Erlotinib Group Research Articles

Bevacizumab Plus Erlotinib in Chinese Patients with Untreated, <i>EGFR</i>-Mutated, Advanced NSCLC (ARTEMIS-CTONG1509): A Multicenter Phase 3 Study

Most patients with advanced non-small-cell lung cancer (NSCLC) develop resistance to first-line treatment. However, dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathway inhibition may delay therapeutic resistance. We assessed erlotinib plus bevacizumab versus erlotinib alone in an open-label, phase 3 study of Chinese patients with untreated EGFR-mutated metastatic NSCLC. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Safety was assessed in all treated patients. In total, 311 patients received bevacizumab plus erlotinib (n=157) or erlotinib only (n=154). Median IRC-assessed PFS was 17.9 months (95% confidence interval [CI] 15.2–19.9) for bevacizumab plus erlotinib and 11.2 months (95% CI 9.7–13.8) for erlotinib only (Hazard Ratio 0.55 [95% CI 0.41–0.73], p < 0.001). Grade ≥3 treatment-related adverse events occurred in 86 (54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib significantly improved PFS in patients with untreated EGFR-mutated NSCLC. The baseline mutation landscape was comparable between the two groups with 41% of patients in bevacizumab plus erlotinib group and 45% of patients in erlotinib group harboring concurrent mutations including amplification, oncogenic frusions, MAPK/PI3K alterations and cell cycle gene alterations. The addition of bevacizumab[WT1] did not alter the molecular dynamics of mutations during the course of treatment. At disease progression, EGFR T790M was the major resistance mechanism, acquired by 40% of patients in bevacizumab plus erlotinib group and 61% of patients in erlotinib only group, with a comprable detection rate in both groups (p=0.188).

Incidence of T790M in Patients With NSCLC Progressed to Gefitinib, Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA

BackgroundInsights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non–small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib. Patients and MethodsThe present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay. ResultsA total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001). ConclusionsAlthough gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.

Efficacy comparison of erlotinib and pemetrexed in treatment of advanced non-small cell lung cancer

Objective To compare the efficacy of erlotinib and pemetrexed in treatment of advanced non-small cell lung cancer (NSCLC) and its effect on the immunity of patients. Methods A total of 82 patients with NSCLC at the First Affiliated Hospital of Hainan Medical College from June 2014 to May 2018 were retrospectively analyzed. According to the different treatment methods, the patients were divided into erlotinib group (150 mg/d, oral administration, 2 hours after the meal) and pemetrexed group (500 mg/m2, intravenous drip, 21-day each cycle). There were 41 cases in each group. The clinical effects of the two groups were analyzed. Flow cytometry was used to detect the immune index. Results The objective effective rate in pemetrexed group was lower than that in erlotinib group [34.2% (14/41) vs. 39.0% (16/41), χ2 = 0.210, P = 0.647). There was no significant difference in T lymphocyte subsets between the two groups before and after treatment (both P > 0.05). The values of CD3+ T cells, CD4+ T cells, CD4+/CD8+ in both groups after the treatment were decreased compared with the values before the treatment; CD8+ T cells was increased after the treatment compared with the value before the treatment (all P < 0.05). Quality of life questionnaire-C30 (QLQ-C30) score in erlotinib group was higher than that in pemetrexed group [(75.1±13.5) vs. (68.9±12.9), t = 2.158, P = 0.017]. Myelosuppression and gastrointestinal reactions were the main adverse events in pemetrexed group; rashes and diarrhoea were the main adverse reactions in erlotinib group. Grade Ⅰ-Ⅱ side effects occurred in both groups. There were statistical differences in the incidence of myelosuppression, gastrointestinal reactions, rashes and diarrhoea of both groups (all P < 0.05). Conclusions The efficacy of erlotinib and pemetrexed in treatment of advanced NSCLC is similar, and both of them could regulate the immune response. Erlotinib has a significant advantage in improving the quality of life. Key words: Carcinoma, non-small cell lung; Erlotinib; Pemetrexed; T-lymphocyte subsets; Adverse reactions

Brain MRI imaging characteristics predict treatment response and outcome in patients with de novo brain metastasis of EGFR-mutated NSCLC.

Patients with non-small cell lung cancer (NSCLC) and de novo brain metastasis (BM) have poor prognosis. We aim to investigate the characteristic of brain magnetic resonance (MR) imaging and the association with the treatment response of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for lung cancer with BM.EGFR-mutated NSCLC patients with BM from October 2013 to December 2017 in a tertiary referral center were retrospectively analyzed. Patient's age, sex, cell type, EGFR mutation status, treatment, and characteristics of BM were collected. Survival analysis was performed using Kaplan-Meier method. The efficacy of different EGFR-TKIs were also analyzed.Among the 257 eligible patients, 144 patients with Exon 19 deletion or Exon 21 L858R were included for analysis. The erlotinib group had the best progression free survival (PFS) (median PFS 13 months, P = .04). The overall survival (OS) revealed no significant difference between three EGFR-TKI groups. Brain MR imaging features including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen or cerebellum) were factors associated with poor prognosis. Patients with poor prognostic imaging features, the high-risk group, who received erlotinib had the best PFS (median PFS 12 months, P < .001). However, the OS revealed no significant difference between 3 EGFR-TKI groups. The low risk group patients had similar PFS and OS treated with three different EGFR-TKIs.In NSCLC patients with common EGFR mutation and de novo BM, those with poor prognostic brain MR characteristics, erlotinib provided better PFS than afatinib or gefitinib.

Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague–Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles

Gastrointestinal toxicity is a frequently observed adverse event during cancer treatment with traditional chemotherapeutics. Currently, traditional chemotherapeutics are often combined with targeted biologic agents. These biologics, however, possess a distinct toxicity profile, and they may also exacerbate the adverse effects of traditional chemotherapeutics. In this study, we aimed to characterize the gastrointestinal and metabolic changes after a 2-week treatment period with aflibercept, an antiangiogenic VEGFR decoy, and with erlotinib, a tyrosine-kinase inhibitor. Male rats were treated either with aflibercept or erlotinib for 2 weeks. During the 2-week treatment period, the animals in the aflibercept group received two subcutaneous doses of 25 mg/kg aflibercept. The erlotinib group got 10 mg/kg of erlotinib by oral gavage every other day. The control groups were treated similarly but received either saline injections or oral gavage of water. Intestinal toxicity was assessed by measuring intestinal permeability and by histological analyses of intestinal tissues. Metabolic changes were measured with 1H nuclear magnetic resonance in serum and urine. Neither aflibercept nor erlotinib induced changes in intestinal permeability or intestinal tissue morphology. However, aflibercept treatment resulted in stunted body weight gain and altered choline, amino acid, and lipid metabolism. Two-week treatment with aflibercept or erlotinib alone does not induce observable changes in gastrointestinal morphology and function. However, observed aflibercept-treatment related metabolic changes suggest alterations in intestinal microbiota, nutrient intake, and adipose tissue function. The metabolic changes are also interesting in respect to the systemic effects of aflibercept and their possible associations with adverse events caused by aflibercept administration.

Induction chemotherapy with and without erlotinib in patients with oral cavity squamous cell carcinomas (OCSCCs) amenable for surgical resection.

6067 Background: We have previously demonstrated activity of erlotinib in head and neck SCCs as monotherapy prior to surgical resection, or in combination with chemotherapy for recurrent/metastatic disease (William et al. ASCO 2011, 2017). The aim of this study was to evaluate the efficacy of induction chemotherapy with a platinum-taxane regimen and explore the potential benefit of erlotinib as part of induction therapy in patients with resectable OCSCCs. Methods: This was a randomized, placebo-controlled, phase II trial of induction chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 6 with docetaxel 75 mg/m2 every 3 weeks for 3 cycles) with erlotinib (150mg oral daily) or placebo in patients with OCSCCs stage III-IVB amenable for surgical resection. The primary endpoint was major pathological response (MPR, defined as &lt; 10% viable tumor cells in the surgical specimen). Secondary endpoints included safety and long-term efficacy outcomes. Results: From April 1, 2014, to June 7, 2017, 52 patients were enrolled, of whom 47 underwent planned surgery. MPR was achieved in 7/23 (30%) in the erlotinib group and 10/24 (41%) in the placebo group. With a median follow up of 26.5 months, the 2-year long-term progression-fee survival (PFS) were estimated at 75% (95% CI: 59.5-94.5) in the erlotinib arm, and 58.6% (95% CI: 40.9-84.1) in the placebo arm, and 2-year overall survival at 73.5% (95% CI: 57.2-94.5) for the erlotinib group and 73.1% (95% CI: 55.9-95.6) for the placebo group. In patients who achieved MPR (n = 17), the 2-year PFS was 77.4% (95% CI: 57.3-100), compared to 64.5% (95% CI: 49.0-84.8) in patients who did not achieve MPR (n = 29, p = .16). All 7 patients in the erlotinib group who achieved MPR remained disease-free. The majority of patients (87%) completed all 3 cycles of induction chemotherapy. The common side effects were expected and distributed similarly between erlotinib and placebo groups. As expected, rash, diarrhea and dehydration were more common in the erlotinib group. Conclusions: Platinum and docetaxel-based induction chemotherapy induced major pathological response in 17/47 (36%) of resectable OCSSC patients. Two-year overall survival was 73%. Responders had improved long-term outcome. Addition of erlotinib did not improve the rate of MPR, but might have contributed to improved PFS. Clinical trial information: NCT01927744.

Difference in central nerve system metastasis during gefitinib or erlotinib therapy in patients with EGFR-mutated non-small cell lung cancer: a retrospective study.

Central nervous system (CNS) metastasis is a poor prognostic factor in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation EGFR-mutant NSCLC and is associated with a deteriorated quality of life (QOL). Some clinical studies have suggested a possible difference in the incidence of CNS metastasis between EGFR-mutant NSCLC patients treated with gefitinib and erlotinib, both of which are classified as first-generation EGFR tyrosine kinase inhibitors (TKIs). However, the difference in the incidence of CNS metastasis between patients receiving these two drugs has not yet been sufficiently well investigated. We analyzed the frequency of occurrence/progression of CNS metastasis in EGFR-mutant NSCLC patients treated with erlotinib and gefitinib as the first-line treatment. We analyzed the incidence of CNS metastasis, frequency of progression of CNS metastasis and the treatment outcomes in EGFR-mutant patients who received gefitinib or erlotinib as the first-line EGFR-TKI treatment. CNS progressive disease (PD) was defined as progression of CNS metastasis during EGFR-TKI treatment. We also evaluated the progression-free survival (PFS), CNS-PFS, and overall survival (OS) of the patients who received each of the two drugs. A total of 170 patients were enrolled in the study, of which 144 had received gefitinib, and 26 had received erlotinib. The frequency of CNS PD in the erlotinib group tended to be lower than that in the gefitinib group (11.5% vs. 29.9%, P=0.06). In patients with no existing CNS metastasis at the start of the EGFR-TKI treatments, the incidence of CNS PD was significantly lower in the erlotinib group than that in the gefitinib group (4.8% vs. 24.5%, P=0.04). A re-biopsy after failure of EGFR-TKI treatment was performed in 48 patients. The incidence of EGFR T790M tended to be higher among patients with CNS PD than in those without CNS PD, although the difference was not statistically significant (66.7% vs. 40.4%; P=0.23). The incidence of progression of CNS metastasis during erlotinib treatment was lower than that during gefitinib treatment. In addition, the difference in the incidence in patients without existing CNS metastasis at the time of start of EGFR-TKI treatment was significantly lower in the patients treated with erlotinib than in those treated with gefitinib.

Abstract P3-10-15: Evaluating contribution of hyperactive c-Met and ErbB signaling to tumor progression in mouse breast tumor xenografts: An in vivo study of c-Met and ErbB targeted therapies

Abstract Background: Hyperactive c-Met signaling, including cross-talk between c-Met and ErbB family receptors, is suspected of contributing to tumor progression in a variety of cancer types. Clinical trials evaluating c-Met inhibitors alone and in combination with other targeted therapies, have produced mostly negative results in patients with amplified c-Met. This suggests other biological factors, such as c-Met and ErbB signaling activity, may be important to measure when identifying patients eligible for c-Met therapies. To measure the c-Met and ErbB signaling activity of a patient's live tumor cells, a new assay using an impedance biosensor, the CELx multi-pathway signaling function (CELx MP) test, was developed. The CELx MP test measures a patient's ex vivo live tumor cell response in real-time to specific ErbB and c-Met agonists to diagnose breast cancer tumors with hyperactive HER1, HER2, HER3, HER4, and c-MET signaling activity. In this study, to further elucidate the role of c-Met signaling and its potential involvement with ErbB signaling as a cancer driver, we studied in vivo response to a c-Met inhibitor (tepotinib), an EGFR inhibitor (erlotinib), a pan-HER inhibitor (neratinib), and a combination of these therapies using breast tumor xenograft models. Methods: HCC1954, a HER2+ cell line with hyperactive c-Met and EGFR signaling and normal HER3 and HER2-driven signaling, according to the CELx MP test, was studied. Sixty 4-5-week-old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or one of five treatment groups that received either neratinib, tepotinib, erlotinib, erlotinib and tepotinib, or neratinib and tepotinib for 17 days. Results: The most effective treatment was the combination of neratinib plus tepotinib, where the average tumor size reduction relative to the control group was 71% (p=0.0003). The average tumor size in the neratinib plus tepotinib treated group was 37% smaller (p=0.049) than the neratinib treated group, and 67% smaller (p=0.0026) than the tepotinib treated group. In the erlotinib plus tepotinib treatment group, the average tumor size was 51% smaller than the control group tumors, but the difference was not statistically significant (p=0.11). No significant difference in tumor size was found between the control group and the erlotinib or tepotinib treated groups. Conclusions: The results demonstrate that hyperactive and coincident c-Met and EGFR signaling contributes to the progression of certain breast cancers. This breast cancer sub-type is more responsive to treatment with a c-Met inhibitor plus a pan-HER inhibitor than a c-Met inhibitor plus an EGFR inhibitor or any of the single agents studied. This suggests that when hyperactive c-Met signaling and a hyperactive ErbB family member is present in a patient's tumor, each of the ErbB pathways as well as the c-Met pathway must be inhibited to treat the tumor most effectively. These findings provide strong evidence that HER2-negative breast cancer patients with coincident hyperactive c-MET and ErbB signaling may respond to treatment with a combination of pan-HER and c-Met inhibitors. Citation Format: Laing LG, Burns DJ, Khan S, MacNeil IA, Rich BE, Kharbush SM, Soltani SM, Sullivan BF. Evaluating contribution of hyperactive c-Met and ErbB signaling to tumor progression in mouse breast tumor xenografts: An in vivo study of c-Met and ErbB targeted therapies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-15.

Repeat biopsy procedures and T790M rates after afatinib, gefitinib, or erlotinib therapy in patients with lung cancer

ObjectivesAfatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used for EGFR-mutant non-small cell lung cancer (NSCLC). However, there are few reports about its resistance mechanisms. The aims of this study are to evaluate resistance mechanisms of afatinib compared with other TKIs and analyze the performance of repeat biopsy which is critical for subsequent treatment. Materials and methodsWe screened EGFR-mutant NSCLC patients who started first-line afatinib, gefitinib, or erlotinib from 2014 to 2016, and included patients who acquired resistance. Among those patients, T790 M mutation rates and histologic transformation were compared as an acquired resistance mechanism. ResultsA total of 524 patients started EGFR-TKIs, and 347 experienced disease progression until April 2018. After excluding nine patients with de novo T790 M mutations or who were treated with two TKIs before repeat biopsy, 338 patients were included. Among these patients, 263 (78%) were successfully biopsied and evaluated for EGFR mutations and histologic transformation. T790 M mutation was documented in 35 (41%) of 86 evaluable patients in afatinib group, which is significantly lower than in gefitinib (55%, 73/133) and erlotinib groups (57%, 25/44) (p = 0.026). In multivariate analysis considering both baseline EGFR mutation types (deletion 19 or L858R) and sex, the odds ratio for T790M in afatinib group was 0.45 (95% confidence interval: 0.254-0.795, p = 0.006), compared with gefitinib or erlotinib groups. Five histologic transformations (two small cell, three squamous cell) were detected in afatinib group, while one small cell transformation was detected in gefitinib group, and no transformations were detected in erlotinib group. ConclusionsIn our clinical practice, repeat biopsy was possible in nearly four of five patients. Although T790 M mutation appears to be the main resistance mechanism for afatinib, it affects a lower proportion of patients than observed with first-generation TKIs.

Preventive effect of Diallyl Trisulfide on cutaneous toxicities induced by EGFR inhibitor

Cutaneous toxicities are the commonest side effects in patients with cancer treated using epidermal growth factor receptor inhibitors such as erlotinib. For patients with such toxicities, there is a lack of safe, effective pharmacological agents. Here we established a skin toxicity model and investigated the preventive and therapeutic effect of Diallyl Trisulfide (DATS) in vivo. The mouse skin toxicities model was established through continuous administration of erlotinib for 49 days. Meanwhile, the mice in the experimental group underwent DATS treatment for 49 days. Hematoxylin and eosin (HE) staining and oil red O staining of back and limb skin was performed to determine whether DATS aqueous extract can reverse the skin toxicities caused by erlotinib. Compared with the erlotinib group, the incidence of rash in the DATS group was lower. In addition, in the DATS group, the degree of skin redness and herpes was mild, the body weight was stable, and the activity was favorable. By comparing the HE and oil red O staining results for the mouse skin, the degree of keratin hyperplasia was determined to be lower in the experimental group than in the erlotinib group, and the number of purulent neutrophils decreased. The number of follicles was relatively less. The release of TNF-α, IL-6 and other inflammatory factors was reduced by DATS. Erlotinib hydrochloride can cause severe skin toxicities, and DATS prevents skin toxicities, its mechanism may be related to DATS reduced erlotinib-induced inflammatory injury.

Erlotinib versus gefitinib for brain metastases in Asian patients with exon 19 EGFR-mutant lung adenocarcinoma: a retrospective, multicenter study

BackgroundThe purpose of this study was to compare clinical outcomes of Erlotinib versus Gefitinib in the treatment of Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and newly diagnosed brain metastases.MethodsConsecutive Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and newly diagnosed brain metastases were identified and initially received peroral administration of 150 mg/d erlotinib or 250 mg/d gefitinib during 2009–2015. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS) was the second endpoint.ResultsThe cohort consisted of 227 Asian patients (erlotinib-treated cohort: n = 112, mean age = 58.5 years [SD: 20.13]; gefitinib-treated cohort: n = 115, mean age = 58.4 years [SD: 19.52]). In a multivariate analysis controlling for age, sex and time span of smoking history, significant difference was detected in the 36-month OS between erlotinib and gefitinib groups (58.3% vs. 49.1%, p = 0.012). There was also significant difference in the 36-month PFS between erlotinib and gefitinib groups (64% vs. 53%, p = 0.013).ConclusionFor Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and brain metastases, erlotinib was associated with a significantly longer OS and a more prolonged PFS and compared with gefitinib.

Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations

BackgroundCompared with standard chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, data comparing the efficacies of different EGFR−TKIs, especially regarding the presence of brain metastasis, are lacking.MethodsEGFR-TKI naive patients with recurrent or stage IIIB/IV NSCLC harboring EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively determined progression-free survival (PFS) using the Kaplan−Meier method with log-rank test in patients treated with either gefitinib or erlotinib, cumulative incidence of central nervous system (CNS) progression using the Fine and Gray competing risk regression model, and favorable prognostic factors for CNS progression by multivariate analysis.ResultsSeventy-seven EGFR-TKI-naive patients were started on either gefitinib (n = 55) or erlotinib (n = 22) in our hospital from April 2010 to April 2016. Among the patients with brain metastasis, PFS tended to be longer in the erlotinib than in the gefitinib group. In the analysis of cumulative incidence, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, in a subgroup analysis of the patients with brain metastasis, there was a significant difference between the erlotinib and gefitinib groups (hazard ratio 0.25; 95% confidence interval, 0.08–0.81; p = 0.021). Of the prognostic factors for CNS progression evaluated, the absence of brain metastasis before EGFR-TKI therapy and receiving erlotinib (vs gefitinib) had a significantly favorable effect on patient prognosis.ConclusionAlthough this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than gefitinib for treatment of brain metastasis in patients with EGFR-mutant NSCLC.

Concurrent EGFR-TKI and Thoracic Radiation Therapy as 1st-Line Treatment of Stage IV NSCLC Patients Harboring EGFR Active Mutation (CERTAIN study)

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been approved as first-line standard treatment for stage IV non-small cell lung cancer (NSCLC) patients harboring active EGFR mutation. As reported, EGFR-TKI could radiosensitize tumor cells in vitro and thoracic radiotherapy (TRT) could improve the local control of primary lesion. A prospective CERTAIN study on the combination of EGFR-TKI with TRT as first-line treatment for stage IV NSCLC patients has been registered on ClinicalTrials.gov (NCT 02353741). This is an open-labeled, single-arm, phase II clinical trial aiming to evaluate the efficacy and safety of EGFR-TKI combined with TRT as first-line treatment for stage IV NSCLC patients harboring EGFR active mutation. According to ENSURE study (Wu YL, et al. Ann Oncol. 2015, 26(9):1883), the 1-year progression-free survival (PFS) rate of erlotinib group is 43% and the PFS is 11.0 months. In the current study, the estimated 1-year PFS rate is 60%. According to Freedman rule at one-sided α=0.1, β=0.2, the sample size should be 47. Enrolled patients receive EGFR-TKI (gefitinib 250mg or erlotinib 150 mg qd) plus TRT (54-60Gy/27-30F/5.5-6w) within 2 weeks until disease progression or intolerable toxicities. The primary endpoint is 1-year PFS rate. The secondary endpoints include PFS, time to progression of irradiated lesion (iTTP), objective response rate (ORR), overall survival (OS), and side effects. From January 2015 to February 2018, the median follow-up was 14.3 months. Altogether 175 patients were screened, among whom there were 53 patients declining radiotherapy, 79 cases with uncontrolled intracranial metastasis, pleural effusion and bone metastases, 24 cases who previously received chemotherapy, 8 cases who received TRT more than two weeks later, and 2 cases with uncompleted TRT. Finally, 9 patients (5 male and 4 female) with a median age of 53.7 years (range, 40-75) were eligible. The mean dose limit of both lungs was V20 12%, V30 8%, V5 40%, MLD 5.25Gy. Kaplan-Meier analysis showed that the 1-year PFS rate was 44.4%, PFS was 9.6 months. iTTP was 12.6 months, ORR was 77.8% and OS was immature. The incidence of treatment-related side effects of all grades was 44.4% (4/9). The side effects of grade 3 or higher were radiation pneumonia (33.3%, 3/9) and rash (22.2%, 2/9). One patient died of radiation pneumonia. Compared with ENSURE study, the current study showed no significant improvement in 1-year PFS rate or PFS. The iTTP was 12.6 months, suggesting that TRT could achieve a long-term local control. The risk of severe radiation pneumonia should be considered.

P2.13-20 The Comparative Effectiveness of Gefitinib Versus Erlotinib on the Intracranial Progression-Free Survival in Patients with Brain Metastasis

The high peak plasma concentrations and better blood-brain barrier permeability of erlotinib compared with gefitinib was reported. However, there were few researches comparing their treatment effect for brain metastasis. This study aimed to investigate the comparative effectiveness of gefitinib versus erlotinib on the survival in patients with brain metastasis from lung adenocarcinoma. Incident lung adenocarcinoma patients at National Taiwan University Hospital between Jan 2013 and May 2015 were reviewed and analyzed. The inclusion criteria were: (1) tumor harboring either EGFR exon 19 deletion or L858R mutation (2) patient taking gefitinib or erlotinib as their first-line treatment (3) patients with brain metastasis. Kaplan-Meier analyses with long-rank testing were used to estimate the intracranial progression-free survival (PFS) and overall survival between the gefitinib and erlotinib group. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence intervals (CI) for age, gender, gefitinib vs. erlotinib, Eastern Cooperative Oncology Group performance status(ECOG), and pre-treatment for brain metastasis. Cumulative incidence of intracranial progression using competing risks regression model was also conducted. A total of 84 patients were included; 61 patients were female. 37 patients harbored EGFR exon 19 deletion. 39 patients received erlotinib as their first-line treatment.73 patients had Eastern Cooperative Oncology Group performance status scores of 0-1. 48 patients had multiple brain metastases (number >5) and 14 patients had brain metastasis ≥ 3 cm in size. 25 patients received whole brain radiation therapy and 7 patients received stereotactic radiosurgery before taking the tyrosine kinase inhibitors. The median overall survival for the gefitinib group and the erlotinib group was 874 vs. 750 days (p=0.86, Fig 1), and the median intracranial PFS 652 vs. 833 days (p=0.38, Fig 2). Multivariable analysis indicated that erlotinib was associated with a better intracranial PFS. (HR: 0.34, 95% CI: 0.12-0.97). The competing risks regression model showed erlotinib was associated with a trend toward lower probability of intracranial progression, with adjusted subdistribution hazard ratio of 0.40 (95% CI, 0.16-1.03; p=0.06, Fig 3). In patients with brain metastasis from lung adenocarcinoma, this study showed the beneficial effectiveness of erlotinib on the intracranial progression-free survival compared with gefitinib.

Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial

Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC. In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175. Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported. Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC. National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.

Gefitinib provides similar effectiveness and improved safety than erlotinib for east Asian populations with advanced non\u2013small cell lung cancer: a meta-analysis

BackgroundThe first-generation epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have both been proven effective for treating advanced non–small cell lung cancer (NSCLC), especially in East Asian patients. We conducted this meta-analysis to compare their efficacy and safety in treating advanced NSCLC in this population.MethodsWe systematically searched PubMed, ScienceDirect, The Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar for the relevant studies. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) were analyzed as primary endpoints.ResultsWe identified 5829 articles, among which 31 were included in the final analysis. Both gefitinib and erlotinib were effective for treating advanced NSCLC, with comparable PFS (95% confidence interval [CI]: 0.97–1.10, p = 0.26), OS (95% CI: 0.89–1.21, p = 0.61), ORR (95% CI: 1.00–1.18, p = 0.06), and DCR (95% CI: 0.93–1.05, p = 0.68). Erlotinib induced a significantly higher rate of dose reduction (95% CI: 0.13–0.65, p = 0.002) and grade 3–5 AEs (95% CI: 0.27–0.71, p = 0.0008). In subgroup analysis of AEs, the erlotinib group had a significantly higher rate and severity of skin rash, nausea/vomiting, diarrhea, fatigue and stomatitis.ConclusionsWith equal anti-tumor efficacy and fewer AEs compared with erlotinib, gefitinib is more suitable for treating advanced NSCLC in East Asian patients. Further large-scale, well-designed randomized controlled trials are warranted to confirm our findings.

Clinical efficacy and pharmacoeconomics analysis of three targeted drugs in the treatment of non-small cell lung cancer

Objective To compared the clinical efficacy and pharmacoeconomics of gefitinib, erlotinib, icotinib in the treatment of non-small cell lung cancer (NSCLC), thus to provide guidance on drug selection for patients from safety, efficiency and economical aspects after medical reform. Methods The patients with NSCLC who admitted to the First Affiliated Hospital of China Medical University from 2014 to 2017 and treated by gefitinib, erlotinib, icotinib were selected (30 patients in each group). All the patients were diagnosed with NSCLC by tissue or cytology study and eventually disease progressed.The clinical efficacy of the three drugs was evaluated by retrospective analysis.Specially, cost-effectiveness and cost-utility were evaluated in terms of disease control rates(DCR) and quality adjusted life years(QALY), respectively. Results The results demonstrated that the progression free survival (PFS) of gefitinib, erlotinib and icotinib were 0.934 years, 1.079 years and 1.063 years, respectively.There was no statistically significant difference in PFS among the three groups(F=0.001, P=0.9 990). The major drug adverse reactions were rash, diarrhea and hepatic injury.The DCR of gefitinib, erlotinib and icotinib were 66.7%, 70.0% and 63.3%, respectively, the difference was statistically significant(χ2=0.300, P=0.8 607). The total cost of treatment in the three groups were 85 118 CNY, 70 513 CNY and 7 2213 CNY, respectively.The cost-utility ratios of three drugs were 91 133, 65 389 and 67 973, respectively.The cost-effectiveness ratios of three drugs were 1 276, 1 007 and 1 141, respectively.The erlotinib group had lower cost and higher utility (effectiveness). Sensitivity analysis showed that the conclusion was relative stable when the price of three drugs changed at the same time. Conclusion All of the three drugs are applicable for targeted therapy of NSCLC and show similar curative effect and adverse reaction.However, erlotinib shows better economy than others. Key words: Carcinoma, non-small-cell lung; Costs and cost analysis; Gefitinib; Erlotinib; Icotinib

Gefitinib provides similar effectiveness and improved safety than erlotinib for advanced non-small cell lung cancer: A meta-analysis.

The epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib are effective for advanced non-small cell lung cancer (NSCLC). This meta-analysis compared their effectiveness and safety. We searched systematically in PubMed, ScienceDirect, The Cochrane Library, Scopus, Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar for relevant clinical trials regarding gefitinib versus erlotinib for NSCLC. Antitumor effectiveness (overall survival [OS], progression-free survival [PFS], objective response rate [ORR] and disease control rate [DCR]) and adverse effects [AEs]) were assessed. Forty studies comprising 9376 participants were included. The results suggested that gefitinib and erlotinib are effective for advanced NSCLC with comparable PFS (95% confidence intervals [CI]: 0.98-1.11, P = .15), OS (95% CI: 0.93-1.19, P = .45), ORR (95% CI: 0.99-1.16, P = .07), and DCR (95% CI: 0.92-1.03, P = .35). For erlotinib, dose reduction was significantly more frequent (95% CI: 0.10-0.57, P = .001) as were grade 3 to 5 AEs (95% CI: 0.36-0.79, P = .002). In the subgroup analysis, the erlotinib group had a significant higher rate and severity of skin rash, nausea/vomiting, fatigue, and stomatitis. Gefitinib was proven to be the better choice for advanced NSCLC, with equal antitumor effectiveness and fewer AEs compared with erlotinib. Further large-scale, well-designed randomized controlled trials are warranted to confirm our validation.

Comparison of the effects of the three major tyrosine kinase inhibitors as first-line therapy for non-small-cell lung cancer harboring epidermal growth factor receptor mutations

IntroductionPatients with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR)-activating mutations have good response rate and longer progression-free survival (PFS) when treated with the tyrosine kinase inhibitors (TKI) compared with platinum-based chemotherapy. However, studies comparing the effectiveness of these drugs as first-line therapy in such patients are limited.ResultsWe analyzed 422 patients with EGFR-mutated advanced lung adenocarcinoma receiving first-line gefitinib (n = 195, 46.2%), erlotinib (n = 123, 29.1%), or afatinib (n = 104, 24.6%). The PFS of the afatinib group was longer (12.2 months) than that of the gefitinib group (9.8 months) (p = 0.035) but similar to that of the erlotinib group (11.4 months) (p = 0.38). In patients without brain metastasis (BM), subgroup analysis showed that the afatinib group had significantly longer PFS (13.1 months) than erlotinib (11.7 months) and gefitinib (9.8 months) groups (p = 0.010). Patients with exon 19 deletions in the afatinib and erlotinib groups had potentially long PFS (p = 0.073). Efficacy of afatinib was similar between the 30 mg and 40 mg arms (median PFS 16.1 months vs. 10.3 months; p = 0.923).ConclusionsAfatinib may be the optimal EGFR-TKI for advanced lung adenocarcinoma harboring EGFR-activating mutations, particularly in the absence of BM. Patients with exon 19 deletions taking afatinib had potentially long PFS. An afatinib dose of 30 and 40 mg has similar effect.MethodsWe conducted this retrospective study at a single medical center from January 2013 to March 2017 and used PFS to evaluate the effectiveness of gefitinib, erlotinib, and afatinib in patients with advanced lung adenocarcinoma harboring EGFR mutations.

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model.

Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82±1.03%, 4.83±0.25%, and 2.62±0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11±2.00%, 5.73±1.31%, and 2.69±0.31%, respectively. Gefitinib exhibited the strongest antitumor activity (pgefitinib vs. erlotinib=0.005; pgefitinib vs. icotinib=0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib (p=0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group (pgefitinib vs. erlotinib=0.995; pgefitinib vs. icotinib=0.028; perlotinib vs. icotinib=0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib.