Anti-Resistant Strategies: Icotinib Derivatives as Promising Non-Small Cell Lung Cancer Therapeutics.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients often benefit from EGFR inhibitors like gefitinib. However, drug resistance remains a significant challenge in treatment. The unique properties of 1,2,3-triazole, a nitrogen-based compound, hold promise as potential solutions due to its versatile structural attributes and diverse biological effects, including anticancer properties. MATERIALS AND METHODS: Our synthesis process involved the huisgen cycloaddition chemical method, which generated diverse icotinib derivatives. We evaluated the anticancer capabilities of these derivatives against various cancer cell lines, with a specific focus on NSCLC cells that exhibit drug resistance. Additionally, we investigated the binding affinity of selected compounds, including 3l, towards wild-type EGFR using surface plasmon resonance (SPR) experiments. RESULTS: Notably, icotinib derivatives such as derivative 3l demonstrated significant efficacy against different cancer cell lines, including those resistant to conventional therapies. Compound 3l exhibited potent activity with IC50 values below 10 µM against drug-resistant cells. SPR experiments revealed that 3l exhibited enhanced affinity towards wild-type EGFR compared to icotinib. Our research findings suggest that 3l acts as a compelling antagonist for the protein tyrosine kinase of EGFR (EGFR-PTK). CONCLUSION: Icotinib derivative 3l, featuring a 1,2,3-triazole ring, demonstrates potent anticancer effects against drug-resistant NSCLC cells. Its enhanced binding affinity to EGFR and modulation of the EGFR-RAS-RAF-MAPK pathway position 3l as a promising candidate for the future development of anticancer drugs.

Successful Treatment of Switching EGFR-TKIs for Advanced Lung Adenocarcinoma Due to Interstitial Lung Disease: A Case Report.

INTRODUCTION: Icotinib and almonertinib are efficacious for non-small cell lung cancer (NSCLC) factor patients with epidermal growth receptor (EGFR)-mutation. Patients who previously used EGFR tyrosine kinase inhibitor (EGFR TKI) may switch to another one due to the adverse events. CASE PRESENTATION: Here, we report a case of a 73-year-old male patient with advanced lung adenocarcinoma in which an EGFR (exon 21 L858R substitution) was found. Icotinib (125mg three times daily) was administered initially. He achieved partial response two months later but developed acute interstitial lung disease (grade 2) with dry cough and chest tightness five months later. Icotinib was discontinued, and treatment with methylprednisolone improved the interstitial lung disease. Chemotherapy with pemetrexed, carboplatin, and bevacizumab was initiated as subsequent therapy. Considering the effectiveness of EGFR-TKIs, we decided cautiously to rechallenge the third-generation TKI almonertinib administration. The patient successfully received almonertinib for almost one year without the recurrence of interstitial lung disease and tumor progression. ILD was an infrequent but often life-threatening reaction associated with icotinib. CONCLUSION: This is the first reported case of successful switching from icotinib to another EGFR TKI because of interstitial lung disease associated with icotinib, suggesting that EGFR-TKIs rechallenge because of adverse events rather than progression might provide a significant benefit in patients with EGFR driver positive NSCLC.

Low Expression of SCN4B Predicts Poor Prognosis in Non-Small Cell Lung Cancer.

BACKGROUND: Sodium voltage-gated channel beta subunit 4 (SCN4B) plays a suppressive role in various tumors. However, the role of SCN4B in non-small cell lung cancer (NSCLC) is not yet clear. This study aims to investigate the expression of SCN4B in NSCLC patients and its correlation with prognosis. METHODS: Firstly, the expression of SCN4B in non-small cell lung cancer (NSCLC) was analyzed using The Cancer Genome Atlas (TCGA) database. Then, differential expression genes (DEGs) were identified using R software. Next, DEG enrichment pathways were analyzed using the R package clusterProfiler. Protein-protein interaction networks were revealed through STRING analysis. A heatmap showed significant differential expression of SCN4B. Further analysis included examining SCN4B expression in a pan-cancer context and its correlation with 24 types of immune cells in NSCLC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blot, immunohistochemistry, and clinical data were used to validate SCN4B expression and prognostic value in NSCLC patients. RESULTS: SCN4B mRNA expression in non-small cell lung cancer tissues was significantly lower than in adjacent normal tissues (p < 0.001). Clinical correlation analysis confirmed its association with clinical pathology. Gene set enrichment analysis (GSEA) and tumor immune-related analyses indicated that SCN4B is involved in NSCLC-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and participates in immune infiltration. qRT-PCR, Western Blot, and immunohistochemistry also confirmed that SCN4B is downregulated in NSCLC patients and is associated with poor prognosis. CONCLUSION: SCN4B is downregulated in tumor tissues of NSCLC patients and is associated with a poor prognosis.

Case report: Efficacy of icotinib treatment in lung adenocarcinoma with esophageal squamous cell carcinoma: a rare case of double primary malignant tumors.

Background: Lung adenocarcinoma with esophageal squamous cell carcinoma is rare and the prognosis is poor, therefore there is an urgent need to improve this situation. The objective of this study was to explore the effect of first-generation tyrosine kinase inhibitors (TKIs) in the patient of the double primary malignant tumors. Case report: We report a case of lung adenocarcinoma with esophageal squamous cell carcinoma treated by icotininb after five-year follow-up. A 71-year-old Chinese woman complaining of swallowing obstruction, heartburn, regurgitation of gastric acid for more than 2 months. An esophageal lesion was found by chest CT scans in T7 vertebral level. The diagnosis by gastroscopic biopsy was squamous cell carcinoma (SCC) with EGFR over-expression. Simultaneously, chest CT showed a 2 cm x 1 cm solitary lesion in the right superior pulmonary. The histological diagnosis by percutaneous lung Biopsy was "adenocarcinoma." Epidermal growth factor receptor (EGFR) gene mutation status was evaluated by Sanger sequencing, and an exon 21 point mutation (L858R) was identified. When the double primary malignant tumors were diagnosed, the patient refused operation and received a tyrosine kinase inhibitor (TKI), icotinib, at the dose of 125 mg, three times per day. All serum tumor biomarkers such as CEA and cancer antigen 125 (CA125) were in the normal range during the treatment period. After five-year follow-up, the patient has no evidence of recurrence or metastasis. The lung cancer was stable, meanwhile the esophageal lesion was almost cured. Conclusion: Icotininb is an effective treatment in the patients of the double primary malignant tumors of lung adenocarcinoma with EGFR gene mutation and esophageal squamous cell carcinoma with EGFR over-expression.

The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism.

This study aimed to investigate the interactions between icotinib/apatinib and oxycodone in rats and to unveil the underlying mechanism. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine oxycodone and its demethylated metabolite simultaneously. In vivo, Sprague-Dawley (SD) male rats were administered oxycodone with or without icotinib or apatinib. Blood samples were collected and subjected to UPLC-MS/MS analysis. An enzyme incubation assay was performed to investigate the mechanism of drug-drug interaction using both rat and human liver microsomes (RLM and HLM). The results showed that icotinib markedly increased the AUC(0-t) and AUC(0-∞) of oxycodone but decreased the CLz/F. The Cmax of oxycodone increased significantly upon co-administration of apatinib. In vitro, the Km value of oxycodone metabolism was 101.7 ± 5.40 µM and 529.6 ± 19.60 µM in RLMs and HLMs, respectively. Icotinib and apatinib inhibited the disposition of oxycodone, with a mixed mechanism in RLM (IC50 = 3.29 ± 0.090 µM and 0.95 ± 0.88 µM, respectively) and a competitive and mixed mechanism in HLM (IC50 = 22.34 ± 0.81 µM and 0.48 ± 0.05 µM, respectively). In conclusion, both icotinib and apatinib inhibit the metabolism of oxycodone in vitro and in vivo. Therefore, the dose of oxycodone should be reconsidered when co-administered with icotinib or apatinib.

The novel EGFR mutations (p.E746_S752delinsI, p.T751_I759delinsG, p.L747_S752delinsAA) in patients with non-small cell lung cancer and the clinical treatment strategy: three case reports.

Epidermal growth factor receptor (EGFR) is an established driver gene in non-small cell lung cancer (NSCLC) and the common Exon 19 del mutation (p.E746_A750 del) has exhibited remarkable responses for EGFR tyrosine kinase inhibitors (TKIs). However, there is even less comprehension of the treatment strategy in NSCLC patients harboring uncommon Exon 19 delins mutation. Here, we identified three novel EGFR Exon 19 mutations (p.E746_S752delinsI, p.T751_I759delinsG, p.L747_S752delinsAA), and described the clinical treatment process. To our knowledge, the EGFR p.E746_S752delinsI mutation of the patient with advanced NSCLC could benefit from the treatment with Icotinib. Otherwise, for the NSCLC patients with early-stage, one harboring p.T751_I759delinsG mutation had an excellent recovery and the other harboring p.L747_S752delinsAA experienced a relapse after receiving horacoscopic radical resection, which means the patients with different Exon 19 delins mutation might have different prognosis. Our study also demonstrated that next-generation sequencing (NGS) is a crucial tool in guiding clinical treatment decisions in NSCLC. Furthermore, the real incidence of these mutation is not known, the routinely use of NGS surely will increase the detection of EGFR del-ins respect to the old tools used to screen for EGFR mutations.

A fully validated method for simultaneous determination of icotinib, osimertinib, gefitinib and O-desmethyl gefitinib in human plasma using UPLC-MS/MS for therapeutic drug monitoring.

BACKGROUND AND AIMS: A few researches have reported the exposure-efficacy/toxicity relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). On account of the large interpatient pharmacokinetic variability, therapeutic drug monitoring (TDM) seems promising for optimizing dosage regimen and improving treatment efficacy and safety. Therefore, a rapid and convenient ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of icotinib, osimertinib, gefitinib and O-demesthyl gefitinib in human plasma for TDM. MATERIALS AND METHODS: Icotinib-D4 and osimertinib-13CD3 were used as the internal standards (ISs). The samples were prepared by protein precipitation using acetonitrile. Chromatographic separation was achieved on a 40 â„ƒ Shimadzu Shim-pack Scepter C18-120 column (2.1 ×50 mm, 3.0 µm, Japan) by a Shimadzu 30 A solvent management system. Detection was carried out using a Shimadzu LC-MS 8050CL triple quadrupole mass spectrometer coupled with an electrospray ionization source in positive mode. RESULTS: This analytical method was fully validated with selectivity, carry-over, linearity, lower limit of quantification, accuracy (from 92.68% to 106.62%) and precision (intra- and inter-day coefficients of variation ranged from 0.92% to 9.85%), matrix effect, extraction recovery, stability and dilution integrity. The calibration curves were developed to be within the concentration ranges of 200-4000 ng/mL for icotinib, 50-1000 ng/mL for osimertinib, gefitinib and O-desmethyl gefitinib in human plasma which meet the needs of routine TDM. CONCLUSIONS: The proposed method was used in 100 patients with non-small cell lung cancer for monitoring plasma concentration of the mentioned EGFR-TKIs. The trough concentrations of ICO were distributed between 226.42 ng/mL and 3853.36 ng/mL, peak concentrations were between 609.20 ng/mL and 2191.54 ng/mL. The trough concentrations of OSI were distributed between 110.48 ng/mL and 1183.13 ng/mL. The trough concentrations of GEF were distributed between 117.71 ng/mL and 582.74 ng/mL, while DeGEF was distributed from 76.21 ng/mL to 1939.83 ng/mL with two less than 20 ng/mL. The results of therapeutic drug monitoring aimed to investigate exposure-efficacy/toxicity relationship and improve the efficacy and safety of targeted therapies.

Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.

Small molecule protein kinase inhibitors approved by regulatory agencies outside of the United States.

Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.

Rapid vision improvement by using icotinib in a patient with bilateral choroidal metastases symmetrically from lung cancer.

INTRODUCTION: The metastases of lung cancer to bilateral choroids symmetrically and simultaneously are very rare. Almost all patients with choroid metastasis can be treated with external beam radiotherapy in order to increase quality of life and preserve vision. MATERIAL AND METHODS: We documented a case and studied the effect of icotinib on choroidal metastases in bilateral eyes simultaneously from pulmonary adenocarcinoma. RESULTS: A 49-year-old Chinese man presented with bilateral vision losing simultaneously for 4 weeks, it was as an initial presentation in the clinical. The examinations with ophthalmofundoscopy, ultrasonography, and fluorescein angiography showed the lesions in bilateral choroids, two solitary juxtapapillary yellow-white choroidal metastases inferior to the optic discs with bleeding. Positron emission tomography confirmed the choroidal metastases and further proved that it was from lung cancer with lymph nodes and multiple bone metastasis. The biopsy taken from the lung by bronchoscopy and needle biopsy from supraclavicular lymph nodes revealed the pulmonary adenocarcinoma with epithelial growth factor receptor mutation (exon 21). The patient was treated with oral icotinib (125 mg, three times a day, TID). Five days after starting icotinib therapy, the patient's visions were rapidly recovered. Two months after the treatment with icotinib, the choroidal metastases regressed to small lesions, and the visions were preserved to before. The lung tumor and other metastatic lesions were partly regressive. There was no evidence of recurrence for eye lesions at 15-months follow-up. After 17 months treating by icotinib, the patient presented headache and dizzy with multiple brain metastases determined by magnetic resonance imaging; however, the lesions of the choroidal metastases remained progressing-free. Almonertinib with radiotherapy were used to treat the brain metastases, and he is surviving with progress-free more than 2 years until now. CONCLUSION: Bilateral choroidal metastases from lung cancer symmetrically are very rare. Icotinib following by almonertinib was an alternative therapy for choroidal metastasis from non-small cell lung cancer with epithelial growth factor receptor mutation.

Randomized phase II adjuvant trial to compare two treatment durations of icotinib (2 years versus 1 year) for stage II-IIIA EGFR-positive lung adenocarcinoma patients (ICOMPARE study).

BACKGROUND: Despite the prolonged median disease-free survival (DFS) by adjuvant targeted therapy in non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the relationship between the treatment duration and the survival benefits in patients remains unknown. PATIENTS AND METHODS: In this multicenter, randomized, open-label, phase II trial, eligible patients aged 18-75 years with EGFR-mutant, stage II-IIIA lung adenocarcinoma and who had not received adjuvant chemotherapy after complete tumor resection were enrolled from eight centers in China. Patients were randomly assigned (1 : 1) to receive either 1-year or 2-year icotinib (125 mg thrice daily). The primary endpoint was DFS assessed by investigator. The secondary endpoints were overall survival (OS) and safety. This study was registered at ClinicalTrials.gov (NCT01929200). RESULTS: Between September 2013 and October 2018, 109 patients were enrolled (1-year group, n = 55; 2-year group, n = 54). Median DFS was 48.9 months [95% confidence interval (CI) 33.1-70.1 months] in the 2-year group and 32.9 months (95% CI 26.6-44.8 months) in the 1-year group [hazard ratio (HR) 0.51; 95% CI 0.28-0.94; P = 0.0290]. Median OS for patients was 75.8 months [95% CI 64.4 months-not evaluable (NE)] in the 2-year group and NE (95% CI 66.3 months-NE) in the 1-year group (HR 0.34; 95% CI 0.13-0.95; P = 0.0317). Treatment-related adverse events (TRAEs) were observed in 41 of 55 (75%) patients in the 1-year group and in 36 of 54 (67%) patients in the 2-year group. Grade 3-4 TRAEs occurred in 4 of 55 (7%) patients in the 1-year group and in 3 of 54 (6%) patients in the 2-year group. No treatment-related deaths or interstitial lung disease was reported. CONCLUSIONS: Two-year adjuvant icotinib was shown to significantly improve DFS and provide an OS benefit in EGFR-mutant, stage II-IIIA lung adenocarcinoma patients compared with 1-year treatment in this exploratory phase II study.

Prognosis prediction of icotinib as targeted therapy for advanced EGFR-positive non-small cell lung cancer patients.

Clinical trials on icotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), have shown promising results as targeted therapy for non-small cell lung cancer (NSCLC). This study aimed to establish an effective scoring system to predict the one-year progression-free survival (PFS) of advanced NSCLC patients with EGFR mutations treated with icotinib as targeted therapy. A total of 208 consecutive patients with advanced EGFR-positive NSCLC treated with icotinib were enrolled in this study. Baseline characteristics were collected within 30 days before icotinib treatment. PFS was taken as the primary endpoint and the response rate as the secondary endpoint. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox proportional hazards regression analysis were used to select the optimal predictors. We evaluated the scoring system using a five-fold cross-validation. PFS events occurred in 175 patients, with a median PFS of 9.9 months (interquartile range, 6.8-14.5). The objective response rate (ORR) was 36.1%, and the disease control rate (DCR) was 67.3%. The final ABC-Score consisted of three predictors: age, bone metastases and carbohydrate antigen 19-9 (CA19-9). Upon comparison of all three factors, the combined ABC-score (area under the curve (AUC)= 0.660) showed a better predictive accuracy than age (AUC = 0.573), bone metastases (AUC = 0.615), and CA19-9 (AUC = 0.608) individually. A five-fold cross-validation showed good discrimination with AUC = 0.623. The ABC-score developed in this study was significantly effective as a prognostic tool for icotinib in advanced NSCLC patients with EGFR mutations.

Development and internal validation of a nomogram for predicting survival of nonoperative EGFR-positive locally advanced elderly esophageal cancers.

Purpose: This study aims to develop and validate a prediction model for non-operative, epidermal growth factor receptor (EGFR)-positive, locally advanced elderly esophageal cancer (LAEEC). Methods: A total of 80 EGFR-positive LAEEC patients were included in the study. All patients underwent radiotherapy, while 41 cases received icotinib concurrent systemic therapy. A nomogram was established using univariable and multivariable Cox analyses. The model's efficacy was assessed through area under curve (AUC) values, receiver operating characteristic (ROC) curves at different time points, time-dependent AUC (tAUC), calibration curves, and clinical decision curves. Bootstrap resampling and out-of-bag (OOB) cross-validation methods were employed to verify the model's robustness. Subgroup survival analysis was also conducted. Results: Univariable and multivariable Cox analyses revealed that icotinib, stage, and ECOG score were independent prognostic factors for LAEEC patients. The AUCs of model-based prediction scoring (PS) for 1-, 2-, and 3-year overall survival (OS) were 0.852, 0.827, and 0.792, respectively. Calibration curves demonstrated that the predicted mortality was consistent with the actual mortality. The time-dependent AUC of the model exceeded 0.75, and the internal cross-validation calibration curves showed good agreement between predicted and actual mortality. Clinical decision curves indicated that the model had a substantial net clinical benefit within a threshold probability range of 0.2 to 0.8. Model-based risk stratification analysis demonstrated the model's excellent ability to distinguish survival risk. Further subgroup analyses showed that icotinib significantly improved survival in patients with stage III and ECOG score of 1 (HR 0.122, P<0.001). Conclusions: Our nomogram model effectively predicts the overall survival of LAEEC patients, and the benefits of icotinib were found in the clinical stage III population with good ECOG scores.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.

[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.

Icotinib, an EGFR tyrosine kinase inhibitor, as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE).

The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer.

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.

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.

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.