Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors In Patients Research Articles

492P - Feasibility of rebiopsy and sequential treatment of EGFR tyrosine kinase inhibitors in real world patients with EGFR mutant non-small cell lung cancer

BackgroundThe third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is a standard treatment in case of T790M mutation positive after failure to first or second generation EGFR TKI in patients with EGFR-mutant non-small cell lung cancer (NSCLC). We investigated a success rate of rebiopsy and sequential EGFR TKI treatment in real world setting in Korea. MethodsWe retrospectively reviewed medical records of patients with EGFR mutant advanced NSCLC who received first- or second- generation EGFR TKI between Jan 2012 and Jun 2018 at a single center in Korea. ResultsAmong 221 patients with EGFR-mutant NSCLC, 68 patients who were lost to follow up (n = 19) or still on 1st- or 2nd- generation TKI (n = 49) at time of analysis were excluded. Forty-three out of remaining 153 patients (28%) did not have a chance of consideration for second line treatment because of deterioration of performance status (n = 21) or death (n = 22), especially in elderly over 70 years. Tests for acquired EGFR mutation were performed in 76% (84/110), among which 73 cases were tissue rebiopsy and 11 cases were plasma EGFR mutation analysis. Acquisition of tumor tissue in rebiopsy was successful in 93% (68/73). The most common reason of not doing rebiopsy was lack of sequential treatment options (n = 24). Ten patients with negative T790M or failure at initial rebiopsy underwent more than two times of repeated EGFR mutation analysis, among which four patients had eventually positive T790M at some point of disease course. Overall T790M positive rate was 54% (45/84). Among 7 patients with initially negative T790M mutation in plasma analysis, further rebiopsy from tumor tissue was performed only in one patients because of patient's refusal (n = 2), physician's decision to continue post-progression EGFR TKI (n = 2), poor performance status (n = 1), and unaccessibility to tumor tissue (n = 1). ConclusionsAbout 30% of patients with EGFR mutant NSCLC did not have a chance of consideration for second line EGFR TKI treatment, especially in elderly over 70 years. Success rate of tumor tissue rebiopsy was over 90% in real world setting, and repeated rebiopsy may increase detection rate of acquired T790M mutation. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer.

Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable genomic drivers of non-small cell lung cancer (NSCLC), occurring in approximately 50% and 10-15% of adenocarcinomas of the lung in Asian and Western populations, respectively. The most common EGFR-activating mutations, the exon 19 deletion and the L858R point mutation occurring in the receptor tyrosine kinase domain, are susceptible to inhibition. The first EGFR tyrosine kinase inhibitors (TKIs) to be evaluated were the reversible first-generation EGFR TKIs, gefitinib and erlotinib, followed by the irreversible second-generation EGFR TKIs, afatinib and dacomitinib. The study of acquired resistance mechanisms to first- and second-generation EGFR TKIs in patients with activating EGFR-mutated NSCLC identified the gatekeeper T790M point mutation, present in over 50% of cases, as the most common mechanism of acquired resistance. The need to overcome this resistance mechanism led to the development of third-generation EGFR TKIs, of which osimertinib is the only one to date with regulatory approval. In this review, we present the clinical context leading to the development of third-generation EGFR TKIs, the mode of action of these inhibitors and the clinical data supporting their use. We review third-generation TKI agents that are approved, in development, and those that failed in clinical trials. Finally, we will touch upon ongoing studies and future directions, such as combination treatment strategies, currently being explored to improve the efficacy of treatment with third-generation EGFR TKIs.

502P - Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced non-small cell lung cancer with uncommon mutations: A multicenter observational study

BackgroundTreatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations remains unclear. MethodsWe retrospectively surveyed a consecutive database of patients with NSCLC with EGFR mutations. We analyzed the data of patients with NSCLC with uncommon mutations, including single or compound mutations, who were treated with EGFR-TKIs between May 2016 and October 2018. ResultsData from 543 patients were collected from five institutions, among whom 23 had EGFR uncommon mutations. Twenty-one patients who were treated with any EGFR-TKIs were analyzed in this study, 18 of whom were treated with EGFR-TKIs as first-line therapy (gefitinib 5, erlotinib 3, afatinib 10 patients). In contrast, three patients underwent cytotoxic chemotherapy as first-line therapy and were treated with EGFR-TKIs as second- and third-line therapy (gefitinib 1, erlotinib 1, afatinib 1 patient). According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was 56%, and the disease control rate was 78%. The median progression-free survival (PFS) was 14.0 months in all patients with uncommon mutations. The median PFS of patients who were treated with first and second generation EGFR-TKIs were 14.0 months (n = 10) and 7.3 months (n = 11), respectively. Moreover, the PFS of patients with the G719X mutation (n = 12, median PFS: 32.9 months) was longer than that of patients with the L861Q mutation (n = 4, median PFS: 11.1) and compound mutations (n = 4, median PFS 7.3 months). ConclusionsFirst and second generation EGFR-TKIs are effective treatments for patients with NSCLC with uncommon mutations. Notably, a greater favorable response was observed in patients with G719X mutations than those with L861Q and compound mutations. Clinical trial identificationUMIN000028989. Legal entity responsible for the studyFumio Imamura. FundingAstraZeneca. DisclosureF. Imamura: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

P1.01-106 Clinical Features and Tumor Immune Microenvironment Related to Acquired Resistance to EGFR-TKI in NSCLC Patients with EGFR Mutation

First generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide significant clinical benefit in advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, patients with initial response to EGFR-TKI ultimately develop acquired resistance to EGFR-TKI treatment, which approximately 50% resistant patients develop second EGFR T790M mutation. New treatment strategy for NSCLC patients harboring EGFR T790M mutation has been available. For those EGFR T790M negative patients, chemotherapy is currently the standard treatment. However, the efficacy of immunotherapy in EGFR T790M mutation NSCLC patients is unknown. Our study focused on the relationship between the clinical features and EGFR T790M mutation status, and the tumor immune microenvironment change before and after acquired resistance to EGFR-TKI in NSCLC patients with EGFR mutation. In this study, we retrospectively evaluated 89 patients with EGFR mutation who received first generation EGFR-TKIs treatment at the First Affiliated Hospital of Zhejiang University between February 2012 and July 2018. All patients were performed second biopsy after acquired resistance to EGFR-TKI. EGFR T790M mutation, epithelial-mesenchymal transition (EMT) and tumor-infiltrating CD4 and CD8 lymphocytes (TILs) in 13 patients with paired biopsy specimens before and after resistance to EGFR-TKI were measured by next generation sequencing (NGS) and immunohistochemistry analyses respectively. Among the 89 eligible patients, EGFR T790M mutation rate was 59.6% (53/89). EGFR T790M mutation was not related with age, gender, smoking status, tumor stage, performance status, but related to the initial EGFR mutation type (EGFR exon 19 deletion or exon 21 L858R mutation). Patients with EGFR exon 19 deletion had significantly higher T790M mutation rate than that with exon 21 L858R mutation (p=0.025). Interestingly, among 11 patients with family cancer history, 10 patients acquired T790M mutation. Furthermore, patients with T790M mutation had longer progression-free survival (PFS) compared to T790M-negative patients (75.5% vs 63.9%, P<0.05). In the small cohort of 13 patients, 6 patients developed EMT after acquired resistance. TILs according to the CD4+ and CD8+ lymphocyte density were not significantly changed in all 13 patients before and after acquired resistance. Our findings indicate that patients with EGFR exon 19 deletion, longer PFS or family cancer history may have higher possibility to develop second EGFR T790M mutation after resistance to EGFR-TKI treatment. The incidence of EMT was higher than we expected, providing further research and clinical treatment ideas. There is no change in TILs after resistance to EGFR-TKI in patients with or without EGFR T790M mutation, but this need further study due to the limited samples in this study.

A Review of EGFR-TKIs Therapy of Non-small Cell Lung Cancer with Uncommon EGFR Mutations

肺癌是目前最常见的癌症，也是导致癌症死亡的首要原因。非小细胞肺癌（non-small cell lung cancer, NSCLC）占85%以上，且高达50%的亚洲NSCLC患者携带表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变。研究证明，伴有EGFR突变的NSCLC患者接受表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）治疗能获得更好的生存结果。然而，因为EGFR罕见突变相对治疗效果较差，会对研究结果带来负面影响，所以大部分研究EGFR-TKIs疗效的临床试验都不包含罕见突变患者，另外EGFR罕见突变本身就少见，就导致临床试验中这部分患者数量较少。由于EGFR罕见突变样本量少且具有高度异质性，EGFR-TKIs对EGFR罕见突变患者的疗效仍然不清楚。本文就EGFR罕见突变与EGFR-TKIs的疗效关系进行综述，为携带EGFR罕见突变的NSCLC患者合理选择治疗方式提供指导和建议。

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.

Afatinib is effective in the treatment of lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations

ObjectivesEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line standard treatment for advanced lung adenocarcinoma with mutant EGFR. Nevertheless, few studies have demonstrated the efficacy of first- and second-generation EGFR TKIs in patients harboring the uncommon p.L747P and p.L747S mutations in exon 19 of EGFR. Materials and methodsFrom 2005–2018, we identified patients with lung adenocarcinoma with EGFR p.L747P or p.L747S mutations using DNA and cDNA sequencing or commercial kits and recorded their clinical data. Published data pertaining to these mutations were also reviewed. ResultsTwelve eligible patients were enrolled at National Taiwan University Hospital (NTUH), and ten additional patients were identified in published literature. In NTUH cohort, the direct DNA sequencing had a 60.0% (3 of 5 patients) false-negative rate, and use of commercial kits all caused misidentification of EGFR p.L747P or p.L747S. Of the 7 patients receiving EGFR TKI treatment, five stage-IV lung adenocarcinoma patients that received afatinib had a 80.0% objective response rate (ORR), while two patients administered gefitinib or erlotinib showed a 0% ORR. The median progression-free survival (PFS) rates were 11.97 and 0.92 months (P = 0.012) for afatinib and gefitinib/erlotinib, respectively. No patients (0%) acquired p.T790 M resistance after failure of afatinib (n = 3). Of 10 patients harboring EGFR p.L747P from published literature, six patients used first-generation EGFR TKIs as treatment also showed 0% ORR and 1.00 month median PFS. ConclusionsPatients with the uncommon EGFR mutations p.L747P and p.L747S could be incorrectly classified as having wild-type EGFR or a 19DEL when using direct DNA sequencing or commercial kits. Moreover, use of afatinib may provide significantly improved PFS in patients with advanced lung adenocarcinoma with one of these two EGFR mutations.

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers

Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.See related commentary by Cheng and Oxnard, p. 899.

First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis.

BackgroundEGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA).MethodsA systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments.ResultsThirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib.ConclusionOur study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC.

Plasma relative abundance of epidermal growth factor receptor mutations predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma

Objective: To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods: In this prospective study, adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumor tissues were detected by ADx-amplification refractory mutation system (ADx-ARMS). EGFR mutations of plasma free tumor DNA were detected by ADx-ARMS and ADx-super amplification refractory mutation system (ADx-SuperARMS) at the same time. Patients with EGFR-mutant in tumor tissues and receiving EGFR-TKIs were finally enrolled. Plasma mutation-positive patients with both methods were high abundance group.Patients with positive mutations by ADx-SuperARMS but negative by ADx-ARMS were medium abundance group. Mutation-negative patients with both methods were recognized as low abundance group. The correlation between EGFR mutation abundance and clinical response to EGFR-TKIs were analyzed. Results: Among 71 patients enrolled, 42 harbored EGFR mutations in plasma were detected by ADx-ARMS, while 53 were found by ADx-SuperARMS.There were 42 patients in high abundance group, 11 in medium group while the other 18 in low group. The objective response rates (ORRs) were 69.0%, 7/11 and 10/18 in high, medium and low groups, respectively. The difference was significant between high and low abundances groups (P=0.006). Median progression-free survival (PFS) in high, medium and low groups were 11.0, 8.5 and 9.0 monthes, respectively (P<0.001). In patients with tumor 19-Del, the ORRs were 70.4%, 5/7 and 6/11 in high, medium and low abundance groups, respectively. The median PFS of high abundance group was significantly longer than the other two groups (12.0 monthes vs 9.0, 9.0 monthes). As to subjects with L858R mutation, the ORRs were 10/15, 2/4 and 3/6, respectively, with median PFS 9.6, 5.5 and 9.5 monthes. Conclusions: The relative abundance of EGFR mutations in plasma predicts clinical response to EGFR-TKIs in patients with advanced lung adenocarcinoma. The higher the mutation abundance is, the better the efficacy of EGFR-TKIs is.

513P - Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer

513P - Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer

Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis

ABSTRACTPurpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC).Methods: EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients.Results: The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002).Conclusion: The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

BackgroundOsimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC).MethodsIn this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.ResultsThe median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).ConclusionsOsimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)

Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer.

Introduction:Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This study evaluated the efficacy of three epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC.Methods:Patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from 1 December 2013 to 30 November 2017 were analyzed retrospectively. They received gefitinib, erlotinib, or afatinib until disease progression, death, or intolerable adverse events. The cumulative incidence of subsequent BM of initial non-BM patients, progression-free survival (PFS), and overall survival (OS) of the BM and non-BM patients were estimated and compared using the Kaplan–Meier and log-rank tests.Results:306 NSCLC patients were enrolled, with 116, 75, and 115 receiving first-line gefitinib, erlotinib, and afatinib, respectively. The afatinib group had a better PFS [12.7 versus 9.8 months; hazard ratio (HR) 0.59, p = 0.001] and OS (39.1 versus 22.0 months; HR 0.64, p = 0.035) than the gefitinib group. Afatinib tended to provide better BM prevention than gefitinib (BM cumulative incidence, HR 0.49; 95% confidence interval 0.34–0.71, p < 0.001) according to a Cox model adjusted for possible confounders. Patients with initial BM had a shorter PFS (p < 0.001) and OS (p = 0.015) than those without initial BM. Among the former, there were no differences in median PFS (p = 0.34) and median OS (p = 0.46) in the three EGFR-TKI groups.Conclusions:Our data suggested that, compared with gefitinib, afatinib provided better benefits significantly in terms of PFS and OS. Both had the same effectiveness in preventing subsequent BM.

P2.03-013 Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.

P3.01-018 Mutation Abundance Affects the Therapeutic Efficacy of EGFR-TKI in Patients with Advanced Lung Adenocarcinoma: A Retrospective Analysis

Purpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments o...

Uncommon mutation types of epidermal growth factor receptor and response to EGFR tyrosine kinase inhibitors in Chinese non-small cell lung cancer patients.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined. Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. We categorised EGFR uncommon mutations as: sensitizing rare mutations (group 1: G719X, L861Q, S768I); Ex20 ins (group 2), or complex mutations (G719X + L861Q, G719X + S768I, 19 del + T790M, 19 del + L858R, L858R + S768I, and L858R + T790M; group 3). Of 66 patients given EGFR-TKI treatment, rare sensitive mutations, Ex20 ins, and complex mutations were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) cases, respectively. TKI efficacy in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8months. Additionally, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins cases (8.6 vs. 4.1 vs. 3.1months; p = 0.041). Importantly, complex EGFR mutations were independent predictors of increased overall survival (Hazard Ratios = 0.31; 95% confidence intervals: 0.11-0.90; p = 0.031). Among them, patients harboring Del-19 combined with L858R mutations showed a tendency to have higher response rate (RR) and improved PFS than those with other complex mutation patterns (RR: 66.7 vs. 14.3%, p = 0.021; PFS: 10.1 vs. 8.6months, p = 0.232). Personalized treatment should be evolving in different types of uncommon EGFR mutations. Clinical benefit from EGFR-TKIs was higher in NSCLC patients with complex EGFR mutations than those with other uncommon EGFR mutation types.

Correlation between Serum Tumor Markers and Efficacy of First-line EGFR-TKIs in Patients with Advanced Lung Adenocarcinoma

背景与目的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）在EGFR突变型肺腺癌人群中能显著提高生存，从而改变了晚期肺癌的治疗模式，但并不是所有EGFR敏感突变者均能从EGFR-TKIs治疗中获益。本研究欲通过外周血肿瘤标志物的检测对突变型肺腺癌患者的靶向治疗进行预测及指导。方法回顾性分析2009年6月-2014年6月于北京大学肿瘤医院胸部肿瘤内一科一线接受EGFR-TKIs治疗的EGFR突变型Ⅲb期-Ⅳ期肺腺癌患者的临床资料，分析其基线肿瘤标志物与EGFR-TKIs疗效及生存的关系。结果总体人群客观有效率（objective response rate, ORR）52.8%，疾病控制率（disease control rate, DCR）89.3%。基线癌胚抗原（carcino-embryonic antigen, CEA）水平升高者对EGFR-TKIs疗效更佳（ORR 61.3% vs 35.9%, DCR 95.2% vs 74.4%, P < 0.001），治疗1个月后CEA、细胞角蛋白19片段（cytokeratin 19 fragments, CYFRA21-1）以及CA125水平下降者有效率更高（ORR分别是61.5% vs 25%，P=0.002；58.5% vs 37.5%，P=0.004；61.8% vs 20%，P=0.027）。生存分析中，基线CEA水平正常者较高水平者无进展生存期（progression-free survival, PFS）明显缩短（中位PFS 5.9个月vs 9.8个月，P=0.027），而基线CYFRA21-1、CA125水平升高者PFS明显缩短（中位PFS 9.0个月vs 11.4个月，P=0.029；9.0个月vs 11.5个月，P=0.023）。多因素分析显示，美国东部肿瘤协作组（Eastern Cooperative Oncology Group, ECOG）评分0-1分、基线CYFRA21-1正常水平、治疗1月后CEA下降阳性患者PFS更长。总生存期（overall survival, OS）与CYFRA21-1、CA125升高有关（中位OS分别为25.1个月vs 52.5个月，P=0.003；22.7个月vs 55.0个月，P < 0.001），而多因素分析中总生存与CEA下降有关（P=0.046）。结论治疗前高水平CEA以及治疗后CEA下降可以预测晚期肺腺癌患者一线接受EGFR-TKIs的疗效，而治疗前高水平CYFRA21-1以及CA125则预示着生存期缩短。

Gefitinib in combination with pemetrexed in patients with advanced non-small cell lung cancer harboring EGFR mutations: is there any difference in acquired resistance mechanism between gefitinib monotherapy and the combination treatment?

Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are the most reliable predictors of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). In randomized phase III trials, EGFR-TKIs in patients with advanced EGFR mutant NSCLC were associated with longer progression-free survival (PFS) and higher radiographic response rates than the standard first-line platinum-based chemotherapy (1-7). Based on these results, three types of EGFR-TKIs, gefitinib, erlotinib and afatinib have been approved for treatment of advanced EGFR-mutant NSCLC as a first-line setting. Despite an initially marked response, almost all patients treated with EGFR-TKIs eventually acquire resistance to these drugs, with an average PFS of around 1 year. To improve these results, several combinations of EGFR-TKIs and other drugs, such as targeted drugs and chemotherapy, have been developed.

Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis.

IntroductionThe introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) iŝ12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC.MethodsLiterature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan–Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy.ResultsNine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for erlotinib. There was no evidence for differences between EGFR-TKI monotherapies, as all 95% CrIs included the null value.ConclusionAlthough data for erlotinib plus bevacizumab came from a single Phase 2 study, the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced EGFR+ NSCLC.