Abstract
Purpose
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.
Methods
Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. We categorised EGFR uncommon mutations as: sensitizing rare mutations (group 1: G719X, L861Q, S768I); Ex20 ins (group 2), or complex mutations (G719X + L861Q, G719X + S768I, 19 del + T790M, 19 del + L858R, L858R + S768I, and L858R + T790M; group 3).
Results
Of 66 patients given EGFR-TKI treatment, rare sensitive mutations, Ex20 ins, and complex mutations were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) cases, respectively. TKI efficacy in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Additionally, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins cases (8.6 vs. 4.1 vs. 3.1 months; p = 0.041). Importantly, complex EGFR mutations were independent predictors of increased overall survival (Hazard Ratios = 0.31; 95% confidence intervals: 0.11–0.90; p = 0.031). Among them, patients harboring Del-19 combined with L858R mutations showed a tendency to have higher response rate (RR) and improved PFS than those with other complex mutation patterns (RR: 66.7 vs. 14.3%, p = 0.021; PFS: 10.1 vs. 8.6 months, p = 0.232).
Conclusions
Personalized treatment should be evolving in different types of uncommon EGFR mutations. Clinical benefit from EGFR-TKIs was higher in NSCLC patients with complex EGFR mutations than those with other uncommon EGFR mutation types.
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Introduction
As one of the most common malignant tumors, lung cancer is the leading cause of cancer-related mortality worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for 85% of primary lung cancer [2]. Regarding to patients with lung adenocarcinoma, around 50% cases are diagnosed with a somatic mutation of the epidermal growth factor receptor (EGFR) gene in East Asian [3, 4], while mutations of EGFR were found in 10–20% of Caucasian patients [5, 6]. Therapies targeting driver mutations incorporate EGFR inhibitors such as gefitinib and erlotinib, resulting in extended survival in patients with NSCLC [7,8,9]. Icotinib also provides a similar efficacy to gefitinib, and with better tolerability in NSCLC patients [10].
The two most common EGFR mutations include deletions in exon 19 (Del-19) and L858R substitution in exon 21, which can be regarded as positive predictive biomarkers for response to EGFR tyrosine kinase inhibitors (TKIs) [6, 11]. Previous study has showed the response rate to EGFR TKIs was significantly higher in individuals with classic EGFR mutations than in those with uncommon mutations such as G719X, L861Q, S768I, Ex20 ins and so on [12]. However, EGFR uncommon mutation-positive cases are a heterogeneous group of molecular alterations with variable responses to EGFR-targeted drugs. Patients who had G719X, L861Q or S768I mutations could lead to favorable responses and longer progression-free survival (PFS) than the remaining rare mutation cases [13, 14], though not as favorable as for patients with classic mutations [12]. The 2017 NCCN guidelines Version 8. of NSCLC showed that there is a significant association between EGFR mutations-especially Del-19 and exon 21 (L858R, L861Q), exon 18 (G719X), and exon 20 (S768I) mutations-and sensitivity to EGFR TKIs [11, 15,16,17]. Moreover, the Ex20 ins predicts primary resistance to clinically achievable levels of TKIs [18, 19]. Collectively, studies characterizing the TKI sensitizing effect of individual rare mutations are indispensable to stagey patients who may benefit from anti-EGFR therapy.
Despite abundant literatures on common activating and secondary resistant EGFR mutations (T790M in exon 20), little is known about complex EGFR mutations due to the low incidence and complicated subtypes. And this gap in knowledge may constitute a challenge for the clinician in daily practice. To date, some studies showed that co-mutation might be associated with the primary resistance to TKIs [20, 21]. However, another study observed that patients with uncommon compound EGFR mutations (G719X + L861Q, G719X + S768I) had a significantly favorable PFS than did patients with a single mutation [22]. Therefore, comparative information about TKI efficacy within the EGFR co-mutated group is needed to optimise treatment.
In the present study, we aimed to investigate the clinical characteristics and efficacy of EGFR-TKIs in patients carrying uncommon EGFR mutations. The incidence of rare mutations varies in different ethnic groups and is also influenced by environmental factors. For this very reason, we informed the clinical decisions for the sensitivity of uncommon EGFR mutations to TKIs therapy in a Chinese cohort of advanced NSCLC patients. The results were discovered in a subset of NSCLC patients, which could help facilitate individual patient profiling and accurate prediction of response to EGFR TKIs therapy.
Materials and methods
Study design
Among 755 NSCLC patients with EGFR mutations, we retrospectively collected 66 patients with uncommon EGFR genotypes and treated for advanced NSCLC using EGFR-TKIs (Gefitinib, Erlotinib, Icotinib or Afatinib) during October 2010 and December 2015 at Zhejiang Cancer Hospital, China. Patients who harbored the acquired T790M substitution in exon 20 were excluded. Histological type and grade were decided based on lung tumor classification criteria of the World Health Organization (WHO). The TNM stages of patients were determined according to the 7th staging system of the International Association for the Study of Lung Cancer (IASLC). The protocol was approved by the institutional review board of Zhejiang Cancer Hospital, and all patients were provided informed consent.
EGFR mutational analysis
The tumor EGFR mutational status was determined by analyzing the DNA isolated from tumor specimens embedded in formalin-fixed and paraffin-embedded blocks. All samples were tested using an amplification refractory mutation system-based EGFR mutation detection kit (Amoy Diagnostics, Xiamen, People’s Republic of China). The method enabled the detection of 29 mutations in exons 18, 19, 20, and 21. In exon 20, two mutations (S768I and T790M) and one insertion were included.
Clinical data collection and efficacy evaluations
All patients had complete clinicopathological data and follow-up information. Demographic data included age, gender, smoking history, and Eastern Cooperative Oncology Group performance status (ECOG PS). Clinicopathological factors included histological type, clinical stage, radical surgery experience, types of EGFR mutations, types of EGFR-TKIs, and treatment line. Patients were visited every 4 weeks, and tumor response were evaluated by enhanced computed tomography before treatment initiation and 1 month after therapy, then every 2–3 months according to NHI regulations. EGFR-TKI beyond progression was determined by the specialized physicians. Objective response rates (RRs) and disease control rates (DCRs) of the patients with measurable tumors were calculated according to response evaluation criteria in solid tumors 1.1. PFS was calculated from the date of initiation of EGFR-TKI treatment to the date of disease progression or death. Overall survival (OS) was estimated from the date of initiation of EGFR-TKI treatment until death or last available follow-up. The median follow-up time of the 66 patients was 38 months.
Statistical analysis
Data were analyzed as categorical variables. Survival curves were plotted in a Kaplan–Meier method and compared using a log-rank test. Univariate and multivariate analyses of potential risk factors were performed using Cox proportional hazards regression model. Statistical analyses were performed using SPSS 13.0 for Windows (Chicago, IL). p value ≤ 0.05 in a two-tailed test was considered statistical significance.
Results
Demographics and clinical characteristics
The demographic characteristics of the patients with uncommon EGFR mutations are listed in Table 1. Among the 66 patients, 47.0% (31 patients) were male, 72.7% (48 patients) were younger than 65 years, and 45.5% (30 patients) had smoking experience. Most patients had good performance status with ECOG 0 or 1 (N = 57, 86.4%). The majority of patients were stage IV (N = 50, 75.8%) when receiving TKI treatment and diagnosed with NSCLC of predominantly adenocarcinoma histology (N = 63, 95.5%). Thirteen patients (19.7%) received radical surgery when initially diagnosed with NSCLC at I–IIIa stage. Then they were treated with EGFR-TKIs once disease recurrence after surgery.
EGFR mutation types and subtypes
Among the 755 patients with EGFR mutations, 66 (8.7%) cases had uncommon EGFR mutant. To further analyze the different responses of uncommon EGFR mutations to TKIs, when combining the effectiveness of EGFR-TKIs mentioned above in each mutation type, mutation variations were divided into three groups, such as rare sensitive mutations (group 1: G719X, L861Q, and S768I), Ex20 ins group 2, and complex mutations (G719X + L861Q, G719X + S768I, 19 del + T790M, 19 del + L858R, L858R + S768I, and L858R + T790M; group 3).
There were 46 patients had a single mutation [37 (56.1%) cases with sensitizing rare mutations, and 9 (13.6%) patients harboring Exon 20 ins], and 20 (30.3%) patients carried complex EGFR mutations (Table 2). Amino acid substitution mutations, G719X, L861Q, and S768I, were observed in 19 (28.8%), 16 (24.2%), and 2 (3.0%) patients, respectively. And Ex20 ins was noted in 9 (13.6%) patients (Fig. 1). Remaining 20 patients had co-mutations, which occurred in: G719X + L861Q (2 cases), G719X + S768I (2 cases), 19 del + T790M (1 cases), 19 del + L858R (6 cases), L858R + S768I (2 cases), and L858R + T790M (7 cases). EGFR-TKIs were used as first-line treatment for 30 (45.5%) patients. And Icotinib was prescribed more frequently in patients with EGFR-TKIs therapeutics.
Response to EGFR-TKIs treatment
Table 2 lists the treatment response of EGFR uncommon mutation types and subtypes to TKIs. Combining the response rate and sample number of patients with uncommon mutations, the efficacy of TKIs in each mutation types was showed in Fig. 2. The RR of the individuals with uncommon EGFR mutations was 28.8% (19 of 66) and the DCR was 81.8% (54 of 66). In subgroup analyses, patients carrying complex mutation had a RR of 30.0% and DCR of 80.0%. Of them, patients harboring Del-19 and L858R mutations showed a RR of 66.7% (4 of 6), which was significantly higher than those with other complex mutations patterns (RR = 14.3%, 2 of 14, p = 0.021). Regarding to the patients carrying de novo T790M combined with 19del or L858R mutation, the RR displayed 25.0% (2 of 8), and the DCR was 75.0% (6 of 8). In addition, patients in rare sensitive mutation group (G719X, L861Q, and S768I) had the RR of 32.4% and DCR of 83.8%, while a RR of 11.1% and a DCR of 77.8% were observed in Ex20 ins group.
Survival
After EGFR-TKIs treatment, patients with uncommon mutations had a median PFS of 4.8 months [95% confidence intervals (CI) 3.5–6.1, Fig. 3] and a median OS of 15.7 months (95% CI 11.6–19.7). In the subset analysis, patients with compound mutations had the most favorable PFS, followed by those with rare sensitive mutations and Ex20 ins (median PFS: 8.6 vs. 4.1 vs. 3.1 months, p = 0.041). We also detected an OS difference between them (median OS: 20.5 vs. 15.2 vs. 16.1 months), although no significant difference was reached (p = 0.271).
Interestingly, in the tumors harboring co-mutation, longer PFS was found for patients with Del-19 occurred with L858R mutation that the median PFS reached 10.1 months compared with 8.6 months for those with other co-mutation patterns, although exhibited nonsignificant differences (p = 0.232, Fig. 4). And the median OS was 20.5 months and 17.8 months, respectively (p = 0.713). Moreover, the median PFS and OS of patients occurred with de novo T790M combined Del-19 or L858R mutation was 8.6 and 21.6 months, respectively.
In the multivariate analysis (Table S1), performance status, radical surgery, the types of EGFR mutation, and line of EGFR-TKI therapy were identified as independent predictors for OS after adjusting by clinicopathological factors. First, complex EGFR mutations were independent predictor of increased OS [Hazard ratio (HR) = 0.31; 95% confidence interval (CI): 0.11–0.90; p = 0.031]. Second, patients with worse performance status were more likely to have shorter OS than those with better performance status (HR = 9.38; 95% CI 1.41–62.2; p = 0.020). Compared with patients who did not go through radical surgery, those who underwent it were at lower risk for disease death (HR = 0.16; 95% CI 0.06–0.48; p = 0.001). Finally, NSCLC patients with EGFR uncommon mutations who received EGFR-TKIs as their second-line or third-line treatment had reduced risk for death (HR = 0.32; 95% CI 0.15–0.72; p = 0.006; for second-line; and HR = 0.20; 95% CI 0.06–0.66; p = 0.008; for third-line).
Discussion
In the present study, 8.7% (66/755) of NSCLC patients carrying uncommon EGFR mutant, similar to East-Asian studies where the incidence of rare mutations was ranging from 7 to 8% [13], while the incidence in Caucasian cohort was only 1.9–2.7% [23, 24]. Then we observed a RR of 28.8% and a median PFS of 4.8 months in our patients after receiving TKIs treatments, and both results were inferior to the patients with common EGFR mutations that the RR was 70–80% and the median PFS was 9.4–11.9 months [22, 25, 26]. The RR of 28.8% in our study was in accordance with the 31% demonstrated in Johnson’s study [27], and the PFS of 4.8 months was comparable to the 5-month PFS in a East-Asian study performed by Wu et al. [12]. Moreover, the OS of 15.7 months in our cohort was also similar with 15.0 months in Wu’s study [12]. Considering the patients with uncommon EGFR mutant showed a worse efficacy than those with classic mutations after TKIs treatment, additional subtypes analyses in therapeutic responses among uncommon EGFR mutations should be urgent warranted.
Subgroup analysis showed patients with rare sensitive EGFR mutations (G719X, L861Q, and S768I) exhibited a RR of 32.4% and a median PFS of 4.1 months. The RR of 32.4% was consistent with data previously reported of 35.9% (51/142, p > 0.05), while the PFS of 4.1 months was shorter than 6.5 months observed in their study [22]. Previous researches have indicated that tumor with S768I mutation showed a variable response to TKIs treatment [28, 29], which might result in the shorter PFS among our patients with G719X, L861Q, and S768I mutant. Furthermore, in a post hoc analysis from three clinical trails on Afatinib (LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6), 14 (77.8%) patients with G719X had an objective response, as did nine (56.3%) with L861Q, and eight (100.0%) with S768I [30, 31]. Notably, the median PFS of them was reached to 10.7 months [30], which was inconsistent with our findings. The potential reasons might be listed as follows. First, Afatinib as a second-generation irreversible TKI could combine the targeted gene more firmly, inducing its favorable responses in G719X/L861Q/S768I [31]. Second, the scale of these two cohorts was not large enough (37 vs. 31 cases) to elucidate this problem, resulting in the different responses to EGFR-TKIs in these two studies. Collectively, first-generation TKIs demonstrated certain efficacy in patients with G719X, L861Q, and S768I mutations, while Afatinib might be a priority choice in these individuals.
Regarding to the TKI activity in NSCLC patients with Ex20 ins, we detected a RR of 11.1% and a median PFS of 3.1 months. The PFS was line with the 2.7 months reported previously [30]. However, the outcome was worse than that of the cisplatin-pemetrexed combination regimen treating lung adenocarcinoma with EGFR mutations (median PFS: 6.9 months; RR: 23%) in LUX-Lung 2 clinical trial [32]. As a result, first-line chemotherapy rather than EGFR-TKIs treatment seems to achieve a better efficacy in Ex20 ins mutated cases.
Consistent with previously published data [13], 20 (2.6%) individuals carried complex EGFR mutations. And our further subtype analysis suggested these patients had a longer PFS than those with G719X/L861Q/S768I mutations or Ex20 ins, indicating those patients may benefit more from first-line EGFR-TKIs treatment. Similar to the findings by Johnson et al. [27], multivariate analysis demonstrated complex EGFR mutations could be an independent predictor of increased OS in NSCLC patients carrying uncommon EGFR mutations.
EGFR compound mutations were composed of heterogeneous groups, resulting in the different responds to TKIs treatment. Further precise definition is crucial for individualized therapy in EGFR mutant lung adenocarcinoma. Analysis on PFS revealed that patients combined Del-19 and L858R mutations had significantly higher RR and a trend toward longer PFS than those carrying other patterns of complex EGFR mutations. Considering the median PFS of 10.1 months and the RR of 66.7% were in line with the effectiveness of TKIs in patients harboring classic mutations [25, 26], patients with Del-19 and L858R are strongly recommended to receive EGFR-TKIs as their first-line treatment.
Complex mutations of de novo T790M combined with other mutation types (such as Del-19 or L858R) were also detected in this study. Notably in these patients, the RR to EGFR-TKIs was 25.0%, and the median PFS was 8.6 months. Consistent with previous report [33], the efficacy of complex mutations including de novo T790M to first-generation and second-generation TKIs was inferior to the classic EGFR mutations. However, third-generation agent (Osimertinib) has proved to be effective in NSCLC cell lines with EGFR sensitizing and T790M resistant mutations [34]. Moreover, Osimertinib has been approved by FDA and EMA for the treatment of patients with advanced EGFR T790M mutated NSCLC who have disease progressed during first-generation or second-generation TKI therapeutics [35, 36]. Another research indicated that Osimertinib as first-line therapy for advanced NSCLC patients harboring EGFR mutation (including 5 patients with de novo T790M mutation) resulted in a high RR, favorable PFS and manageable tolerability profile [37]. Therefore, Osimertinib has being investigated its efficacy in patients with de novo T790M mutation as a first-line treatment (versus gefitinib) in the phase 3 FLAURA trial (NCT02296125), then the results are worth looking forward to. In conclusion, distinct clinical features of different EGFR co-mutations were displayed. A further crystal structure analysis of the compound EGFR mutations is required to elucidate the mechanisms underlying these observations. Our findings of these complex mutations and their association to EGFR-TKIs, help to guide the application of EGFR-TKIs in patients with EGFR co-mutations.
This study provided the systematical treatment options for the sensitivity of uncommon EGFR mutations types and subtypes, especially the complex mutations to EGFR-TKIs therapy. Personalized treatment should be applied to different types of uncommon EGFR mutations in NSCLC patients. EGFR-TKIs as first-line treatment seems to achieve certain effectiveness in patients harbored types of G719X, L861Q, and S768I mutations, but Afatinib might be a priority selection for these patients. However, less benefit from TKIs treatment was gained in Ex20 ins mutated cases. Moreover, different responds to TKIs were existed in EGFR compound mutations subtypes. It is strongly recommended TKIs as first-line therapy in patients harboring Del-19 compound L858R mutations; while might not be effective in patients with de novo T790M combined with other mutation types. Collectively, our study indicated the predictive and prognostic values of uncommon EGFR mutations with regard to TKI therapy in a cohort of East-Asian population, which should be evaluated in wide multinational studies. Then the integrated data could help inform clinical decisions for patients in different ethnic groups with NSCLC harboring uncommon EGFR mutations.
References
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin. doi:10.3322/caac.21387
Dearden S, Stevens J, Wu YL, Blowers D (2013) Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 24(9):2371–2376. doi:10.1093/annonc/mdt205
Shi Y, Li J, Zhang S, Wang M, Yang S, Li N, Wu G, Liu W, Liao G, Cai K, Chen L, Zheng M, Yu P, Wang X, Liu Y, Guo Q, Nie L, Liu J, Han X (2015) Molecular epidemiology of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology: Mainland China Subset Analysis of the PIONEER study. PLoS ONE 10(11):e0143515. doi:10.1371/journal.pone.0143515
Kobayashi Y, Mitsudomi T (2016) Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci 107(9):1179–1186. doi:10.1111/cas.12996
Zaric B, Stojsic V, Kovacevic T, Sarcev T, Tepavac A, Jankovic R, Spasic J, Radosavljevic D, Zarogoulidis P, Vukobradovic-Djoric N, Perin B (2014) Clinical characteristics, tumor, node, metastasis status, and mutation rate in domain of epidermal growth factor receptor gene in serbian patients with lung adenocarcinoma. J Thorac Oncol 9(9):1406–1410. doi:10.1097/JTO.0000000000000242
Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M, Spanish Lung Cancer Group (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967. doi:10.1056/NEJMoa0904554
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, North-East Japan Study Group (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388. doi:10.1056/NEJMoa0909530
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12(8):735–742. doi:10.1016/s1470-2045(11)70184-x
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M, West Japan Oncology Group (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11(2):121–128. doi:10.1016/S1470-2045(09)70364-X
Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, Zhang Y, Chen J, Cheng Y, Feng J, Zhang H, Song Y, Wu YL, Xu N, Zhou J, Luo R, Bai C, Jin Y, Liu W, Wei Z, Tan F, Wang Y, Ding L, Dai H, Jiao S, Wang J, Liang L, Zhang W, Sun Y (2013) Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 14(10):953–961. doi:10.1016/s1470-2045(13)70355-3
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500. doi:10.1126/science.1099314
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC (2011) Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 17(11):3812–3821. doi:10.1158/1078-0432.CCR-10-3408
Lohinai Z, Hoda MA, Fabian K, Ostoros G, Raso E, Barbai T, Timar J, Kovalszky I, Cserepes M, Rozsas A, Laszlo V, Grusch M, Berger W, Klepetko W, Moldvay J, Dome B, Hegedus B (2015) Distinct Epidemiology and clinical consequence of classic versus rare EGFR mutations in lung adenocarcinoma. J Thorac Oncol 10(5):738–746. doi:10.1097/JTO.0000000000000492
Klughammer B, Brugger W, Cappuzzo F, Ciuleanu T, Mok T, Reck M, Tan EH, Delmar P, Klingelschmitt G, Yin AY, Spleiss O, Wu L, Shames DS (2016) Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations. J Thorac Oncol 11(4):545–555. doi:10.1016/j.jtho.2015.12.107
Cappuzzo F, Finocchiaro G, Metro G, Bartolini S, Magrini E, Cancellieri A, Trisolini R, Castaldini L, Tallini G, Crino L (2006) Clinical experience with gefitinib: an update. Crit Rev Oncol Hematol 58(1):31–45. doi:10.1016/j.critrevonc.2005.08.008
Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, Janne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9(6):485–495. doi:10.1016/j.ccr.2006.04.022
Sequist LV, Joshi VA, Janne PA, Muzikansky A, Fidias P, Meyerson M, Haber DA, Kucherlapati R, Johnson BE, Lynch TJ (2007) Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 12(1):90–98
Lund-Iversen M, Kleinberg L, Fjellbirkeland L, Helland A, Brustugun OT (2012) Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations. J Thorac Oncol 7(9):1471–1473. doi:10.1097/JTO.0b013e3182614a9d
Yasuda H, Kobayashi S, Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13(1):e23–e31. doi:10.1016/S1470-2045(11)70129-2
Massarelli E, Johnson FM, Erickson HS, Wistuba II, Papadimitrakopoulou V (2013) Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 80(3):235–241. doi:10.1016/j.lungcan.2013.01.018
De Pas T, Toffalorio F, Manzotti M, Fumagalli C, Spitaleri G, Catania C, Delmonte A, Giovannini M, Spaggiari L, de Braud F, Barberis M (2011) Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol 6(11):1895–1901. doi:10.1097/JTO.0b013e318227e8c6
Chiu CH, Yang CT, Shih JY, Huang MS, Su WC, Lai RS, Wang CC, Hsiao SH, Lin YC, Ho CL, Hsia TC, Wu MF, Lai CL, Lee KY, Lin CB, Yu-Wung Yeh D, Chuang CY, Chang FK, Tsai CM, Perng RP, Chih-Hsin Yang J (2015) Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations. J Thorac Oncol 10(5):793–799. doi:10.1097/jto.0000000000000504
Boch C, Kollmeier J, Roth A, Stephan-Falkenau S, Misch D, Gruning W, Bauer TT, Mairinger T (2013) The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open. doi:10.1136/bmjopen-2013-002560
Pallis AG, Voutsina A, Kalikaki A, Souglakos J, Briasoulis E, Murray S, Koutsopoulos A, Tripaki M, Stathopoulos E, Mavroudis D, Georgoulias V (2007) ‘Classical’ but not ‘other’ mutations of EGFR kinase domain are associated with clinical outcome in gefitinib-treated patients with non-small cell lung cancer. Br J Cancer 97(11):1560–1566. doi:10.1038/sj.bjc.6604068
Keam B, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, Chung DH, Heo DS (2014) Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 19(4):594–600. doi:10.1007/s10147-013-0602-1
Costa DB, Kobayashi S, Tenen DG, Huberman MS (2007) Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer 58(1):95–103. doi:10.1016/j.lungcan.2007.05.017
Johnson ML, Sima CS, Chaft J, Paik PK, Pao W, Kris MG, Ladanyi M, Riely GJ (2013) Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas. Cancer 119(2):356–362. doi:10.1002/cncr.27730
Leventakos K, Kipp BR, Rumilla KM, Winters JL, Yi ES, Mansfield AS (2016) S768I mutation in EGFR in patients with lung cancer. J Thorac Oncol 11(10):1798–1801. doi:10.1016/j.jtho.2016.05.007
Kancha RK, von Bubnoff N, Peschel C, Duyster J (2009) Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin Cancer Res 15(2):460–467. doi:10.1158/1078-0432.CCR-08-1757
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL (2015) Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16(7):830–838. doi:10.1016/S1470-2045(15)00026-1
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O’Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV (2015) Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16(2):141–151. doi:10.1016/S1470-2045(14)71173-8
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334. doi:10.1200/JCO.2012.44.2806
Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, Ho BC, Chang GC, Shih JY, Yu SL, Yang PC (2012) Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 30(4):433–440. doi:10.1200/JCO.2011.38.3224
Carmi C, Cavazzoni A, Vezzosi S, Bordi F, Vacondio F, Silva C, Rivara S, Lodola A, Alfieri RR, La Monica S, Galetti M, Ardizzoni A, Petronini PG, Mor M (2010) Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion. J Med Chem 53(5):2038–2050. doi:10.1021/jm901558p
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA, Investigators A (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376(7):629–640. doi:10.1056/NEJMoa1612674
Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, Blackhall F, Haggstrom D, Yoh K, Novello S, Gold K, Hirashima T, Lin CC, Mann H, Cantarini M, Ghiorghiu S, Janne PA (2017) Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. doi:10.1200/JCO.2016.70.3223
Ramalingam S, Yang JC, Lee CK, Kurata T, Kim DW, John T, Nogami N, Ohe Y, Janne PA (2016) LBA1_PR: osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts. J Thorac Oncol 11(4 Suppl):S152. doi:10.1016/s1556-0864(16)30324-0
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Chen, K., Yu, X., Wang, H. et al. Uncommon mutation types of epidermal growth factor receptor and response to EGFR tyrosine kinase inhibitors in Chinese non-small cell lung cancer patients. Cancer Chemother Pharmacol 80, 1179–1187 (2017). https://doi.org/10.1007/s00280-017-3464-9
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DOI: https://doi.org/10.1007/s00280-017-3464-9