[Expert consensus on icotinib as adjuvant therapy for non-small cell lung cancer].

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using.

Expert consensus on icotinib as adjuvant therapy for non-small cell lung cancer / 中华肿瘤杂志

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using.

Efficacy of Icotinib, an EGFR Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer Patients with Exon 19 Deletion and Exon 21 L858R: A Retrospective Analysis in China.

INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

Icotinib alone or with bevacizumab as first-line therapy in Chinese patients with advanced nonsquamous non-small cell lung cancer and activating EGFR mutations: A retrospective study.

BACKGROUND: This study focused on comparing the safety and therapeutic effects between icotinib monotherapy and icotinib plus bevacizumab combined therapy in non-small cell lung cancer (NSCLC) cases harboring EGFR mutations. METHODS: Data were collected retrospectively from the Cancer Institute and Hospital of Tianjin Medical University between October 2018 and December 2019, where the NSCLC cases that harbored EGFR mutations underwent first-line therapy with icotinib in the presence or absence of bevacizumab. This study included 90 cases, of which 60 patients were in the icotinib group (I) and 30 in the icotinib plus bevacizumab group (IB). RESULTS: The follow-up period to evaluate median PFS in our study was 18 months. Median PFS was 18.0 months (95% confidence interval [CI]: 14.7-21.3) with icotinib plus bevacizumab and 11 months (95% CI: 8.9-13.1) with icotinib alone (hazard ratio 0·54, 95% CI: 0.31-0.92; p = 0.029). According to the subgroup analyses based on the type of EGFR genomic aberration, a prolonged median PFS was observed in the cases harboring exon 21 point mutation (Ex21.L858R) in the IB group compared to the I group (not reached vs. 11 months [8.8-13.2], p = 0.021). However, the difference between the cases harboring exon 19 deletions in the EGFR gene was not significant. The DCR and ORR were comparable between both groups. Substantially higher incidences of hypertension and proteinuria were observed in the combined group compared to the icotinib monotherapy group. CONCLUSIONS: This is the first study to provide further evidence of the benefits of applying icotinib in combination with bevacizumab as first-line treatment for advanced NSCLC cases harboring EGFR mutations. However, these findings need to be verified through prospective phase 3 clinical studies.

Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial.

BACKGROUND: Icotinib has provided survival benefits for patients with advanced, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). We aimed to compare icotinib with chemotherapy in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection. Here, we report the results from the preplanned interim analysis of the study. METHODS: In this multicentre, randomised, open-label, phase 3 trial done at 29 hospitals in China, eligible patients were aged 18-70 years, had histopathogically confirmed stage II-IIIA NSCLC, had complete resection up to 8 weeks before random assignment, were treatment-naive, and had confirmed activation mutation in exon 19 or exon 21 of the EGFR gene. Participants were randomly assigned (1:1) with an interactive web-based response system to receive either oral icotinib 125 mg thrice daily for 2 years or four 21-day cycles of intravenous chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 of each cycle plus cisplatin 75 mg/m2 on day 1 of each cycle for adenocarcinoma or squamous carcinoma; or pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every 3 weeks for non-squamous carcinoma). The primary endpoint was disease-free survival assessed in the full analysis set. Secondary endpoints were overall survival assessed in the full analysis set and safety assessed in all participants who received study drug. This trial is registered with ClinicalTrials.gov, NCT02448797. FINDINGS: Between June 8, 2015, and August 2, 2019, 322 patients were randomly assigned to icotinib (n=161) or chemotherapy (n=161); the full analysis set included 151 patients in the icotinib group and 132 in the chemotherapy group. Median follow-up in the full analysis set was 24·9 months (IQR 16·6-36·4). 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median disease-free survival was 47·0 months (95% CI 36·4-not reached) in the icotinib group and 22·1 months (16·8-30·4) in the chemotherapy group (stratified hazard ratio [HR] 0·36 [95% CI 0·24-0·55]; p<0·0001). 3-year disease-free survival was 63·9% (95% CI 51·8-73·7) in the icotinib group and 32·5% (21·3-44·2) in the chemotherapy group. Overall survival data are immature with 14 (9%) deaths in the icotinib group and 14 (11%) deaths in the chemotherapy. The HR for overall survival was 0·91 (95% CI 0·42-1·94) in the full analysis set. Treatment-related serious adverse events occurred in two (1%) of 156 patients in the icotinib group and 19 (14%) of 139 patients in the chemotherapy group. No interstitial pneumonia or treatment-related death was observed in either group. INTERPRETATION: Our results suggest that compared with chemotherapy, icotinib significantly improves disease-free survival and has a better tolerability profile in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection. FUNDING: Betta Pharmaceuticals TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Tuning the Kinetic Inertness of Bi3+ Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for 213Bi Targeted Alpha Therapy.

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.

Complete remission following icotinib administration in an advanced ectopic thymic carcinoma patient harbouring the EGFR exon 19 deletion.

BACKGROUND: Ectopic thymic carcinoma (TC) is an extremely rare disease with a poor prognosis. The main treatment for early TC is surgery, although an effective treatment for advanced TC is lacking. METHODS: We present the case of a 61-year-old man with advanced posterior mediastinum thymic squamous cell carcinoma. Amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) analysis was used to investigate the molecular and mutational characteristics of this tumour. RESULTS: After chemotherapy and radiotherapy, the tumour showed disease progression. Immunohistochemistry revealed that the tumour was positive for CD117 (specific for primary TC), CK19, CD56 and Ki67. ARMS-PCR analysis revealed an EGFR exon 19 deletion in the patient. The patient subsequently received icotinib treatment and achieved complete remission for 3 years. CONCLUSIONS: This case report suggests that tyrosine kinase inhibitors are a potential treatment strategy for patients with TC harbouring EGFR alterations.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. OBJECTIVES: To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. SEARCH METHODS: We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.

Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer.

Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib.

Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and smoking status. TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR. EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance. DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.

Icotinib With Concurrent Radiotherapy vs Radiotherapy Alone in Older Adults With Unresectable Esophageal Squamous Cell Carcinoma: A Phase II Randomized Clinical Trial.

Importance: Palliative radiotherapy (RT) is generally recommended for older patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis. A new combination treatment is therefore needed. Objective: To assess the efficacy and toxicity of RT plus icotinib vs RT alone in older patients with ESCC. Design, Setting, and Participants: This randomized, multicenter, open-label, phase II clinical trial was conducted in China, with enrollment between January 1, 2015, and October 31, 2016. Patients aged 70 years or older with clinical stage T2 to T4, N0/1, M0/1a unresectable (because of comorbidities, T4 disease, unresectable lymph node, or refused surgery) ESCC were randomized 1:1 to receive RT plus icotinib or RT alone. Radiation was prescribed at 60 Gy in 30 fractions in both groups, and icotinib was administered at a dosage of 125 mg 3 times a day in the RT plus icotinib group. The last follow-up was completed on June 30, 2019, and data were analyzed from July 1 to September 30, 2019. Interventions: Patients were randomized to either RT plus icotinib or RT alone. Main Outcomes and Measures: The primary end point was overall survival (OS). Treatment-related toxic effects were evaluated. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression if available. Results: A total of 127 patients (median age, 76 years [range, 70-91 years]; 76 men [59.8%]) were enrolled and were eligible for survival analysis. Median OS was 24.0 (95% CI, 22.2-25.8) months in the RT plus icotinib group vs 16.3 (95% CI, 13.8-18.8) months in the RT group (hazard ratio, 0.53; 95% CI, 0.33-0.87; P = .008). No difference was observed in grades 3 or 4 adverse events. Patients with EGFR overexpression had a significantly better median overall survival (not reached vs 16.3 months [range, 2.6-45.1 months]; P = .03) in the RT plus icotinib group. Conclusions and Relevance: In this randomized clinical trial, icotinib plus RT was well tolerated and improved OS in older patients with ESCC relative to RT alone. Patients with EGFR overexpression benefitted more from icotinib with RT. Trial Registration: ClinicalTrials.gov Identifier: NCT02375581.

A first case report of clinical response to targeted therapy in a patient with primary myoepithelial carcinoma of the lung harboring EGFR exon 19 deletion.

BACKGROUND: Primary myoepithelial carcinoma of the lung is a rare subtype in lung cancer. Comprehensive molecular profiling of myoepithelial carcinoma of the lung is absent, neither was clinical evidence of targeted therapy available for this disease. Therefore, the optimal treatment regimen of this tumor needs to be established. CASE PRESENTATION: Here we present a case of a 68-year-old patient with stage IVB primary myoepithelial carcinoma of the lung who harbored EGFR exon 19 deletion and KRAS mutation and underwent icotinib targeted therapy, achieving partial response (PR) with progression free survival (PFS) of 3 months. CONCLUSION: To our knowledge, this study describes the first documented case of primary myoepithelial carcinoma lung cancer patient harboring EGFR exon 19 deletion and KRAS mutation, and showed clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) treatment in this patient.

Bisdemethoxycurcumin Enhances the Sensitivity of Non-small Cell Lung Cancer Cells to Icotinib via Dual Induction of Autophagy and Apoptosis.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.

Dual Loading of Nanoparticles with Doxorubicin and Icotinib for the Synergistic Suppression of Non-Small Cell Lung Cancer.

Background: Combination chemotherapy plays an important role in the clinical therapy of non-small cell lung cancer (NSCLC). However, the pharmacokinetic differences between drugs are an insurmountable barrier in traditional treatment. For the synergistic therapy of NSCLC, synergistic nanoparticles (EDS NPs) loaded with both an EGFR inhibitor and doxorubicin (DOX) were designed and prepared. Methods: Erlotinib, apatinib and icotinib were evaluated for optimal combination with DOX in treatment of NSCLC via CCK-8 assay. Then the cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were applied to coencapsulate DOX and EGFR inhibitor to form the EDS NPs. EDS NPs were evaluated in NSCLC cell lines (A549, NCI-H1975 and PC9) and NSCLC xenograft mouse models. Results: Icotinib was found to be the optimal synergistic drug in combination with DOX in the tested. Subsequently, icotinib and DOX were coencapsulated in the NPs. EDS NPs were roughly spherical with an average size of 65.7±6.2 nm and possessed stable loading and releasing properties. In the in vitro investigation, EDS NPs could efficiently deliver payloads into cells, exhibited cytotoxicity and produced strong anti-migration properties. In vivo hypotoxicity was confirmed by acute toxicity and hemolytic assays. The in vivo distribution showed that EDS NPs could enhance accumulation in tumors and decrease nonspecific accumulation in normal organs. EDS NPs significantly promoted the in vivo synergistic effects of icotinib and DOX in the mouse model. Conclusions: The study suggests that EDS NPs possess noteworthy potential for development as therapeutics for NSCLC clinical chemotherapy.

Icotinib: efficacy in different solid tumors and gene mutations.

Icotinib is a first-generation inhibitor of epidermal growth factor receptor, which has been approved by the Chinese National Medical Products Administration, for the treatment of non-small cell lung cancer with epidermal growth factor receptor sensitive mutations. In addition, icotinib also shows moderate activity in other solid tumors driven by epidermal growth factor receptor, including non-small cell lung cancer with epidermal growth factor receptor rare non-resistant mutations, and esophageal cancer with epidermal growth factor receptor amplification or overexpression. This article reviews the efficacy of icotinib in different solid tumors with different epidermal growth factor receptor alterations.

Efficacy of early combination of local radiotherapy and GM-CSF for advanced non-small cell lung cancer treated with icotinib.

BACKGROUND: Lung cancer is a disease that severely endangers human health. Non-small cell lung cancer (NSCLC) accounts for approximately 4/5 of lung cancers. AIMS: To investigate the efficacy of early combination of local radiotherapy and granulocyte macrophage colony-stimulating factor (GM-CSF) for advanced NSCLC treated with icotinib. METHODS: Forty-two patients with stage IV NSCLC complicated with EGFR gene mutation were selected and randomly divided into two groups, with 21 patients in each group. Patients in control group were treated with icotinib, and patients in experimental group were treated with icotinib combined with local radiotherapy and subcutaneous injection of GM-CSF. One-year progression free survival between two groups was compared. RESULTS: Three months after treatment, the efficacy in experimental group was significantly better than that in control group, and objective response rate was 95.24% in experimental group, which was higher than the 71.43% in control group. Patients in experimental group had no differences in white blood cell and neutrophil, but had significantly lower carcino-embryonic antigen and neuron-specific enolase levels and higher CD3+, CD4+, and CD4+/CD8+ than those in control group and before treatment. There were no differences in the proportion of patients with adverse reactions between two groups. One-year progression free survival was significantly better in experimental group than in control group. CONCLUSIONS: Early combination of local radiotherapy and GM-CSF has a significant efficacy for advanced NSCLC accounts for approximately 4/5 of lung cancers treated with icotinib, and it can improve patients' autoimmunity and lengthen progression free survival.

Potential mechanism of primary resistance to icotinib in patients with advanced non-small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi-center study.

The incidence of epidermal growth factor receptor uncommon mutation (EGFRum) is relatively low and patients harboring EGFRum are resistant to the first-generation tyrosine kinase inhibitors (TKI). However, the mechanism of primary resistance remains unclear. Medical records of 98 patients who had never been treated by TKI and who accepted icotinib treatment were collected and followed. The circulating tumor DNA (ctDNA) were detected and analyzed using the next-generation sequencing (NGS) platform after progression on icotinib. The potential primary resistance mechanism of icotinib was explored. A total of 21 (21.4%) and 48 (49%) patients developed primary and acquired resistance to icotinib, respectively. The median progression-free survival (PFS) of primary resistance patients was 1.8 months (0.5-2.3, 95% CI = 1.50-2.10). Before treatment, 52.4% (11/21) of patients carried S768I, 23.8% (5/21) L861Q, 14.3% (3/21) G719X and 14.3% (3/21) exon 20-ins mutations. Approximately 23.8% (5/21) of patients harbored the combined pattern mutations and 76.2% (16/21) of patients harbored the single pattern mutations. The combined pattern with EGFR classical mutation (EGFRcm) had worse PFS than the combined with EGFRum and single pattern (P < .05). There were 6 (28.57%) patients with acquired EGFR extracellular domain mutation, 5 (23.81%) with BCL2L11 loss (BIM deletion polymorphism), 3 (14.29%) with MET amplification, 1 (4.76%) with ERBB2 amplification, 1 (4.76%) with MYC amplification, 1 (4.76%) with PTEN mutation, 1 (4.76%) with PIK3CA mutation and 3 (14.29%) with unknown status. EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN and PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in patients with advanced non-small cell lung cancer harboring uncommon mutant epidermal growth factor receptor. Combined targeted therapy or chemotherapy should be considered in this population.

Real-world efficacy and potential mechanism of resistance of icotinib in Asian advanced non-small cell lung cancer with EGFR uncommon mutations: A multi-center study.

The response to icotinib in advanced non-small cell lung cancers (NSCLC) with EGFR uncommon mutation (EGFRum) is unclear. Here we reported the efficacy and potential resistance mechanism of icotinib in Chinese EGFRum NSCLC patients. Between July 2013 and November 2016, 3117 NSCLC patients were screened for EGFRum in a multi-center study in China. Circulating tumor DNA (ctDNA) was detected and analyzed using next-generation sequencing (NGS) after progression from icotinib. The efficacy, safety and the potential resistance mechanism of icotinib were explored. After a median follow-up of 6.2 months, 69 patients (70.41%) developed disease progression, the objective rate (ORR) and disease control rate (DCR) were 13.27% and 29.59% respectively, and the median progression-free survival (PFS) was 5.5 months (95% CI: 1.2-13.0 months). Both complex-pattern with EGFR classical mutations (EGFRcm) and single-pattern have better PFS than complex-pattern without EGFRcm (median PFS was 7.2 (95% CI: 4.65-9.75), 5.2 (95% CI: 3.24-7.16) and 3.2 (95% CI: 2.97-3.44) months, respectively, P < .05); patients harboring S768I mutation had the worst PFS than others (2.0 months, P < .05). Diarrhea was the most frequent side effect (42.9%). Forty-eight (69.6%) patients developed drug resistance after 3.0 months and 81.2% of them acquired T790M mutation. Better response was observed in complex-pattern with the EGFRcm group. S768I mutation carriers may not benefit from icotinib. Acquired T790M mutation was common in icotinib-resistant EGFRum NSCLC patients.

Enhancement of chemosensitivity by WEE1 inhibition in EGFR-TKIs resistant non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is the first-line treatment in non-resectable non-small lung cancer (NSCLC) with EGFR mutation. However, EGFR-TIKs resistance would inevitably develop within 9-14 months after treatment. And, chemotherapy is the main treatment for EGFR-TKIs resistant patients. WEE1 kinase, a G2/M checkpoint regulator, was recently considered as a putative biomarker for the platinum-based chemo-response. The aim of this study is to clarify the relationship between WEE1 kinase and chemosensitivity in EGFR-TKIs resistant NSCLC. WEE1 expression was tested in EGFR-TKIs resistant cell lines (H1299, PC9/G2) and patients' specimens by western blot, qPCR and immunohistochemistry (IHC). In in vitro experiment, WEE1 expression was higher in EGFR-TKIs resistant than EGFR-TKIs sensitive cell lines and was gradually increased following cisplatin or gemcitabine treatment with the enrichment of G2/M cell cycle phase. And, for patients with acquired Icotinib/Gefitinib resistance, 58.4% (7/12) had increased WEE1 expression compared to its initial expression level. In order to explore the impact of WEE1 on chemo-response, WEE1 knockdown was conducted in EGFR-TKIs resistant H1299 and PC9/G2 cells. MTT and colony formation assay showed that the efficacy of cisplatin and gemcitabine was enhanced in the two cell lines after WEE1 knockdown. And, the IC50 value of cisplatin decreased from 8.64 µg/ml to 3.10 µg/ml or 2.38 µg/ml in H1299 and from 3.66 µg/ml to 0.97 µg/ml or 1.18 µg/ml in PC9/G2 after WEE1 knockdown with two specific shRNAs. This study revealed that WEE1 expression was increased after EGFR-TKIs resistance, and WEE1 knockdown could enhance chemosensitivity in EGFR-TKIs resistant NSCLC. It is suggested the combination of WEE1 inhibitor and chemotherapy might improve the clinical outcome of NSCLC patients with acquired EGFR-TKIs resistance.