EGFR Mutation-positive Non-small Cell Lung Cancer Patients Research Articles

OSIRAM-1/TORG1833: Overall survival results of a randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer.

8613 Background: Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). We have previously shown the result of progression free survival (PFS) as a primary endpoint, the median PFS was 20.0 months for Osi+Ram and 24.0 months for Osi, hazard ratio of 1.054 (95% CI 0.674-1.648). In further analyses, we aimed to examine the effects of this combination therapy on overall survival (OS). Methods: Previously untreated EGFR mutation-positive advanced non-squamous NSCLC patients with a performance status of 0 or 1 were eligible. Asymptomatic and/or treated brain metastases were included. Eligible patients were randomized at a 1:1 ratio to receive Osi (80mg) every day either without or with Ram (10mg/kg) every 2 weeks until disease progression or unacceptable toxicity, stratified according to gender and the type of EGFR mutation (exon 19 deletion, L858R). The primary endpoint was PFS assessed by the independent blinded radiologic reviewer. Secondary endpoints included PFS assessed locally, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), OS and safety. Results: Between November 2018 and April 2020, 122 patients (Osi+Ram: 59, Osi: 63) were enrolled. The patients' characteristics were well balanced. 59% were females, and 61% had an exon 19 deletion. Median age was 70 years old (range, 29-86). With a median follow up of 36.0 months, the median OS was 43.4 months (95% CI 36.5-N.R.) for Osi+Ram and N.R. (95% CI 41.3-N.R.) for Osi, resulting in a hazard ratio of 1.159 (95% CI 0.645-2.083, p = 0.62). Median treatment duration for Ram was 140 (14-1239) days. Ram was discontinued in 45 patients (76%) by the treatment related adverse effects. Common reasons for Ram discontinuation were platelet count decreased (n=14), proteinuria (n=12), neutrophil count decreased (n=11), pneumonitis (n=3), bleeding (n=3) and infection (n=3). Pneumonitis was observed in 16% in Osi, 9% in Osi+Ram, with grade 3 observed in 2% of both arms. Conclusions: Both treatment arms demonstrated sustained OS over 43 months. However, this study did not show an advantage of biweekly Ram administration with Osi in terms of PFS and OS. Notably, there was surpassed increase of early discontinuation of Ram due to higher adverse events. Clinical trial information: 2080224085 .

Effect of EGFR amplification on survival of patients with EGFR mutation-positive non-small cell lung cancer.

e21000 Background: Epidermal growth factor receptor (EGFR) mutation is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR mutation generally respond well to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR mutation are often co-occurring with EGFR amplification. However, the effect of EGFR amplification on the survival of patients with EGFR mutations remained unclear. Methods: Treatment-naïve adult patients with advanced NSCLC and EGFR mutation confirmed by next generation sequencing (NGS) at Fujian Provincial Hospital between April 2017 and October 2021 were enrolled in this retrospective clinical study. The patients’ clinical characteristics, gene mutations, treatment and clinical outcomes were extracted. progression-free survival (PFS) and overall response rate (ORR) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Results: EGFR amplification and non-EGFR amplification were identified in 55 patients (36.67%) and 95 patients (63.33%), and there were no significant differences in clinical characteristics. No significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (247 vs. 214 days, P = 0.605). The ORR in EGFR amplification group is higher than non-EGFR amplification group (60.87% vs 32.69%). Conclusions: There is a tendency that EGFR amplification might not be a well predictor in EGFR mutation positive NSCLC patients treated with EGFR-TKIs.

Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer

The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC. Patients with advanced EGFR-tyrosine kinase inhibitor-untreated NSCLC or post-operative recurrence with EGFR-sensitive mutations (exon 19 deletion or L858R mutation) were included. Informed consent was obtained from all participants. The candidate biomarker BIM-γ was measured in CTCs after blood collection (10mL of whole blood) at baseline. CTCs were collected with the ClearCell FX system, and quantitative real-time PCR was performed. Relative expression of BIM-γ mRNA from CTCs, as normalized to the reference gene (GAPDH mRNA), was calculated using the KCL22cell line for calibration. We enrolled 30 EGFR mutation-positive NSCLC patients treated with osimertinib during the period from April 2018 through December 2019. All the patients had an EGFR mutation at the primary site: exon 19 deletion in 15 cases and L858R in 15 cases. Median CTC count at baseline was 12 (range 3-127)/7.5mL, and median BIM-γ mRNA expression was 0.073 (range 0-1.37). Furthermore, the response rate to osimertinib was worse in patients with high than in those with low BIM-γ mRNA expression (n=15 each) (26.6% vs. 73.3%, respectively; p=0.011). Progression-free survival did not significantly differ between groups (p=0.13). BIM-γ mRNA overexpression in CTCs from EGFR mutation-positive NSCLC patients is a potential a biomarker for poor response to osimertinib. UMIN:00032055.

Osimertinib versus osimertinib plus chemotherapy for non–small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: An open-label, randomised phase 2 clinical trial

BackgroundOsimertinib is now a standard treatment for patients with previously untreated EGFR-mutated advanced non–small cell lung cancer (NSCLC). We here investigated whether the combination of osimertinib with cytotoxic chemotherapy might hold additive efficacy, as well as tolerability. Patients and methodsWe conducted an open-label randomised phase 2 study to evaluate osimertinib and carboplatin-pemetrexed combination in comparison with osimertinib monotherapy in EGFR mutation–positive NSCLC patients who experienced disease progression associated with the emergence of the T790M resistance mutation of EGFR during first-line EGFR-TKI therapy. The primary endpoint was PFS, with secondary endpoints, including OS, response, and safety. Given that osimertinib was approved as a first-line treatment during the study, patient accrual was discontinued, and a final analysis was performed for the 62 enrolled patients. ResultsMedian PFS was 15.8 months for the osimertinib monotherapy group and 14.6 months for the combination therapy group (hazard ratio of 1.09, with a 95% confidence interval of 0.51–2.32; P = .83). Median OS was not reached in either group. The overall response rate was 71.4% in the osimertinib monotherapy group and 53.6% in the combination group. The frequency or severity of known adverse events in the combination group was comparable to those with carboplatin and pemetrexed previously reported, and novel adverse events were not observed in this study. ConclusionThis is the first randomised study to investigate the efficacy and safety of the combination of osimertinib and cytotoxic chemotherapy for EGFR-mutated NSCLC. The addition of chemotherapy to osimertinib as a second-line treatment did not prolong survival, while it was found to be generally tolerable. This combination strategy will be further validated in the first-line setting. Trial registrationJapan Registry of Clinical Trials (jRCT) identifier: jRCTs071180062.

P76.68 The Impact of Eligibility for Anti-Angiogenic Treatment to the Prognosis of Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations

Previous studies described the efficacy of erlotinib plus angiogenesis inhibitors (bevacizumab/ramucirumab) combination therapy compared with erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC), regardless of EGFR activating mutation subtype. However, the impact of angiogenesis inhibitors’ eligibility criteria to progression free survival (PFS) and overall survival (OS) is still unclear. Hence, we evaluated the impact of angiogenesis inhibitors’ criteria in patients with NSCLC harboring EGFR activating mutation. We retrospectively collected data of patients with EGFR mutation positive NSCLC who were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy at Shizuoka Cancer Center between 2002 and 2019. Patients whose performance status (PS) was over 3, and those with symptomatic brain metastasis, were excluded from this study. Angiogenesis inhibitors ineligibility was defined as having at least one following conditions; 1) a history of bloody sputum or an exposure of tumor in bronchus, 2) radiologically identified major vessel invasion, 3) a history of cardiovascular disease and 4) history of chemoradiotherapy prior to EGFR-TKI treatment. They were divided into two groups, angiogenesis inhibitors eligible group (AI fit group) and ineligible group (unfit group). A total of 452 patients with NSCLC harboring EGFR activating mutation were included in this study. Among 452 patients, 207 patients had L858R mutation, and 245 patients had exon19 deletion. Median age of all patients was 71 years old (range 31-92), 35.0% were male, 43.1% had history of smoking, and majority of the patients were treated with gefitinib or erlotinib as a first EGFR-TKI (60.3% and 18.8%). AI fit group included 339 patients; 152 patients (44.8%) had L858R and 187 patients (55.2%) had exon19 deletion. In baseline characteristics, patients with PS 2 were more frequently observed in AI unfit group compared with AI fit group. The median PFS of AI fit and unfit group were 12.9 month and 9.6 months (HR 0.72, 95%CI 0.57-0.92, p=0.007), and multivariate analysis indicated PS 2 and AI unfit were associated with shorter PFS. Also, OS was significantly longer in AI fit groups than in unfit group; median OS were 33.0 months and 18.5months, respectively (HR 0.58, 95%CI 0.45-0.74, p<0.001). Multivariate analysis indicated PS 2, AI unfit, EGFR exon 19 deletion, and age ≥75 as significant prognostic factors. Out of four AI eligibility definitions, bloody sputum or exposure of tumor in bronchus were significantly associated with poor PFS (HR 1.43, 95%CI 1.07-1.98 p=0.017) and OS (HR 1.67, 95%CI 1.18-2.36 p=0.004). There was no significant difference in PFS between EGFR mutation subtypes in AI fit group; median PFS were 11.5months in L858R mutation and 13.8months in exon19 deletion (HR 0.85, 95%CI 0.67-1.07 p=0.17). In EGFR mutation positive NSCLC patients, the eligibility of AI was associated with longer PFS and OS, and resulted in insignificance of PFS between L858R and exon19 deletion group. Since these selection bias may have affected previous clinical trials data showing the efficacy of AI plus EGFR-TKI, the results of clinical trials should be carefully considered of its benefits.

Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation.

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry).

Real-world disease burden and outcomes of brain metastases in EGFR mutation-positive non-small-cell lung cancer.

Aim: To evaluate the real-world impact of brain metastases (BM) among patients with EGFR mutation-positive (EGFRm) metastatic non-small-cell lung cancer (NSCLC). Materials & methods: This retrospective, observational matched cohort electronic health record study assessed adults with EGFRm metastatic NSCLC with/without BM. Results: Among 402 patients split equally between both cohorts (±BM), the majority were Caucasian (69%), female (65%) and with adenocarcinoma (92%). Overall symptom burden and ancillary support service use were higher and median overall survival from metastatic diagnosis was significantly shorter in BM patients (11.9 vs 16 months; p = 0.017). Conclusion: BM in EGFRm NSCLC patients can negatively impact clinical outcomes. New targeted therapies that can penetrate the blood-brain barrier should be considered for treating these patients.

Impact of coexisting gene mutations in EGFR-mutated non–small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs

ObjectivesThe T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. Materials and methodsA total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. ResultsProgression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.049). ConclusionsCoexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

P2.14-15 Impact of Coexisting Gene Mutations in EGFR-Mutated Non–Small Cell Lung Cancer Before Treatment on EGFR T790M Mutation Status After EGFR-TKIs

The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after treatment. A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.024). Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

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).

A joint model of tumor size dynamics and survival with new lesions in EGFR mutation-positive non-small cell lung cancer patients with treatment of gefitinib or carboplatin and paclitaxel.

e20697 Background: Tumor dynamics have been serving as significant predictors in diagnosis, staging, prognosis and treatment of patients with non-small cell lung cancer (NSCLC). The purpose of this study is to propose a joint model that links the longitudinal tumor burden to progression free survival (PFS) with the appearance of new lesion in a population of NSCLC patients with gefitinib treatment or Carboplatin/Paclitaxel. Methods: The model was extended to the estimation of new lesion based on a previously developed tumor size and survival joint model. The derivative of the tumor loads and the probability of new lesions served as biomarkers in the survival submodel. Parameters were estimated from the posterior distribution in a Bayesian framework and numerical study was realized with R and STAN. A total of 434 NSCLC patients with EGFR mutation positive treated with gefitinib or chemotherapy (carboplatin+paclitaxel) from IPASS (‘NCT00322452’) were used to construct the model. Predictions were performed on the IFUM study (‘NCT01203917’) with 102 EGFR mutation positive NSCLC patients. Results: The model performed well in PFS prediction in both within-sample and out-of-sample estimations. Further improvement of model specifications is necessary since the tumor load developing rate and appearance of new-lesion negatively impacted survival predictions. About 90% accuracy was realized by the joint model when recapitulating the outcomes from the response evaluation criteria in solid tumors (RECIST). The appearance of new lesion contributed less than tumor size in accommodating drug effect when comparing progression-specific hazards. Conclusions: This Bayesian joint model well recapitulated the outcomes from the RECIST with sequentially updated tumor size that linked to survival predictions. New insights of relative predictive values were provided by the joint model regarding the components of RESICT.

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.

P2.13-19 Prognostic Value Inferred from the Quantitative Measurement of EGFR Mutation Using PNA-Clamping Method in Advanced EGFR Mutant NSCLC Patients

Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Recent advances in the understanding of the biology of tumors and in highly sensitive detection technologies for molecular analysis offer targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, not all EGFR mutation positive NSCLC patients are equally responsive to EGFR-TKIs. Although many factors have been introduced to predict EGFR TKIs response, there seems to be no factor that can clearly explain the mechanism. The aim of this study was to evaluate whether the quantification of EGFR mutation predicts clinical outcomes of EGFR-TKI therapy. This study is retrospective analysis of prospectively collected data about all patients who underwent EGFR mutation test using peptide nucleic acid (PNA)-mediated clamping polymerase chain reaction (PCR) at the Pusan National University Hospital between October 2015 and December 2017. The efficiency of PCR clamping was determined by measuring the Ct value. The delta (Δ) Ct-1 value (standard Ct value minus sample Ct value) was calculated to measure the quantification of EGFR mutation. Among the total 552 patients tested for EGFR mutations and 142 (25.7%) were positive for EGFR mutations. Seventy-one patients received EGFR-TKIs. The patient population was subdivided using a mean ΔCt-1 value of 5.28. There was no clinically significant difference between the two groups. Patients with high ΔCt-1 value had significantly longer median overall survival (OS) than did patients with low ΔCt-1 value (24.5 vs 16.7 months, p=0.002). Patients with common EGFR mutation (exon 19 deletion or L858R) and high ΔCt-1 value showed a significantly longer median OS than did patients with common mutation and low ΔCt-1 value (24.1 vs 18.0 months, p=0.014). Multivariate analysis revealed only high ΔCt-1 value was significant prognostic factor of survival in advanced advanced EGFR mutant NSCLC. The ΔCt-1 value, which refers to EGFR quantification by PNA-clamping method, is a significant good prognostic factor of survival to EGFR-TKI therapy.

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.

Real world treatment and outcomes in EGFR mutation-positive non-small cell lung cancer: Long-term follow-up of a large patient cohort

ObjectivesEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting. Materials and methodsClinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived >5 years from initiation of first-line treatment. ResultsThe full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months; 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs. ConclusionsThis large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies.

Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas® EGFR mutation test

ObjectiveDetection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing. The cobas® EGFR Mutation Test (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) is approved as a companion diagnostic for osimertinib, a third-generation EGFR-tyrosine kinase inhibitor approved in Japan. However, it is not clear whether the EGFR T790M mutation can be detected in cytology samples using this test. The primary objective of this study was to assess concordance of EGFR T790M gene mutation detection between histology and matched cytology samples using the cobas® EGFR Mutation Test. Materials and methodsWe conducted a multicenter, observational study in Japan. Overall, 41 EGFRm NSCLC patients who had both histology and cytology samples collected at the same time at re-biopsy and with the results of EGFR mutation test using histology samples were enrolled. The EGFR mutation status of both sample types was tested using the cobas® EGFR Mutation Test and the concordance rates were calculated. ResultsThe EGFR T790M mutation detection rate in histology and cytology samples was 42.5% and 37.5%, respectively. The overall percent agreement between the histology and cytology samples was 91.7%. ConclusionsThese data demonstrate that the cobas® EGFR Mutation Test can detect the EGFR T790M mutation in both cytology and histology samples.

A sensitive QPCR assay for EGFR mutation in plasma samples of NSCLC patients.

2595 Background: Tyrosine kinase inhibitors (TKI) have improved the overall outlook and quality of life for most of EGFR mutation positive NSCLC patients. However, tumor tissues are often absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment of patients with nonsmall cell lung cancer (NSCLC). An assay that detects EGFR mutations in the plasma would provide a noninvasive technique to assess suitability for TK inhibitor therapy. The ACCB new EGFR Mutation Kit is a ARMS-PCR test for the qualitative detection of 45 mutations in exons 18, 19, 20, and 21 of the EGFR gene in DNA derived from human plasma from NSCLC patients. Methods: 10 mL tubes of blood were collected from patients who never had been treated by EGFR TKI, and plasma circulating tumor DNA were extracted from plasma by Biomark Circulating DNA Kit. Qubit 2.0 Fluorometer was used to make plasma circulating DNA tumor quantitation. The concentration of final DNA sample is ≦2ng/μl. Total, 272 plasma DNA samples from 246 lung adenocarcinoma, 23 lung squamous carcinoma and 3 lung adenosquamous carcinoma patients were collected. 104 paired tissue EGFR mutations were detected by the same kit. Results: EGFR mutation was detected in 88 from 272 plasma DNA samples, 86 lung adenocarcinoma, 1 lung squamous carcinoma, 1 lung adenosquamous carcinoma, with EGFR mutation rate were 35.0% (86/246), 4.3% (1/23), 33.3% (1/3) respectively. In 61 Ⅰ~Ⅲ and 211 Ⅳ stage NSCLC patients, EGFR mutation rate were 21.3% (13/61) and 35.5% (75/211) respectively. Conclusions: The ACCB new EGFR Mutation Kit is a sensitive, accurate, rapid, and reproducible assay capable of testing DNA extracted from human plasma from NSCLC patients.

Real-World Data on Prognostic Factors for Overall Survival in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Gefitinib.

This study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice. We enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan. The median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7-14.2) and 26.9 months (21.2-32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11-0.83], p = .02; 2.69 [1.60-4.51], p < .001; 1.92 [1.24-2.97], p = .003; 2.26 [1.34-3.82], p = .002; 3.38 [1.85-7.78], p < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83-1.93], p = .275 and 0.75 [0.48-1.19], p = .211, respectively). HCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS. The finding that chronic hepatitis C virus (HCV) infection might predict poor overall survival (OS) in epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (NSCLC) patients treated with first-line gefitinib may raise awareness of benefit from anti-HCV treatment in this patient population. Brain metastasis in the initial diagnosis or intracranial progression during gefitinib treatment is not a prognostic factor for OS. This study, which enrolled a real-world population of NSCLC patients, including sicker patients who were not eligible for a clinical trial, may have impact on guiding usual clinical practice.

P3.02b-097 Experience of Re-Biopsy (Biopsy at Progression) of EGFR Mutant Non-Small Cell Lung Cancer Patients in Japan: A Retrospective Study: Topic: EGFR RES

To confirm mechanisms of resistance to targeted therapy and to evaluate future treatment strategy, biopsy at progression is important and necessary. Since biopsy at progression is not standard of care, we investigated real-world clinical practice in Japanese patients with non-small cell lung cancer (NSCLC) patients harboring the epidermal growth factor receptor (EGFR) gene mutation. This was a retrospective, multi-center, observational study in Japan. EGFR mutation positive NSCLC patients who developed disease progression after treatment by EGFR tyrosine kinase inhibitor were enrolled. The primary objective was the success rate of re-biopsy (biopsy at progression). The secondary objectives were differences of between the first biopsy and re-biopsy (e.g. sampling method, target organ of biopsy) and complications associated with re-biopsy. 395 patients were evaluated, median age was 63 years, and the most common histological type was adenocarcinoma (96.2%). Success rate of re-biopsy was 79.5% (314/395) of patients. Compared with the first biopsy, surgical biopsy increased from 1.8% to 7.8%, percutaneous tissue biopsy increased from 7.6% to 29.1%. Most commonly performed gene mutation tests using specimen collected by re-biopsy were EGFR (94.3%), EML4-ALK (22.0%) and KRAS (14.3%). T790M mutation was detected in 147 (49.7%) out of 296 patients. 23 patients (5.8%) had complications associated with re-biopsy, the most common complication was pneumothorax. A repeated re-biopsy was successful in 87.5% (28/32) of patients.TableRe-biopsy success rate by site and sampling methodNo. of patientsSuccess rate (%)By SitePrimary site220168 (76.4%)Metastatic site121103 (85.1%)Lymphnodes5040 (80.0%)Others43 (75.0%)By sampling methodTransbronchial biopsy; forceps204147 (72.1%)Transbronchial biopsy; needle4134 (82.9%)Percutaneous needle biopsy under CT guidance7766 (85.7%)Percutaneous needle biopsy under ultrasonic guidance3634 (94.4%) Open table in a new tab The observed success rate of re-biopsy was approximately 80% in this study. T790M detection rate was comparable to the previously reported studies. Re-biopsy for the EGFR TKI failure NSCLC patients is feasible in Japan.

P3.02b-065 Third Line Therapy in EGFR Positive Advanced Non-Small Cell Lung Cancer: Topic: EGFR Clinical

This study was designed to evaluate the response and outcomes to third line chemotherapy in classic activating EGFR mutation positive non-small cell lung cancer (NSCLC) who had progressed on both TKI and intravenous chemotherapy. 85 EGFR mutation positive NSCLC patients who had received both TKI and intravenous chemotherapy (mainly Pemetrexed and platinum, 80 patients) were selected for this analysis. The treatment regimens, response in accordance with RECIST v1.1 and treatment outcomes were noted. Descriptive statistics was performed. Kaplan Meier survival analysis was used for estimation of PFS and OS. 85 patients received third line therapy of which weekly paclitaxel was given in 43 (50.6%) patients, Docetaxel in 15 (17.6%) patients, Gemcitabine in 6 (7.1%) patients, rechallenged TKI in 11 (13%) patients and other chemotherapy in 10 (11.8%) patients. Out of 85 patients, 67 were evaluable for response; 13(19.4%) patients had partial response, 34 (50.7%) patients had stable disease and 20 (29.9%) patients had progression as best response. In 7 patients chemotherapy had to be stopped. It was because of toxicity in 5 patients and patient preference in 2 patients. The median PFS & OS were 4.2 months (95% CI 3.4-4.9 months) and 8.4 months (95% CI 6.9-9.9 months) respectively. There was no difference in PFS and OS between weekly Paclitaxel and other regimens. Third line therapy in EGFR mutated patients post TKI and Pemetrexed progression is associated with meaningful PFS and OS.