Epidermal Growth Factor Receptor Mutation-positive Patients Research Articles

Budget Impact Analysis of EGFR Mutation Liquid Biopsy for First- and Second-Line Treatment of Metastatic Non-Small Cell Lung Cancer in Greece.

Within the European Union, Greece has the highest incidence of lung cancer among people under 45 years of age. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are indicated for the treatment of patients with EGFR mutation-positive metastatic non-small cell lung cancer (mNSCLC). Tumor tissue biopsy is the standard method for EGFR mutation detection but is invasive, is resource-intensive, and has risks of complications. The objective of this analysis was to estimate the financial impact on the Greek National Health System of adopting plasma biopsy and to identify the cost-optimal approach for EGFR mutation testing of patients with mNSCLC. We developed a budget impact model to estimate total costs for three EGFR mutation testing approaches: (1) plasma test, (2) combined testing (tissue and plasma test), and (3) reflex testing, compared to the current scenario of tissue biopsy only. One-way sensitivity and scenario analyses were conducted to evaluate the impact of uncertainty and variance of different input parameters on the results. In the first-line (1L) setting, base-case results showed that adopting plasma testing in a combined testing approach identified more EGFR mutation-positive patients and yielded cost savings (−€17 per correctly classified patient) relative to tissue testing alone. The reflex testing approach was the cost-optimal strategy in the second-line (2L) setting as it identified the most EGFR mutation-positive patients with cost savings of −€42 per correctly classified patient relative to tissue testing alone. This analysis suggests that access to both EGFR mutation tissue and plasma testing are important for optimizing mNSCLC treatment decisions in Greece. Inclusion of plasma testing in either a combined or reflex testing approach may be cost optimal for EGFR mutation plasma test implementation.

Prospective Observational Study of Treatment Resistance-related Gene Screening Using Plasma Circulating Tumor DNA in Third-generation EGFR-TKI Osimertinib Therapy (Elucidator)

BackgroundOsimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR activating and EGFR T790M resistance mutations. Osimertinib was found to be more effective than first-generation EGFR-TKIs in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) harboring EGFR-positive mutations in a prior phase III trial. Osimertinib is, therefore, one of the most important standard therapies for EGFR mutation-positive patients. However, there are few reports about osimertinib resistance mechanisms in first-line EGFR-TKI therapy. Understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies in patients with NSCLC with EGFR-positive mutations. To clarify the resistance mechanisms of first-line osimertinib, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing method. Patients and MethodsWe aim to collect ctDNA samples from patients with the following key inclusion criteria: histologically or cytologically proven NSCLC, activating EGFR mutation-positive, planned treatment with first-line osimertinib, and written informed consent. Patients with comorbidities, who are deemed unsuitable for participation by an attending physician, would be excluded. We plan to enroll 180 cases and estimate a final analysis of 120 cases following registration and 2-year observation. ctDNA samples are collected at osimertinib treatment initiation, 3 and 12 months later, and disease progression. The key primary endpoint is to clarify the incidence and ratio of osimertinib resistance. The key secondary endpoint is to examine how the quantity of osimertinib resistance-associated mutations detected in ctDNA at treatment initiation influences disease progression.

Screening Circular RNAs Related to Acquired Gefitinib Resistance in Non-small Cell Lung Cancer Cell Lines

Background: Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used to treat EGFR mutation-positive patients with non-small cell lung cancer (NSCLC). However, the efficacy of gefitinib is limited by the development of acquired resistance. Studies have shown that circular RNAs (circRNAs) are involved in the acquired resistance to many anticancer agents. However, the expression profiles and functions of circRNAs in gefitinib resistance in NSCLC are poorly understood so far.Methods: In this study, circRNA expression profiling was explored in two gefitinib-resistant NSCLC cell lines (HCC827/GR and PC9/GR) and their parental sensitive cells (HCC827 and PC9) using high-throughput RNA sequencing. Quantitative real-time PCR (qRT-PCR) was used to confirm the expression of selected differentially expressed circRNAs. Bioinformatic tools including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), network analysis, and Kaplan-Meier plotter database were used to predict the functions and pathways of these differentially expressed circRNAs.Results: We identified 46 and 56 differentially expressed circRNAs in HCC827/GR and PC9/GR cell lines, respectively, compared with those in their parental cell lines. Gene ontology and KEGG pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions. We found that hsa_circ_0000567 was consistently up-regulated, and hsa_circ_0006867 was consistently down-regulated in two resistant cell lines. We further used hsa_circ_0000567 and hsa_circ_0006867 as key circRNAs to construct circRNA-miRNA-mRNA networks. Several target mRNAs of these two circRNAs had been shown to significantly associate with the overall survival of patients with lung cancer.Conclusions: In this study, we generated the comprehensive expression and functional profiles of the differentially expressed circRNAs between gefitinib-resistant and -sensitive NSCLC cells, and showed that dysregulation of circRNAs might play an important role in the development of acquired resistance to gefitinib in NSCLC.

CMET-40. IMPACT OF WHOLE BRAIN RADIOTHERAPY ON LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to assess the impact of whole brain radiotherapy (WBRT), chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on survival. METHODS Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Sanjiu Brain Hospital were retrospectively reviewed. Survival was assessed by Kaplan-Meier analyses. RESULTS The median age was 54.5 (range 30–76) years. LM were diagnosed by MRI (36/74), cytology (4/74), or both (34/74). Eighteen patients (24.3%) were diagnosed at the initial presentation of lung cancer. Forty-seven (63.5%) patients harboring EGFR positive mutation while other twenty-seven patients (36.5%) were EGFR wild type. The median overall survival from diagnosis of LM was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients who received EGFR-TKIs after LM had longer survival than those who did not (10.5 vs. 4.4 months, p＜0.001). No significant differences in survival were seen between patients who were treated with WBRT and those without, whether in EGFR mutation positive patients (11.6 vs. 15.0 months, p=0.353), or in EGFR wild type ones (5.1 vs. 3.3 months, p=0.116). Similarly, intravenous chemotherapy after LM had no impact on overall survival (7.5 vs. 8.1 months, p=0.9). CONCLUSION Median overall survival was higher than historical experience in our retrospective analysis. Survival was not improved by WBRT or intravenous chemotherapy. EGFR-TKIs could prolong survival of patients with LM from NSCLC.

Epidermal growth factor receptor mutation subtype has differential effects on adjuvant chemotherapy for resected adenocarcinoma pathological stages II-III.

The aim of the present study was to investigate epidermal growth factor receptor (EGFR) mutations as a prognostic factor for postoperative patients with positive EGFR mutations treated with postoperative platinum-based adjuvant chemotherapy (PBAC), and whether two common EGFR mutations exhibit different responses to PBAC. A total of 110 patients who underwent complete surgical resection were enrolled, and overall survival (OS) and disease-free survival (DFS) were investigated based on EGFR mutation status and PBAC. The 3 year OS rate in patient groups were as follows: Patients with EGFR mutations (MT) undergoing PBAC, 89.3%; MT patients without PBAC, 83.3%; wild-type (WT) patients with PBAC, 82.3%; and WT patients without PBAC, 62.2%. Statistically significant differences were observed between WT patients based on PBAC (P=0.026). No statistically significant differences were observed between MT patients with PBAC and MT patients without PBAC. On the basis of mutation subtypes, the 3 year OS rate of patient groups were as follows: Patients with in-frame deletions in exon19 (19 del) with PBAC, 92.3%; patients with 19 del without PBAC, 85.7%; patients with the point mutation L858R inexon21 (21L858R) with PBAC, 86.7%; and patients with 21L858R without PBAC, 81.5%; the respective 3-year DFS rates were 53.8, 14.3, 40.2 and 26.9%. Statistically significant differences were observed in the DFS rates in 19 del patients, which was dependent on PBAC (P=0.040). EGFR mutation-positive patients exhibited a decreased benefit from PBAC for increasing in survival rate compared with WT patients. It may be necessary to consider postoperative strategies based on EGFR mutations and their subtype in the future.

P2.14-57 Efficacy of 3rd Generation EGFR-TKIs After Failing First or Second Generation EGFR-TKIs in EGFR Mutation-Positive NSCLC (ROOT-EGFR)

Over the past decade, treatment of EGFR mutation –positive NSCLC has been revolutionized with the development of next generation EGFR TKIs. Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available in Korea. Recent trials have compared the available and emerging EGFR TKIs head to head. The highly anticipated findings of the phase III FLAURA trial showed a nearly doubling of PFS with frontline osimertinib, a third-generation TKI, versus erlotinib or gefitinib. The optimal sequence of EGFR TKIs is still controversial. And many countries 3rd generation EGFR TKI is not readily available. The purpose of this study is to analyze the efficacy in patients who received first-line gefitinib, erlotinib, or afatinib and followed by 3rd generation EGFR-TKIs. This non-interventional observational study through big data analysis will retrospectively collect de-identified patient data from clinical data warehouse (CDW) using a unique algorithm with Standard Query Language (SQL) called ROOT project. Over 10 years, 2,358 patients were diagnosed recurrent or metastatic non-small cell lung cancer and received 1st or 2nd generation EGFR TKIs at Samsung Medical Center. 72.9% (1720/2358) of EGFR mutation-positive NSCLC patients received 1st or 2nd generation EGFR-TKIs as first line palliative chemotherapy. In total population, 30.8% (727/2358) patients received 3rd generation EGFR TKIs. Among them, patients who received 3rd generation EGFR TKI after 1st or 2nd generation EGF TKIs showed better overall survival (45.0 months (95% CI, 41.8-48.2). Among 1720 patients who received 1st or 2nd generation EGFR-TKIs as first line palliative chemotherapy, 313 patients received 3rd generation EGFR-TKIs as 2nd line chemotherapy and 200 patients received as more than 3rd line chemotherapy. However, there was no difference of overall survival between them (44.0 months vs 47.0months, p-value=0.104). This study was meaningful as a study of what can be the best sequence in EGFR-TKI treatment. Updated and detail clinical and exploratory biomarker outcome will be presented at the meeting.

P2.01-69 NSCLC Mutation Frequency in the Central American and Caribbean Region

Lung Cancer (LC) constitutes a leading cause of death in the World. Non-small cell lung cancer subtype adenocarcinoma (NSCLC-A) has been associated with epidermal growth factor receptor (EGFR) mutations, which is essential for treatment decisions. The EGFR mutation frequency has been proven to have regional variability in this NSCLC-A population. The current study presents the EGFR mutation incidence and T790M frequency in NSCLC-A cases diagnosed in Central American and Caribbean (CA&C) region. A cross-sectional evaluation was performed in patients diagnosed with NSCLC-A between 2016 and 2018 in five CA&C countries. Patients were obtained from Reference Centers in Dominican Republic, Nicaragua, Panama, Honduras and Costa Rica through the AstraZeneca testing program. EGFR mutations were evaluated through Real-Time PCR. The research included 972 cases. Mean of age at the diagnosis was 62.79(28.12-90.46) years. Overall distribution of cases by gender was female in 52.37% (509/972) and male in 47.64% (463/972). For the group of antiEGFR TKI naïve patients, tissue samples were processed in 67.83% (601/886). The group of post antiEGFR TKI, patient’s plasma samples were processed in 90.70% (78/86). AntiEGFR TKI naïve group, EGFR mutations were present in 26.64% (236 / 886), the mean of age was 63.17 years (28.12-90.46). The frequency of Exon 19 was 53.38% (126/236) and Exon 21 was 27.54% (65/236) and 11.01% (26/236) were complex mutations. T790M mutations in this treatment naïve population was 2.14% (19/886). For the group of post antiEGFR TKI patients the frequency of T790M mutation was 50.00% (43/86) where 78.57% were obtain from plasma samples. The frequency of NSCLC EGFR mutation positive patients in the CA&C region was similar to that previously described in other Latin American (LA) countries. In the treatment naïve population, tissue samples remain the most important sample to analyze for EGFR mutations. T790M mutations can be seen in treatment naïve population. For patients that progressed to an antiEGFR TKI, T790M mutations were seen in a similar frequency as describe in previous LA countries. For post antiEGFR TKI patients, plasma samples were the preferred method to evaluate T790M mutations with an adequate sensibility.

Five Technologies for Detecting the EGFR T790M Mutation in the Circulating Cell-Free DNA of Patients With Non-small Cell Lung Cancer: A Comparison

Third-generation tyrosine kinase inhibitors (TKIs) were developed to overcome T790M-mediated resistance to earlier generations of epidermal growth factor receptor (EGFR)-targeted TKIs. We compared four well-established and one in-house method for the analysis of the EGFR T790M mutation in plasma cell-free DNA (cfDNA), in hope to find a better way to select non-small cell lung cancer (NSCLC) patients appropriate for 3rd-generation TKI therapy. For sensitivity levels of each method, plasmid DNA with EGFR T790M mutations was serially diluted with cfDNA from healthy controls with wild type EGFR. The clinical performance was analyzed in a clinical cohort of EGFR mutation-positive NSCLC patients with acquired EGFR TKI resistance (n = 40). All methods except the therascreen kit (Qiagen) had a sensitivity level of 10 copies of T790M plasmid DNA in the spiked specimen. The detection rates of the EGFR T790M mutation in plasma cfDNA from the clinical cohort were 42.5, 35, 32.5, 22.5, and 17.5% for the in-house ARMS method, Bio-Rad droplet digital PCR, PANAMutyper, Therascreen EGFR Plasma RGQ PCR Kit and Cobas EGFR Mutation kit (with suboptimal template amounts), respectively. Osimertinib was given to 17 of 20 patients with EGFR T790M mutations. The best treatment responses, based on the RECIST criteria, included 6 partial responses (PR) and 7 stable diseases (SD). The PANAMutyper and the Bio-Rad droplet digital PCR were comparable, the Cobas EGFR Mutation kit required significantly more template for testing. The best combination would be the in-house ARMS method plus the PANAMutyper or Bio-Rad droplet digital PCR, which would have a detection rate of 50% (20/40) and a disease control rate of 76% (13/17).

Cost-effectiveness of tyrosine kinase inhibition in first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer.

e20504 Background: Patients with advanced non-small cell lung cancer (NSCLC) harbouring an epidermal growth factor receptor (EGFR) mutation have improved survival with tyrosine kinase inhibitor (TKI) treatments, but the economic efficiency of this application is unclear, especially in limited health resource settings. To inform policy makers about the value of these medications, we developed a Markov model to compare the cost-effectiveness of these strategies. Methods: A Markov model was developed to compare the cost-effectiveness of chemotherapy, gefitinib, erlotinib, afatinib and osimertinib treatments from a public payers’ perspective in the U.S and China. Health states consisted of progression-free survival, progressive disease, and death. Model transition, adverse event probabilities, disease progression, and death were obtained from randomized clinical trials and network meta-analysis. Costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) over a 10-year lifetime horizon were calculated. One-way and probabilistic sensitivity analyses were performed by multiple potentially modifiable parameters. Results: The tyrosine kinase inhibitors were more cost-effective than chemotherapy treatment in both the U.S and China. In the U.S, compared with erlotinib, afatinib had an ICER of $241,420/QALY while osimertinib had an ICER of $351,315/QALY. In China, the incremental utility for osimertinib versus gefitinib was 0.68QALYs, and the ICER was $25,622/QALY. The probability sensitivity analyses also illustrated that the erlotinib was the optimal treatment at a willingness-to-pay (WTP) threshold of $150,000/QALY in the U.S and osimertinib was the most cost-effective treatment at a WTP of $26,508/QALY in China. Conclusions: Based on our current analysis, erlotinib appears to be the preferred first-line treatment for advanced EGFR mutation-positive NSCLC patients in the US at a WTP of $150,000/QALY. However, because of the price reduction and more health benefits, osimertinib was considered to be most cost-effective at a WTP of $26,508/QALY in China.

Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

9035 Background: Several lines of evidence suggested a role for metformin in sensitizing diabetic NSCLC patients to EGFR tyrosine kinase inhibitors (TKIs). However, data regarding its effects on non-diabetic populations remained scarce. We hereby examined metformin’s first-line use alongside gefitinib in EGFR mutation positive (EGFRm) patients without diabetes. Methods: In this trial (NCT01864681), 224 non-diabetic patients with treatment naïve stage IIIB-IV EGFRm NSCLC were randomly assigned at 1:1 to receive gefitinib plus metformin or placebo. Gefitinib was administered at 250 mg once daily, while metformin/placebo was initiated at 500 mg once daily and then escalated to 1000 mg twice daily over 2 weeks. Dose reduction was permitted for metformin/placebo in case of intolerable toxicity. The primary endpoint was progression-free survival (PFS) rate at 1 year. Secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of interleukin-6 were also subjected to exploratory analysis. Results: Baseline characteristics were well balanced between treatment groups. The median duration of follow-up was 19.15 (IQR 12.99-28.44) months. The estimated 1-year PFS rate was 41.2% (95% confidence interval [CI] 30.0-52.2) in the metformin group versus 42.9% (95% CI 32.6-52.7) in the placebo group (p = 0.6268). Metformin did not increase median PFS (10.3 months vs. 11.4 months), median OS (22.0 months vs. 27.5 months), or ORR (66.0% vs. 66.7%) over placebo. No significant treatment group differences in terms of PFS were detected across subgroups either, including those with elevated levels of interleukin-6. Metformin plus gefitinib shared a similar safety profile with the control group, except for a remarkably higher incidence of diarrhea (78.38% vs. 43.24%). Conclusions: Our study did not show enhanced gefitinib efficacy upon addition of metformin and hence does not support its concurrent use with first-line EGFR-TKI therapy in non-diabetic EGFRm NSCLC patients. Clinical trial information: NCT01864681.

NSCLC mutation frequency in the central American and Caribbean region.

e14278 Background: Lung Cancer (LC) constitutes a leading cause of death in the World. Non-small cell lung cancer subtype adenocarcinoma (NSCLC-A) has been associated with epidermal growth factor receptor (EGFR) mutations, which is essential for treatment decisions. The EGFR mutation frequency has been proven to have regional variability in this NSCLC-A population. The current study presents the EGFR mutation incidence and T790M frequency in NSCLC-A cases diagnosed in Central American and Caribbean(CA&C) region. Methods: A cross-sectional evaluation was performed in patients diagnosed with NSCLC-A between 2016 and 2018 in five CA&C countries. Patients were obtained from Reference Centers in Dominican Republic, Nicaragua, Panama, Honduras and Costa Rica through the AstraZeneca testing program. EGFR mutations were evaluated through Real-Time PCR. Results: The research included 972 cases. Mean of age at the diagnosis was 62.79(28.12-90.46) years. Overall distribution of cases by gender was female in 52.37% (509/972) and male in 47.64% (463/972). For the group of antiEGFR TKI naïve patients, tissue samples were processed in 67.83% (601/886). For the group of post antiEGFR TKI patients plasma samples were processed in 90.70% (78/86). For the group of antiEGFR TKI naïve patients, EGFR mutations were present in 26.64% (236 / 886), the mean of age was 63.17 years (28.12-113.47). The frequency of Exon 19 was 53.38(126/236)% and Exon 21 was 27.54%(65/236)% and 11.01% (26/236) were complex mutations. T790M mutations in this treatment naïve population was 2.14%(19/886). For the group of post antiEGFR TKI patients the frequency of T790M mutation was 50.00% (43/86) where 78.57% were obtain from plasma samples. Conclusions: The frequency of NSCLC EGFR mutation positive patients in the CA&C region was similar to that previously described in other Latin American (LA) countries. In the treatment naïve population, tissue samples remain the most important sample to analyze for EGFR mutations. T790M mutations can be seen in treatment naïve population. For patients that progressed to an antiEGFR TKI, T790M mutations were seen in a similar frequency as describe in previous LA countries. For post antiEGFR TKI patients, plasma samples were the preferred method to evaluate T790M mutations with an adequate sensibility.

Sequencing of therapy following first-line afatinib in patients with EGFR mutation-positive non-small cell lung cancer

ObjectivesWith the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. MethodsPost-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan–Meier estimates. ResultsAmong 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. ConclusionsMost patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.

Rationale and Design of a Phase II Trial of Osimertinib Combined With Bevacizumab in Patients With Untreated Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer and Malignant Pleural and/or Pericardial Effusion (SPIRAL II Study)

Progression-free survival (PFS) of patients with non–small-cell lung cancer with pleural or pericardial effusion is expected to be prolonged with combination use of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor plus bevacizumab compared with that with an EGFR-tyrosine kinase inhibitor alone. Phase I clinical trial data have been reported for combined treatment with osimertinib plus bevacizumab and demonstrated their safety, but the efficacy remains unclear, particularly in patients with pleural or pericardial effusion. This is an ongoing single arm, prospective, open-label, multicenter, phase II trial to evaluate the efficacy and safety of osimertinib plus bevacizumab combination therapy in EGFR mutation-positive patients with untreated or recurrent non–small-cell lung cancer and pleural and/or pericardial effusion. Osimertinib will be administered orally once daily at a dose of 80 mg. One cycle consists of 21 days. Bevacizumab 15 mg/kg will be administered by drip infusion on Day 1 of each cycle. Treatment will be continued until progressive disease or any of the discontinuation criteria are met. The primary endpoint will be the 1-year PFS rate. Secondary endpoints are response rate, PFS, overall survival, survival not requiring pleural/pericardial drainage, and safety. Osimertinib plus bevacizumab combination therapy is expected to prolong PFS and reduce adverse events. Trial registration numberUMIN000028071

EGFR Gene Polymorphism Predicts Improved Outcome in Patients With EGFR Mutation-positive Non–small cell Lung Cancer Treated With Erlotinib

BackgroundPatients with advanced-stage non–small cell lung cancer with epidermal growth factor receptor (EGFR) mutations are successfully treated with tyrosine kinase inhibitors (TKIs). However, treatment outcome varies significantly. Previously, we found the polymorphism 181946C>T (rs2293347) located in exon 25 of the EGFR gene to be a predictor of improved outcome. However, these data were based on a subgroup analysis. Furthermore, other minor studies have found conflicting data. Thus, the aim of this study was to demonstrate the association of 181946C>T with clinical outcome in an independent cohort of EGFR-mutated patients treated with erlotinib. Patients and MethodsSeventy-five patients were prospectively enrolled. Blood samples were collected, and genotype for 181946C>T was determined by allele-specific polymerase chain reaction. Genotype was correlated with outcome. ResultsIn 73 patients, 181946C>T was successfully measured. Patients harboring the 181946CT genotype had a significantly longer median progression-free survival compared with patients harboring the 181946CC genotype (49.9 months [95% confidence interval (CI), 5.9-93.9 months] versus 11.1 months (95% CI, 7.4-14.9 months); P = .020). Moreover, a significantly longer median overall survival of 65.6 months (95% CI, 11.0-120.3 months) versus 31.2 months (95% CI, 10.9-51.6 months) was found (P = .019). Both results remained significant in a multivariate analysis adjusting for potential confounders. ConclusionWe demonstrate that the 181946C>T polymorphism is a significant predictor of prolonged progression-free survival and overall survival in an independent cohort of EGFR mutation-positive patients treated with erlotinib. The polymorphism could be an important predictor of treatment response in these patients. A large multicenter cohort study involving other concurrent genetic alterations is warranted.

P3.16-11 Pattern of Recurrence of Completely Resected Lung Adenocarcinoma Varies According to EGFR Mutation Status

The prognostic significance of epidermal growth factor receptor (EGFR) mutations in resectable lung adenocarcinoma is not well defined. We evaluated the influence of EGFR mutation status on postoperative recurrence timing with the use of event dynamics. A total of 644 patients with lung adenocarcinoma who underwent complete resection and examined for EGFR mutation status between 2008 and 2015 were studied. Disease-free survival (DFS) were calculated using the Kaplan-Meier method and compared between EGFR mutation-positive patients (n=322) and EGFR wild-type patients (n=322). Event dynamics, based on the hazard rate, were evaluated and only first events (distant metastases or local recurrence) were considered. There was no statistical significance in recurrence rate (9.9% versus 14.6%; p=0.09) between EGFR mutation-positive patients and EGFR wild-type patients. In patients with pathological stage I, DFS was significantly better in the EGFR mutant group than the wild-type group (p=0.009), whereas the EGFR mutant group had an inferior DFS compared with the wild-type group among patients with pathological stage II or higher (p=0.110). The resulting hazard rate curves indicated that the recurrence risk pattern was definitely correlated with EGFR mutation status, with an early highest peak during the first year for EGFR wild-type patients and a late maximum peak in the fifth year for EGFR mutation-positive patients. The prognostic value of EGFR mutations appears to be different according to pathological stage in completely resected adenocarcinoma. The hazard and the peak times of recurrence differ considerably between EGFR-mutant and wild-type patients.

P2.09-12 EGFR Mutation Status in Squamous Cell Carcinoma or Non-Small Cell Carcinoma Favor Squamous Cell Carcinoma Diagnosed from Small Lung Biopsies

Epidermal growth factor receptor (EGFR) mutation testing is strongly recommended in non-small cell lung cancer (NSCLC) patients with adenocarcinoma subtypes, or patients with mixed-type tumors containing adenocarcinomatous components. However, in clinical practice, patients showing squamous cell carcinoma (SqCC) morphology on small biopsies cannot be ruled out to have an adenocarcinomatous component elsewhere in the lesion due to sampling bias. Therefore, EGFR mutation testing may have been neglected in such circumstances, which would affect the clinical management of patients. In this study, we sought to examine the frequency of EGFR mutations in lung cancer patients with SqCC or Non-Small Cell Carcinoma (NSCC) favor SqCC diagnosed from small biopsies. The correlation between EGFR mutation status and clinicopathological characteristics was also evaluated. One hundred and forty-eight patients diagnosed as SqCC or NSCC favor SqCC from small lung biopsies were enrolled. All of these cases were histologically confirmed by evaluating cellular morphology using hematoxylin-eosin (HE) staining and TTF1, p40 or CK5/6 expression using immunohistochemistry. EGFR mutations were examined using real-time PCR based assay. Among 148 small biopsy cases, 135 (91.2%) were diagnosed as SqCC while 13 (8.8%) were NSCC favor SqCC. Approximately 8.8% (13/148) of all cases were found to have EGFR mutations, including 7 (53.8%) L858R mutation, 4 (30.8%) exon 19 deletion, and 2 (15.4%) cases with coexistent L858R and T790M mutations. EGFR mutation-positive cases accounted for 5.2% (7/135) in SqCC, 46.2% (6/13) in NSCC favor SqCC, and 83.3% (10/12) of all these cases were never smokers. The multivariate analysis showed that EGFR mutations were more prevalent in non-smokers than those in smokers (83.3% versus 16.7%, p = 0.03) and in patients diagnosed as NSCC favor SqCC than in those diagnosed as SqCC (46.2% versus 5.2%, p = 0.002). In addition, 4 out of 13 EGFR mutation-positive patients with SqCC or NSCC favor SqCC morphology were eventually diagnosed as adenosquamous carcinoma after further undergoing surgical resection. To the best of our knowledge, this is the first study directly addressing the importance of EGFR mutation testing in lung cancer patients with SqCC or NSCC favor SqCC diagnosed from small biopsies. Our findings suggest that EGFR mutation testing should not be excluded in such populations, especially in never-smokers, or patients with NSCC favor SqCC subtypes.

Correlation of plasma erlotinib trough concentration with skin rash in Chinese NSCLC patients harboring exon 19 deletion mutation.

Erlotinib is an essential drug for non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations. The relationship between the pharmacokinetics and skin rash and diarrhea of erlotinib in Chinese patients with EGFR mutated NSCLC is unknown. In this study, we evaluated the variability in erlotinib trough concentration and its relationship with the severity of skin rash and diarrhea in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R. EGFR mutation-positive Chinese patients (n = 52) treated with erlotinib were included in our study; the steady-state trough concentrations were assessed; and the occurrence and severity of skin rash and diarrhea after the onset of treatment with erlotinib were recorded. The patients were divided into two groups by mutation type (exon 19 deletions or exon 21 L858R point mutations). Occurrence and severity of skin rash and diarrhea was analyzed in both groups. The overall mean (± SD) steady-state trough concentration for erlotinib was 1380 ± 663ng/mL, and there was no significant difference of erlotinib concentrations between the two mutation groups. Occurrence and severity of skin rash was significantly associated with trough concentration in patients with exon 19 deletions but not exon 21 L858R point mutations. Significant association of erlotinib concentrations with diarrhea was found neither in the exon 19 deletions group nor in the exon 21 L858R point mutation group. The occurrence and severity of skin rash correlated with increase in erlotinib trough concentrations only in Chinese patients with exon 19 deletion; the erlotinib trough concentrations were not associated with diarrhea.

Gefitinib Versus Adjuvant Chemotherapy in Patients With Stage II-IIIA Non–Small-Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study

BackgroundThe superior efficacy of first-line treatment with gefitinib over that of standard chemotherapy was demonstrated in patients with advanced non–small-cell lung cancer (NSCLC) harboring sensitive mutation of epidermal growth factor receptor (EGFR). However, scarce evidence showing the superiority of gefitinib to chemotherapy exists regarding the postoperative adjuvant therapy of EGFR mutation–positive patients with stage II-IIIA NSCLC. To address this important gap, we undertook a retrospective study to assess the efficacy of adjuvant gefitinib versus adjuvant chemotherapy (AC) in patients with completely resected EGFR-mutant stage II-IIIA NSCLC. Patients and MethodsA total of 116 patients with completely resected II-IIIA NSCLC and confirmed positive EGFR mutation (exon 19 deletion or exon 21 Leu858Arg) between January 2013 and March 2017 were included in our study. Disease-free survival (DFS) was analyzed in 55 patients treated with gefitinib and 61 patients treated with a platinum-based 2-drug-combination AC. Propensity score matching allowed the generation of best matched pairs for the 2 categories (1:1 ratio). Factors affecting survival were assessed by the Kaplan-Meier method and Cox regression analysis. ResultsThe matched cohort consisted of 52 gefitinib and 52 AC patients with a median follow-up of 37.1 and 31.5 months, respectively. DFS was significantly longer in the gefitinib group than that in the AC group (34.9 months [95% confidence interval (CI), 21.1-48.7] versus 19.3 months [95% CI, 13.3-25.3]; hazard ratio = 0.36 [95% CI, 0.19-0.68], log-rank P = .001). In the gefitinib group the most common adverse events (AEs) were rash (76.9%), aminotransferase elevation (53.8%), and diarrhea (46.2%), whereas in the AC group the most common AEs were neutropenia (67.3%), nausea or vomiting (63.5%), and anemia (44.2%). Less frequent grade 3 or higher AEs were observed in the gefitinib group (15.4% vs. 38.5% in the AC group). After receiving gefitinib for 3 months, one patient was diagnosed with interstitial lung disease, which was regarded as the most severe treatment-related AE. No deaths were treatment related. ConclusionIn this retrospective study, compared to AC, gefitinib provided a statistically significant DFS benefit, reduced toxicity in EGFR mutation–positive patients with resected II-IIIA NSCLC. These results require further validation by prospective randomized trials.

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

BackgroundErlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection.Methods651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS).Results62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation.ConclusionsOur study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure.Trial registrationClinicalTrials.gov Identifier: NCT01609543.

EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After First-line Gefitinib Therapy in Advanced Non-Small Cell Lung Cancer Patients.

Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate. The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes. The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P<0.0001), whereas male sex (P=0.004) and primary metastatic disease (P=0.032) were independent prognostic factors of poor OS. The EGFR exon 19 deletion was associated with favorable PFS and OS in patients receiving first-line gefitinib treatment. The EGFR mutation subtype should be considered when making treatment decision or designing clinical trials for chemotherapy-naive, EGFR mutation-positive advanced NSCLC patients.