Acquired Epidermal Growth Factor Receptor T790M Mutation Research Articles

Real-world clinical evidence of lazertinib use in acquired EGFR T790M mutated non-small cell lung cancer.

Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting. Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%). The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40). Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.

The MEK/ERK/miR-21 Signaling Is Critical in Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells.

Simple SummaryOur study provided data that the inhibition of MEK/ERK signaling could overcome Osimertinib resistance both in vitro and in vivo. Mechanistically, MEK inhibitor Trametinib suppressed the tumorigenic properties of NSCLC cells by reducing the generation of CAFs. The trametinib-mediated anti-cancer function was also associated with the significantly suppressed level of miR-21, of which primary targets included PDCD4, as shown in this study and MEK inhibitor Trametinib significantly suppressed Osimertinib-resistant NSCLC tumor growth by abolishing both processes.Background: The third-generation epidermal growth factor receptor (EGFR) inhibitor, Osimertinib, is used to treat non-small cell lung cancer (NSCLC) patients with tyrosine kinase inhibitor (TKI) resistance caused by acquired EGFR T790M mutation. However, patients eventually develop resistance against Osimertinib with mechanisms not yet fully clarified. Activated alternative survival pathways within the tumor cells and cancer-associated fibroblasts (CAFs) have been proposed to contribute to Osimertinib resistance. MET and MEK inhibitors may overcome EGFR-independent resistance. Another acquired resistance mechanism of EGFR-TKI is the up-regulation of the RAS/RAF/MEK/ERK signaling pathway, which is the key to cell survival and proliferation; this may occur downstream of various other signaling pathways. In this report, we reveal the possible regulatory mechanism and inhibitory effect of the MEK inhibitor trametinib applied to MEK/ERK/miR-21 axis and PDCD4 in Osimertinib resistance. We found a possible regulatory role of PDCD4 in ERK signaling. PDCD4 is a new type of tumor suppressor that has multiple functions of inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. Previous bioinformatics analysis has confirmed that PDCD4 contains the binding site of miR-21 and acts as a tumor suppressor in the regulation of various processes associated with the development of cancer, including cell proliferation, invasion, metastasis, and neoplastic transformation. Based on the above analysis, we hypothesized that the tumor suppressor PDCD4 is one of the effective inhibitory targets of miR-21-5p. Methods: The expression between EGFR and ERK2 in lung adenocarcinoma was evaluated from the TCGA database. Osimertinib-sensitive and resistant NSCLC cells obtained from patients were used to co-culture with human lung fibroblasts (HLFs) to generate CAF cells (termed CAF_R1 and CAF_S1), and the functional roles of these CAF cells plus the regulatory mechanisms were further explored. Then, MEK inhibitor Trametinib with or without Osimertinib was applied in xenograft model derived from patients to validate the effects on growth inhibition of Osimertinib-resistant NSCLC tumors. Result: ERK2 expression correlated with EGFR expression and higher ERK2 level was associated with worse prognosis of patients and Osimertinib resistance. CAFs derived from Osimertinib-resistant cells secreted more IL-6, IL-8, and hepatocyte growth factor (HGF), expressed stronger CAF markers including α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) plus platelet-derived growth factor receptor (PDGFR), and enhanced stemness and Osimertinib resistance in NSCLC cells. Meanwhile, increased MEK/ERK/miR-21 expressions were found in both CAFs and NSCLC cells. MEK inhibitor Trametinib significantly abrogated the abovementioned effects by modulating β-catenin, STAT3, and ERK. The xenograft model showed combining Osimertinib and Trametinib resulted in the most prominent growth inhibition of Osimertinib-resistant NSCLC tumors. Conclusions: Our results suggested that MEK/ERK/miR-21 signaling is critical in Osimertinib resistance and CAF transformation of NSCLC cells, and MEK inhibitor Trametinib significantly suppressed Osimertinib-resistant NSCLC tumor growth by abolishing both processes.

Different Clinicopathologic and Computed Tomography Imaging Characteristics of Primary and Acquired EGFR T790M Mutations in Patients with Non-Small-Cell Lung Cancer.

PurposeAlthough patients with primary and acquired epidermal growth factor receptor (EGFR) T790M positive non-small-cell lung cancer (NSCLC) respond to osimertinib treatment, the optimal treatment strategy differs for these two groups of patients. This study aimed to compare the clinicopathologic and computed tomography (CT) imaging characteristics between primary and acquired EGFR T790M mutations in patients with NSCLC before treatment.Patients and MethodsWe enrolled two groups of patients with primary or acquired EGFR T790M mutation NSCLC (n = 103 per group) from January 2012 to December 2019. We analyzed their clinicopathologic and CT characteristics and differences between the groups. The groups were further categorized based on 21L858R and 19del to exclude the effect of coexistent mutations.ResultsPrimary, compared to acquired, T790M mutation tends to coexist with 21L858R (P < 0.001), exhibiting earlier tumor stage (P < 0.001), higher differentiation (P = 0.029), higher proportion of lepidic subtype adenocarcinoma (P < 0.001), and significant associations with some CT features (multiple primary lung cancers, ground-glass opacity, air bronchogram, and vacuole sign [all P < 0.001]). The combined model, composed of clinicopathologic and conventional CT signature and CT-radiomic signature, showed good discriminative ability with the area under the receiver operating characteristic curve 0.90 and 0.91 in the training and validation datasets, respectively. The T790M mutation contributed to these differences independently of coexistent mutations.ConclusionWe identified clinicopathologic and CT imaging differences between primary and acquired T790M mutations. These findings provide insights into developing future personalized T790M mutation status-based theranostic strategies.

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M–Mutated Non–Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor

Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. UMIN Clinical Trials Registry Identifier: UMIN000023761.

The Impact of Acquired EGFR T790M Mutation and EGFR Circulating Cell-Free DNA on Survival in Patients with Lung Adenocarcinoma Following EGFR-TKI Therapy.

ObjectiveTo utilize liquid biopsy to investigate the potential clinical factors influencing the incidence of the acquired epidermal growth factor receptor (EGFR) T790M mutation, and the impact of EGFR circulating cell-free DNA (CfDNA) on overall survival for patients with advanced EGFR-mutated adenocarcinoma resistant to first-line EGFR-tyrosine kinase inhibitor (TKI).MethodsA retrospective study was conducted to analyze EGFR-mutated stage IIIB-IV adenocarcinoma patients who received an EGFR-TKI (gefitinib, erlotinib, or afatinib) as first-line therapy and then underwent a liquid biopsy exam at disease progression.ResultsA total of 135 patients were included, and the T790M mutation was detected in 51 patients (37.7%). The incidence of T790M mutation increased with the number of initial metastatic sites (p = 0.015). Liver metastasis (odds ratio [OR], 3.373; p = 0.017) and other metastasis (OR, 3.063; p = 0.023) were also independently correlated with T790M mutation incidence. T790M mutation was also associated with more than two progressive sites (OR, 3.382; p = 0.006), liver progression (OR, 6.204; p = 0.002), and bone progression (OR, 3.366; p = 0.004). However, central nervous system progression was inversely correlated with T790M mutation (OR, 0.183; p = 0.027). Overall survival was the longest among the patients without CfDNA, followed by those shedding T790M mutation and those shedding Del 19/L858R mutations (p = 0.005).ConclusionInitial metastasis to the liver and other sites may be independent factors for secondary EGFR T790M mutation. T790M-positive lung adenocarcinoma has specific progression patterns. Moreover, not having EGFR CfDNA, being positive for Del19/L858R mutations, and being positive for T790M mutation have differing impacts on overall survival for patients with advanced EGFR-mutated adenocarcinoma resistant to first-line EGFR-TKI.

Clinical Factors Affecting the Response to Osimertinib in Non-Small Cell Lung Cancer Patients with An Acquired Epidermal Growth Factor Receptor T790M Mutation: A Long-Term Survival Analysis

Osimertinib is a standard therapy for advanced non-small cell lung cancer (NSCLC) patients with anacquired epidermal growth factor receptor (EGFR) T790M mutation; however, the exploration of clinical characteristics that may affect prognosis and long-term survival is still lacking. This retrospective study aimed to provide long-term survival data and explore meaningful prognostic factors in patients treated with osimertinib. A total of 246 patients with acquired EGFR T790M mutation who were treated with osimertinib were included in this study. Progression-free survival (PFS), overall survival from osimertinib initiation (OS1), overall survival from diagnosis of advanced disease (OS), and possible prognostic clinical features were analyzed. The median PFS, OS1, and OS values were 12.17, 24.33, and 47.86months, respectively. The median PFS of patients harboring EGFR exon 19 deletions/T790M (19del/T790M) and those harboring EGFR 21 L858R/T790M were 13.27 and 9.77months (p = 0.001), respectively, while the median OS1 values were 25.03 and 18.30months (p = 0.023), respectively; however, no significant difference was found in median OS (p = 0.060). Cox regression analysis revealed that coexisting mutation type and extrathoracic metastasis affected survival (PFS, OS1). In addition, gene biopsy specimen type (tissue or blood sample) was related to PFS (p = 0.032), which implied that liquid biopsy may be an independent poor prognostic factor. This is the first reported survival analysis of osimertinib-treated Chinese patients, which indicates a median OS of 47.86months. The EGFR T790M mutation is likely to coexist with 19del and indicate longer PFS and OS1 than EGFR 21 L858R/T790M. Additionally, the extrathoracic metastasis status and biopsy specimen type might also affect the survival of patients treated with osimertinib.

Next-generation sequencing of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive NSCLC patients treated with osimertinib.

e21563 Background: Osimertinib is standard of care for patients with advanced non–small-cell lung cancer (NSCLC) carrying acquired epidermal growth factor receptor ( EGFR) T790M mutation. However, few studies have been conducted to investigate the impact of rebiopsy on clinical outcomes after resistance to osimertinib. We evaluated whether next-generation sequencing (NGS) of tissue and liquid rebiopsy could favor post-progression outcomes of T790M-positive advanced NSCLC patients treated with osimertinib. Methods: Immediately just after resistance to second- or further-line osimertinib, advanced NSCLC patients with acquired EGFR T790M mutation were retrospectively divided into the NGS and non-NGS groups according to whether they underwent NGS of tissue or liquid rebiopsy. The co-primary endpoints were post-progression survival (PPS) defined as the time from osimertinib resistance to subsequent-line treatment resistance, and post-progression overall survival (pOS) defined as from osimertinib resistance to death or end of the last follow-up. Multivariable analyses were done using Cox proportional hazards regression model and log-rank test. Results: Between January 2017 and July 2019, 89 patients (62 vs. 27 for the NGS and non-NGS groups respectively) were eligible for final analyses. In the NGS group, 3.2% (2/62) underwent tissue rebiopsy only, 29.0% (18/62)only had liquid rebiopsy, and 66.8% (42/62)with both tissue and liquid rebiopsy.The NGS group received more targeted or combined therapy after resistance to osimertinib (62.9% vs. 40.8%, P= 0.053). The NGS group was significantly superior to the non-NGS group in the co-primary endpoints. The median PPS was 6.1 vs. 2.7 months (hazard ratio [HR], 0.49; 95%CI, 0.30 to 0.80; 2-sided log-rank P= 0.004). Meanwhile, the median pOS was 11.7 vs. 6.8 months (HR, 0.50; 95%CI, 0.29 to 0.85, 2-sided log-rank P= 0.009). Conclusions: Providing more opportunities for individualized treatment, NGS of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive advanced NSCLC patients treated with osimertinib.

Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation.

Primary epidermal growth factor receptor (EGFR) T790M mutation can be occasionally identified in previous untreated nonsmall cell lung cancer (NSCLC) patients. To compare clinical characteristics and outcomes in patients with primary and acquired EGFR T790M mutation, we collected the data of patients diagnosed with EGFR mutation from 2012 to 2017 in Shanghai Chest Hospital. Primary EGFR T790M mutation was identified in 61 patients (1.1%; 95% confidence interval (CI): 0.8%-1.3%) of 5685 TKI-naive EGFR mutant patients. Acquired T790M mutation was detected in 98 patients (50.3%; 95%CI: 43.2%-57.3%) of 195 TKI-treated patients. T790M mutation always coexisted with sensitizing EGFR mutations. Primary EGFR T790M always coexisted with 21L858R (46/61) whereas acquired T790M coexisted with 19del (68/98), (p < 0.001). Among them, 18 patients with primary T790M mutation received osimertinib and 72 patients with acquired T790M mutation received osimertinib. The median progression-free survival (PFS) of osimertinib was significantly longer in primary T790M group (17.0 months, 95%CI:14.0-20.0 months) compared to acquired T790M group (10.0 months, 95%CI:8.6-11.4 months, p = 0.022). However, the median overall survival (OS) of acquired T790M mutation patients was significantly longer compared to that of primary T790M mutation patients who received osimertinib (50.4 months vs. 29.9 months, p = 0.016). Our findings suggest that primary T790M mutation likely coexists with 21L858R while acquired mutation likely coexists with 19del. Both mutations showed good response to osimertinib. Patients with primary T790M mutation experienced greater benefits from osimertinib. However, patients with acquired T790M mutation had a better overall survival during the entire clinical treatment.

Acquired EGFR T790M Mutation After Relapse Following EGFR-TKI Therapy: A Population-based Multi-institutional Study.

To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42.5%) patients had acquired T790M mutations in EGFR. Patients ≥75 years old and patients with an exon 19 deletion had higher rates of acquired T790M mutation than did younger patients and those with an exon 21 L858R mutation. In 75 patients treated with afatinib, 34 (45.3%) patients had acquired T790M mutation. The sensitivity of T790M mutation detection was lower in plasma specimens than in biopsy specimens. This population-based study confirms previous studies and highlights potential determinants of acquired T790M mutation to be considered in clinical practice.

AZD9291 Increases Sensitivity to Radiation in PC-9-IR Cells by Delaying DNA Damage Repair after Irradiation and Inducing Apoptosis.

AZD9291 is a novel, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which is administered orally. It has been proven effective in non-small cell lung cancer (NSCLC) patients, with both EGFR-sensitizing and EGFR T790M mutations in preclinical models. However, the potential therapeutic effects of AZD9291 combined with other modalities, including ionizing radiation, are not well understood. The presence of AZD9291 significantly increases the cell-killing effects of radiation in PC-9-IR cells with a secondary EGFR mutation (T790M), which was developed from NSCLC PC-9 cells (human lung adenocarcinoma cell with EGFR 19 exon 15 bp deletion) after chronic exposure to increasing doses of gefitinib, and in H1975 cells (human lung adenocarcinoma cell with EGFR exon 20 T790M mutation de novo), but not in PC-9 cells or in H460 cells (human lung adenocarcinoma cell with wild-type EGFR). In PC-9-IR cells, AZD9291 remarkably decreases phosphorylation levels of EGFR, extracellular regulated protein kinase (ERK), and protein kinase B (AKT). AZD9291 increases sensitivity to radiation in PC-9-IR cells by delaying deoxyribonucleic acid (DNA) damage repair after irradiation and inducing apoptosis, and enhances tumor growth inhibition when combined with radiation in PC-9-IR xenografts. Our findings suggest a potential therapeutic effect of AZD9291 as a radiation sensitizer in lung cancer cells with an acquired EGFR T790M mutation, providing a rationale for a clinical trial using the combination of AZD9291 and radiation in NSCLCs harboring acquired T790M mutation.

The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients.

IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.ResultsForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.MethodsAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.ConclusionsT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation.

Abstract 2031: Effects of (-)-epigallocatechin-3-gallate on EGFR or ALK driven lung cancer models.

Abstract There has been considerable evidence that (-)-epigallocatechin-3-gallate (EGCG) inhibited enzyme activities and signal transduction pathways, resulting in the suppression of cell proliferation and enhancement of apoptosis, as well as the inhibition of cell invasion, angiogenesis and metastasis. EGCG has been shown to bind directly to several receptors including epidermal growth factor receptor (EGFR) and to inhibit the functions. EGFR tyrosine kinase inhibitors such as gefitinib and ALK inhibitors such as crizotinib are effective for non-small cell lung cancer harboring activating EGFR mutations and ALK fusion genes, respectively. However, even in the patients with an initial response to the drug, acquired resistance develops after 6-12 months. In this study, we investigated effects of EGCG on EGFR or ALK driven lung cancer models. We used four lung cancer cell lines: PC-9, RPC-9, H1975 and H2228. RPC-9 cells that acquired EGFR T790M mutation were established from parental PC-9 cells harboring EGFR exon 19 deletion mutation in our laboratory. RPC-9 cells that showed a 400-fold resistance to gefitinib compared with parental PC-9 cells. H1975 cells have L858R point mutation in exon 21 with T790M. H2228 cells harbor EML4-ALK fusion genes. Growth inhibition was measured using MTT assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96 h exposure was used to evaluate the effectiveness of EGCG. Protein expression was determined by Western blotting. The IC50s (mean + standard deviation) were 46 + 7.0 μM for PC-9 cells, 37 + 3.6 μM for RPC-9 cells, 32 + 0.6 μM for H1975 cells and 57 + 7.6 μM for H2228 cells: the four cell lines have similar sensitivity to EGCG. Phosphorylated (p)EGFR, pAKT and pERK in RPC-9 and H1975 cells were suppressed by EGCG (50 or 100 μM). pALK, pAKT and pERK in H2228 cells were also inhibited by EGCG (50 or 100μM). The antitumor effect of EGCG was examined using mouse xenograft model. PC-9, RPC-9, H1975, and H2228 cells (2 × 106) were injected s.c. into the backs of the athymic mice at 7 wk of age. At about 1 week after injection, mice harboring about 5 - 10 mm tumor size were randomly assigned into one of two groups that received either EGCG or vehicle. The tumor sizes (mm3; mean + standard deviation) of PC-9 on day 42 were 1114 + 478 (n = 10) in EGCG group and 2803 + 973 (n = 9) in control group (p &amp;lt; 0.05). Similarly, the xenograft tumors of RPC-9, H1975 and H2228 cells in EGCG-treated groups were significantly smaller than those in vehicle-treated groups, respectively. The numbers of tumor blood vessels of xenograft tissues, which were evaluated by immunohistochemistry using CD31 antibody, in EGCG-treated mice were significantly reduced than those in vehicle-treated mice. In conclusion, these preclinical data suggest that EGCG may be effective for both EGFR-driven in spite of T790M presence and ALK-driven lung tumors. Citation Format: Yoshihiro Honda, Nagio Takigawa, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Nobuaki Ochi, Masayuki Yasugi, Toshi Murakami, Mitsune Tanimoto, Katsuyuki Kiura. Effects of (-)-epigallocatechin-3-gallate on EGFR or ALK driven lung cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2031. doi:10.1158/1538-7445.AM2013-2031