfDNA was higher in the progressor than in the non-progressor(62.5% vs.21.3%,P<0.001).Conclusions:PAP can be used for detecting and monitoring EGFR mutations in cfDNA to predict disease progression.

Detection of Rare Mutations in EGFR-ARMS-PCR-Negative Lung Adenocarcinoma by Sanger Sequencing

PURPOSE: This study aimed to identify potential epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer that went undetected by amplification refractory mutation system-Scorpion real-time PCR (ARMS-PCR). MATERIALS AND METHODS: A total of 200 specimens were obtained from the First Affiliated Hospital of Guangzhou Medical University from August 2014 to August 2015. In total, 100 ARMS-negative and 100 ARMS-positive specimens were evaluated for EGFR gene mutations by Sanger sequencing. The methodology and sensitivity of each method and the outcomes of EGFR-tyrosine kinase inhibitor (TKI) therapy were analyzed. RESULTS: Among the 100 ARMS-PCR-positive samples, 90 were positive by Sanger sequencing, while 10 cases were considered negative, because the mutation abundance was less than 10%. Among the 100 negative cases, three were positive for a rare EGFR mutation by Sanger sequencing. In the curative effect analysis of EGFR-TKIs, the progression-free survival (PFS) analysis based on ARMS and Sanger sequencing results showed no difference. However, the PFS of patients with a high abundance of EGFR mutation was 12.4 months [95% confidence interval (CI), 11.6−12.4 months], which was significantly higher than that of patients with a low abundance of mutations detected by Sanger sequencing (95% CI, 10.7−11.3 months) (p < 0.001). CONCLUSION: The ARMS method demonstrated higher sensitivity than Sanger sequencing, but was prone to missing mutations due to primer design. Sanger sequencing was able to detect rare EGFR mutations and deemed applicable for confirming EGFR status. A clinical trial evaluating the efficacy of EGFR-TKIs in patients with rare EGFR mutations is needed.

Study Progression on Non-small Cell Lung Cancer with EGFR Mutation Treated by Immune Checkpoint Inhibitors / 中国肺癌杂志

In recent years, epidermal growth factor receptor tyrosine kinase inhibitors have been recommended by many guidelines as first-line drugs for advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations and no resistance. However, with the prolongation of medication time, most appear acquired resistance. In recent years, breakthroughs in inhibitors of programmed death-1 (PD-1) and its ligand (PD1 ligand, PD-L1) have rapidly changed the therapeutic model of NSCLC. Recent studies have shown that the efficacy of immune checkpoint inhibitors in EGFR-mutant NSCLC patients is not satisfactory, which might be caused by low PD-L1 expression, inhibitory immune microenvironment and low tumor mutation load. This review will elaborate the immune microenvironment of NSCLC patients with EGFR mutation, the latest study progression of immune checkpoint inhibitors and its combined with TKI, expecting to bring new hopes for the treatment of EGFR-mutant NSCLC patients.
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Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. MATERIALS AND METHODS: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. RESULTS: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). CONCLUSION: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

Evolving Cancer Classification in the Era of Personalized Medicine: A Primer for Radiologists

Traditionally tumors were classified based on anatomic location but now specific genetic mutations in cancers are leading to treatment of tumors with molecular targeted therapies. This has led to a paradigm shift in the classification and treatment of cancer. Tumors treated with molecular targeted therapies often show morphological changes rather than change in size and are associated with class specific and drug specific toxicities, different from those encountered with conventional chemotherapeutic agents. It is important for the radiologists to be familiar with the new cancer classification and the various treatment strategies employed, in order to effectively communicate and participate in the multi-disciplinary care. In this paper we will focus on lung cancer as a prototype of the new molecular classification.