Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Journal Pre-proof Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC Shuo Yang (Resources) (Investigation) (Writing - original draft), Shiqi Mao (Resources) (Investigation) (Writing - original draft), Xuefei Li (Resources) (Supervision) (Writing - review and editing), Chao Zhao (Resources) (Writing - review and editing), Qian Liu (Validation), Xiaofei Yu (Validation), Yan Wang (Supervision) (Writing - review and editing), Yiwei Liu (Writing - review and editing), Yingying Pan (Validation), Chunyan Wang (Validation), Guanghui Gao (Resources), Wei Li (Resources), Anwen Xiong (Resources), Bin Chen (Resources), Hui Sun (Resources), Yayi He (Resources) (Writing - review and editing), Fengying Wu (Resources) (Writing - review and editing), Xiaoxia Chen (Methodology) (Supervision) (Writing - review and editing), Chunxia Su (Writing - review and editing), Shengxiang Ren (Conceptualization) (Methodology) (Validation) (Investigation) (Supervision) (Project administration) (Funding acquisition) (Writing - review and editing), Caicun Zhou (Conceptualization) (Methodology) (Supervision) (Writing - review and editing)

PII:

S0169-5002(19)30743-3

DOI:

https://doi.org/10.1016/j.lungcan.2019.11.018

Reference:

LUNG 6209

To appear in:

Lung Cancer

Received Date:

9 October 2019

Revised Date:

16 November 2019

Accepted Date:

23 November 2019

Please cite this article as: Yang S, Mao S, Li X, Zhao C, Liu Q, Yu X, Wang Y, Liu Y, Pan Y, Wang C, Gao G, Li W, Xiong A, Chen B, Sun H, He Y, Wu F, Chen X, Su C, Ren S, Zhou C, Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC, Lung Cancer (2019), doi: https://doi.org/10.1016/j.lungcan.2019.11.018

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Title: Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC Authors: Shuo Yanga# , Shiqi Maoa#, Xuefei Lib, Chao Zhaob, Qian Liua, Xiaofei Yua, Yan Wanga, Yiwei Liua, Yingying Pana, Chunyan Wang a, Guanghui Gaoa, Wei Lia, Anwen Xionga, Bin Chena, Hui Suna, Yayi Hea, Fengying Wua , Xiaoxia Chena, Chunxia Sua, Shengxiang Rena*, Caicun Zhoua. #These authors contributed equally to this work.

ro of

Affiliations: a. Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, PR China b. Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, PR China

lP

re

-p

Email addresses: [email protected] (S. Yang), [email protected] (SQ. Mao), [email protected] (XF. Li), [email protected] (C. Zhao), [email protected] (Q. Liu), [email protected] (XF. Yu), [email protected] (Y. Wang), [email protected] (YW. Liu), [email protected] (YY. Pan), [email protected] (CY. Wang), [email protected] (GH. Gao), [email protected] (W. Li), [email protected] (AW. Xiong), [email protected] (B. Chen), [email protected] (H. Sun), [email protected] (YY. He), [email protected] (FY. Wu), [email protected] (XX. Chen), [email protected] (CX. Su), [email protected] (SX. Ren), [email protected] (CC. Zhou)

ur na

*Corresponding author: Prof. Shengxiang Ren, M.D., Ph.D., Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Rd, Shanghai, 200433, China; Tel: +86-21-65115006; Fax +86-2165111298; E-mail: [email protected]

Jo

Highlights •

Uncommon EGFR mutation associated with lower incidence of acquired T790M mutation.

•

Subsequent osimertinib treatment showed inferior efficacy in uncommon EGFR mutation.

•

19del associated with higher incidence of acquired T790M mutation than L858R.

Abstract: Objectives: Advanced non-small cell lung cancer (NSCLC) patients harboring non-resistant uncommon epidermal growth factor receptor (EGFR) mutations have stepped into the era of targeted therapy. This study aimed to investigate the incidence of acquired T790M

ro of

mutation and their outcome to subsequent osimertinib in patients of advanced NSCLC harboring uncommon EGFR mutations.

-p

Patients and Methods:

re

Patients with EGFR mutation and performed re-biopsy after progression on prior EGFRtyrosine kinase inhibitors (TKIs) were reviewed and analyzed. Those with T790M mutation

ur na

lP

and received subsequent osimertinib treatment were further collected for survival analysis.

Results:

Finally, 754 patients, including 48 with uncommon mutation, 362 with 19del and 344 with L858R were enrolled. T790M mutation was identified in 341 patients (341/754, 45.2%).

Jo

The incidence of T790M mutation was 27.1% in patients harboring uncommon mutations, significantly lower than 55.2% and 37.2% of 19del and L858R (p < 0.001). Logistic regression analysis further found uncommon mutation associated with significantly lower probability of developing T790M (odds ratio [OR] = 0.32, 95% confidence interval [CI] 0.160.64). Among 236 patients received subsequent osimertinib treatment (including 12

uncommon mutation, 145 19del and 79 L858R), patients harboring uncommon mutations showed significantly shorter progression free survival (PFS) (median: 4.6 vs. 11.6 vs. 12.1 months, p < 0.001) and overall survival (OS) (median: 8.1 vs. 35.4 vs. 24.9 months, p = 0.001) compared with 19del and L858R, also associated with numerically lower objective response rate (ORR) (p = 0.085) and lower disease control rate (DCR) (p = 0.074). Multivariate analysis further found that uncommon mutation was the only one significantly

ro of

associated with both PFS (hazard ratio [HR] = 3.44, 95%CI 1.79-6.58) and OS (HR = 3.64, 95%CI 1.66-7.99).

-p

Conclusions:

re

Uncommon EGFR mutation showed a significantly lower incidence of acquired T790M mutation and benefited significantly less from subsequent osimertinib treatment than

ur na

lP

common EGFR mutations in patients with advanced NSCLC.

Key words: Uncommon EGFR mutation; acquired T790M mutation; osimertinib; non-small cell lung cancer

Jo

Introduction:

Targeted therapies with epidermal growth factor receptor (EGFR) – tyrosine kinase inhibitors (TKIs) have dramatically revolutionized the treatment paradigm of patients with advanced non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutations. Serial EGFR-TKIs, including non-covalent first generation (such as gefitinib, erlotinib and icotinib)

and covalent second generation (afatinib and dacomitinib) all showed increased efficacy, decreased toxicity and prolonged survival benefit for patients harboring sensitive EGFR mutations [1-5]. However, the emergence of acquired resistance is inevitable. Several resistance mechanisms have already been identified [6, 7] among that, acquired T790M mutation is the most prevalent with an incidence as 50% [8, 9]. For these with acquired T790M mutation, osimertinib remarkably prolongs patients’ survival than chemotherapy

ro of

(median progression free survival [PFS]: 10.1 vs. 4.4 months, hazard ratio [HR] = 0.30, 95% confidence interval [CI] 0.23-0.41) [10, 11] and has been the standard second-line

-p

treatment [12, 13].

re

Uncommon EGFR mutations, which commonly deemed as mutations other than 19del and L858R are highly heterogeneous and display various sensitivity to EGFR-TKIs. For

lP

example, exon 20 insertion [14] and de novo T790M [15] are resistant to early generation

ur na

EGFR-TKIs. However, other “common” uncommon EGFR mutations include G719X (2-6% of all EGFR mutations), L861Q (1.3-3.2%) and S768I (1.3-3%) [16-20] have been demonstrated sensitive to EGFR-TKIs [18, 21, 22]. Among them, second-generation EGFR-TKI afatinib showed a median PFS as 10.7 months [23] and has been approved by

Jo

Food and Drug Administration (FDA) for patients harboring G719X/L861Q/S768I in 2018. However, the mechanisms of acquired resistance to EGFR-TKIs, especially the incidence of T790M mutation in uncommon EGFR mutation has not been clarified yet.

Herein, we retrospectively collected patients of sensitive EGFR mutations who treated with

front line 1st/2nd generation EGFR-TKIs, and received a re-biopsy after disease progression. We investigated the incidence of acquired T790M mutation within different EGFR mutations. We also compared the efficacy of osimertinib treatment after progression on prior EGFR-TKIs and harboring T790M mutation.

ro of

Patients and Methods: Patients’ population

From October 2013 to November 2018, patients with advanced NSCLC patients, harboring

-p

sensitive EGFR mutations and received acquired T790M mutation detection after

progression on prior early-generation EGFR-TKIs in Tongji University School of Medicine

re

Thoracic Cancer Institute were enrolled. Among them, those with T790M mutation were

lP

further collected for efficacy analysis of osimertinib. Detailed clinicopathological characteristics such as age, gender, smoking status (never smoker was defined as patients

ur na

with the smoking dose of less than 100 cigarettes in their lifetime), tumor histology, type and line of early generation TKI, Eastern Cooperative Oncology Group (ECOG) performance status (PS), treatment regimens used in any line and the outcomes to anti-

Jo

cancer therapies were collected. The Ethics Committee of Shanghai Pulmonary Hospital, Tongji University School of Medicine approved this study.

Molecular Detection Genomic DNA was extracted from the tumor tissue or peripheral blood samples using standard procedures according to the AmoyDx DNA Kit (Amoy Diagnostics Co, Ltd, Cat

No. ADx-BL03 or Car No.8.02.24701 × 036 G) instructions. EGFR mutations were identified with Human EGFR Gene Mutations Fluorescence Polymerase Chain Reaction (PCR) Diagnostic Kit (Amoy Diagnostics Co, Ltd, Cat No. ADx-EG01) for tissue samples or Super-ARMS® EGFR Mutation Detection Kit (Amoy Diagnostics Co, Ltd, Cat No. 8.01.20212X024D) for peripheral blood samples by the method of amplification refractory mutation system (ARMS) per the manufacturer’s instructions. Details have been described

ro of

in detail in our previous studies [24-26].

Evaluation of therapeutic outcomes

-p

Objective tumor responses were determined according to Response Evaluation Criteria in

re

Solid Tumors (RECIST version 1.1). PFS was defined as the time interval from the date of osimertinib treatment initiation to documented disease progression or death of any cause,

lP

whichever occurred first. Patients without disease progression or death were censored.

ur na

Overall survival (OS) was calculated from the date of osimertinib treatment initiation to the date of death from any cause or the last follow-up for surviving patients.

Statistical analysis

Jo

Categorical data were analyzed with Chi-square test or Fisher’s exact test. Numerical data were analyzed with student’s t-test. Log-rank test and Kaplan-Meier curves were used to compare the survival times across different patient groups. Binary logistic regression analysis was used to determine predictive factors of T790M mutation. Cox proportional hazards regression analysis and HRs and 95% CIs were used to determine the survival

difference. All of the statistical analyses were performed using the SPSS statistical software (version 20.0; IBM Corporation, Armonk, NY). Statistical significance was considered as 2-sided p value less than 0.05.

Results： ：

ro of

Patients’ characteristics Between October 2013 to November 2018, a total of 754 patients harboring sensitive

EGFR mutations (including 362 patients with EGFR 19del, 344 with EGFR L858R, and 48

-p

with uncommon sensitive EGFR mutations) received T790M mutation detection after disease progression on prior EGFR-TKIs. Patient distribution and EGFR mutation variant

re

distribution were presented in Figure 1 and Figure 2, respectively. Baseline

lP

clinicopathological characteristics of total 754 patients were presented in Supplementary Table1. Patients harboring uncommon sensitive EGFR mutations tended to be older (p =

ur na

0.01), displayed relatively higher proportion of non-adenocarcinoma histology (p = 0.043) and a higher proportion of covalent EGFR-TKIs used as first-line targeted therapy (p <

Jo

0.001) compared with patients with common mutations.

Among total 754 patients enrolled, 341 patients were identified with positive T790M mutation either based on plasma-based or tissue-based test, with T790M incidence identified as 45.2%. Among them, 236 patients were treated with osimertinib after progression on prior TKIs (including 224 patients with common EGFR mutation and 12 with uncommon sensitive EGFR mutations). We then compared baseline clinicopathological

features between patients with uncommon mutation and common mutations enrolled for osimertinib efficacy comparison (Table 1). Patients with uncommon sensitive EGFR mutation were associated with inferior ECOG - PS (p = 0.023) and higher proportion of covalent EGFR-TKIs as prior EGFR-TKI (p = 0.014) compared with common EGFR mutations. While no differences were observed in gender, histology, smoking history, line

Incidence of T790M mutation across EGFR mutations

ro of

of prior EGFR-TKI, line of osimertinib and sample type used for T790M mutation detection.

Among 754 patients, 530 patients received T790M mutation detection based on tumor

-p

sample, either from primary tumor or from metastatic sites, 281 patients received plasma-

re

based detection, while 57 patients received both tissue-based and plasma-based detection. No difference in sample type used for T790M detection was observed (p = 0.110,

lP

Supplementary Table 2). 341 patients were identified with positive T790M mutation,

ur na

including 13 with uncommon mutations, 362 with 19del and 344 with L858R. Uncommon sensitive EGFR mutations significantly associated with lower incidence of T790M mutation compared with common mutations (27.1% vs. 55.2% vs. 37.2%, p < 0.001) (Figure 2).

Jo

Since tissue-based test remains the standard test for T790M detection, we then mainly focused on the incidence of T790M mutation in tissue-based test. Among 530 patients received tissue-based detection, the incidence of T790M in uncommon sensitive EGFR

mutations and 19del/L858R were 19.4%, 52.0% and 32.5%, respectively. Uncommon sensitive EGFR mutations still associated with significantly lower incidence of T790M

mutation than common mutations (p < 0.001, Supplementary Table 3).

Logistic regression analysis further identified EGFR mutation type as the independent predictive factors of T790M status in tissue-based tests. Patients harboring uncommon sensitive EGFR mutation displayed a 0.245-fold lower probability of developing T790M mutation compared with 19del (adjusted odds ratio [OR] = 0.32, 95%CI 0.16-0.64, p =

ro of

0.001). Uncommon sensitive EGFR mutation still associated with lower probability of

developing T790M mutation when compared with 19del and L858R altogether (adjusted OR = 0.358, 95%CI 0.143-0.899, p = 0.029). In addition, we also found the incidence of

re

0.34-0.63, p < 0.001) (Supplementary Table 4).

-p

T790M was relatively lower in patients with L858R than 19del (adjusted OR = 0.46, 95%CI

lP

Survival analysis of osimertinib treatment

ur na

Totally, 236 patients received subsequent osimertinib treatment after progression on prior TKI，including 12 patients with uncommon sensitive EGFR mutation, 145 with 19del and 79 with L858R. Treatment responses to osimertinib were summarized in Table 1. In 229 evaluable patients, the objective response rate (ORR) was 61.1%, while disease control

Jo

rate (DCR) was 92.1%. Uncommon sensitive EGFR mutation showed numerically lower ORR compared with common mutations (45.5% vs. 66.7% vs. 53.2%, p = 0.085). In terms of DCR, uncommon sensitive EGFR mutation also associated with numerically lower DCR than common mutations (72.7% vs. 93.6% vs. 92.2%, p = 0.074) (Figure 3).

We then compared the survival benefit of osimertinib across EGFR mutations. Uncommon sensitive EGFR mutation showed significantly shorter median PFS compared with common mutations (median: 4.6 vs. 11.6 vs. 12.1 months, p < 0.001). Uncommon EGFR mutation also showed significantly shorter median OS compared with common mutations (median: 8.1 vs. 35.4 vs. 24.9 months, p = 0.001) (Figure 3).

ro of

Cox regression analysis, incorporating gender, age, smoking history, EGFR mutation type, ECOG-PS, type of prior TKI, treatment immediately before osimertinib initiation and line of

osimertinib treatment, further identified uncommon sensitive EGFR mutation and prior

-p

covalent EGFR-TKI as poor prognostic factor. Uncommon sensitive EGFR mutation

re

significantly associated with inferior PFS of Osimertinib compared with 19del (HR = 3.437, 95%CI 1.794-6.583, p < 0.001). Type of prior TKI also associated with inferior PFS,

lP

showing covalent TKI associated with shorter median PFS (HR = 3.866, 95%CI 1.473-

ur na

10.145, p = 0.006) (Table 3). In multivariate analysis of OS of osimertinib, uncommon EGFR mutation also significantly associated with shorter median OS (HR = 3.638, 95%CI 1.657-7.985, p = 0.001) compared with 19del.

Jo

Discussion： ：

To the best of our knowledge, this was the first and largest study to investigate the incidence of acquired T790M mutation and the efficacy of subsequent osimertinib treatment in patients of advanced NSCLC harboring uncommon sensitive EGFR mutations. We found that the incidence of T790M mutations in patients with uncommon sensitive EGFR mutations was significantly lower than patients harboring 19del and L858R (p <

0.001). We also found that patients of EGFR uncommon sensitive mutations who had T790M mutation at re-biopsy had significantly shorter PFS (p < 0.001) and OS (p = 0.001) when compared with those of exon 19 deletion and L858 substitution, which was further confirmed by multivariate analysis.

T790M mutation is the major resistance mechanism of 1st/2nd generation EGFR-TKIs with

ro of

an incidence over 50% [7, 27]. Osimertinib, an irreversible third-generation inhibitor selectively binding with T790M mutation [10], has been the standard care of those

progressed on prior EGFR-TKI with acquired T790M mutation [11]. In the current study, we

-p

found the incidence of acquired T790M mutation was 27.1% in patients harboring

re

uncommon EGFR mutation, which was significantly lower than these with common mutations. In addition, we also found that patients with L858R was less likely to develop

lP

T790M mutation compared with 19del. In line with our result, several previous studies

ur na

found that patients with 19del tended to have a higher incidence of acquired T790M mutation compared with L858R [28, 29]. For example, Ke, et al. reported that the incidence of acquired T790M mutation was 50.4% in Chinese patients with EGFR exon19 deletion,

Jo

while it was 36.5% in patients with L858R substitution (p = 0.043) [28].

Discrepant selective pressure from EGFR-TKIs within various mutation variants might be one of the underlying mechanisms of differential incidence of acquired T790M mutation observed. Series of studies have already demonstrated that 19del associates with relatively higher sensitivity to EGFR-TKIs and relatively higher degree of downstream

pathway inhibition compared with L858R.[30] Real-world studies [31, 32] and clinical trials of prior EGFR-TKIs [2-5, 33] also have shown that patients harboring 19del tend to have better clinical benefit compared with L858R. Furthermore, serial studies further found that longer exposure to EGFR-TKI associated with higher incidence of acquired T790M mutation [34-36]. Thus, differential sensitivity to EGFR-TKIs might be the explanation for various T790M mutation incidence observed. Uncommon mutations comprise of various

ro of

variants, their sensitivity to EGFR-TKIs have also been reported, generally considered not as sensitive as 19del/L858R [21, 37]. Therefore, the relatively inferior efficacy and lower exposure of prior EGFR-TKIs in patients harboring uncommon mutations, which resulted

-p

in a relatively lower selective pressure that not enough to induce the acquisition of T790M

re

mutation might account for the lower incidence of T790M mutation. In addition, we also found a higher incidence of SCLC transformation in patients harboring uncommon

lP

sensitive EGFR mutation than common mutations (9.7% vs. 0.6%, p=0.003)

ur na

(Supplementary Table 5), which suggests the resistance mechanism of uncommon sensitive EGFR mutation could be distinct from common EGFR mutations.

Moreover, the median PFS and OS after the subsequent osimertinib treatment were

Jo

significantly shorter in patients harboring uncommon sensitive EGFR mutations compared with common mutations. Preclinical data showed that uncommon sensitive EGFR

mutations displayed lower sensitivities to osimertinib compared with common mutation, with higher half-maximal inhibitory concentration (IC50) values compared with 19del or L858R [38-40]. Furthermore, Cho J.H., et al.[41] investigated the efficacy of front-line

osimertinib in 35 patients harboring uncommon sensitive mutations (including 19 with G719X, 9 with L861Q, 8 with S768I and 3 with other mutations). The ORR was 50.0% and median PFS was 9.8 months, which is inferior to the efficacy observed in FLAURA study [42]. Consistent with our study, AURA study observed a relatively lower response rate in patients harboring uncommon sensitive EGFR mutation when comparing with these harboring 19del/L858R [43]. Similarly, several cases found the inferior efficacy of

ro of

osimertinib in patients harboring uncommon mutations after progression on prior EGFRTKIs, even in patients with positive T790M mutation [44-46], suggesting an alternative

-p

more potent anti-cancer strategy is needed for this setting.

re

Several limitations in this study must be acknowledged. First, as a single center retrospective study, selection bias could be inevitable. Therefore, the numerically higher

lP

liquid biopsy in uncommon mutation group might also affect the incidence of T790M

ur na

mutation. Second, we adopted ARMS method to detect EGFR mutation, which included 19del/L858R/T790M/exon20ins and G719X/S768I/L861Q, thus several other rare uncommon mutations like E709X [47, 48], V774M [49] and other rare ones [50] also sensitive to EGFR-TKIs were missed. Third, although the patients treated with subsequent

Jo

osimertinib in our institute were currently the largest real-world cohort, but the number of patients with uncommon sensitive EGFR mutations was still limited. Further prospective, multi-institute studies are warranted to verify our findings.

In conclusion, our study demonstrated that patients of uncommon EGFR mutations

associated with lower incidence of acquired T790M mutation after progression on 1st/2nd generation EGFR-TKIs. These patients with acquired T790M mutation had significantly inferior outcome of osimertinib when compared with patients of exon 19 deletion and L858 substitution. Comprehensive analysis of the resistance mechanism of EGFR-TKIs in patients with uncommon EGFR mutations is needed to further improve their prognosis.

Author Contribution Statement

ro of

Shuo Yang：Resources, Investigation, Writing - original draft; Shiqi Mao: Resources, Investigation, Writing - original draft; Xuefei Li: Resources, Supervision, Writing - Review

-p

& Editing; Chao Zhao: Resources, Writing - Review & Editing; Qian Liu: Validation; Xiaofei

Yu: Validation; Yan Wang: Supervision, Writing - Review & Editing; Yiwei Liu: Writing -

re

Review & Editing; Yingying Pan: Validation; Chunyan Wang: Validation; Guanghui Gao:

lP

Resources; Wei Li: Resources; Anwen Xiong: Resources; Bin Chen: Resources; Hui Sun: Resources; Yayi He: Resources, Writing - Review & Editing; Fengying Wu: Resources,

ur na

Writing - Review & Editing; Xiaoxia Chen: Methodology, Supervision, Writing - Review & Editing; Chunxia Su: Writing - Review & Editing; Shengxiang Ren: Conceptualization, Methodology, Validation, Investigation, Supervision, Project administration, Funding acquisition, Writing - Review & Editing; Caicun Zhou: Conceptualization, Methodology,

Jo

Supervision, Writing - Review & Editing.

Funding This work was supported in part by grants from Shanghai Municipal Education Commission (No.16SG18), the Science and Technology Commission of Shanghai Municipality

(No.16411964600), the National Natural Science Foundation of China (No. 81772467), the Shanghai Shen Kang Pharmaceutical Development Co. Ltd (No. SHDC 12015314), and the Backbone Program of Shanghai Pulmonary Hospital (NO. FKGG1802).

Disclosure The authors declare no conflicts of interest.

ro of

Declarations of interest： None

-p

Acknowledgement

The authors would like to thank all the participating patients and their families, and thank

re

all technical assistants of the Department of Pathology of Shanghai Pulmonary Hospital

Jo

ur na

lP

for histology diagnosis.

References: [1] T.S. Mok, Y.L. Wu, S. Thongprasert, C.H. Yang, D.T. Chu, N. Saijo, P. Sunpaweravong, B. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J.J. Yang, B. Chewaskulyong, H. Jiang, E.L. Duffield, C.L. Watkins, A.A. Armour, M. Fukuoka, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, The New England journal of medicine 361(10) (2009) 947-57. [2] C. Zhou, Y.L. Wu, G. Chen, J. Feng, X.Q. Liu, C. Wang, S. Zhang, J. Wang, S. Zhou, S.

ro of

Ren, S. Lu, L. Zhang, C. Hu, C. Hu, Y. Luo, L. Chen, M. Ye, J. Huang, X. Zhi, Y. Zhang, Q. Xiu, J. Ma, L. Zhang, C. You, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a

-p

multicentre, open-label, randomised, phase 3 study, The Lancet. Oncology 12(8) (2011) 73542.

re

[3] Y.K. Shi, L. Wang, B.H. Han, W. Li, P. Yu, Y.P. Liu, C.M. Ding, X. Song, Z.Y. Ma, X.L. Ren,

lP

J.F. Feng, H.L. Zhang, G.Y. Chen, X.H. Han, N. Wu, C. Yao, Y. Song, S.C. Zhang, W. Song, X.Q. Liu, S.J. Zhao, Y.C. Lin, X.Q. Ye, K. Li, Y.Q. Shu, L.M. Ding, F.L. Tan, Y. Sun, First-line

ur na

icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study, Annals of oncology : official journal of the European Society for Medical

Jo

Oncology 28(10) (2017) 2443-2450.

[4] L.V. Sequist, J.C. Yang, N. Yamamoto, K. O'Byrne, V. Hirsh, T. Mok, S.L. Geater, S. Orlov, C.M. Tsai, M. Boyer, W.C. Su, J. Bennouna, T. Kato, V. Gorbunova, K.H. Lee, R. Shah, D. Massey, V. Zazulina, M. Shahidi, M. Schuler, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31(27) (2013)

3327-34. [5] Y.L. Wu, Y. Cheng, X. Zhou, K.H. Lee, K. Nakagawa, S. Niho, F. Tsuji, R. Linke, R. Rosell, J. Corral, M.R. Migliorino, A. Pluzanski, E.I. Sbar, T. Wang, J.L. White, S. Nadanaciva, R. Sandin, T.S. Mok, Dacomitinib versus gefitinib as first-line treatment for patients with EGFRmutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial, The Lancet. Oncology 18(11) (2017) 1454-1466.

ro of

[6] C. Tomasello, C. Baldessari, M. Napolitano, G. Orsi, G. Grizzi, F. Bertolini, F. Barbieri, S. Cascinu, Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives, Critical reviews in oncology/hematology 123 (2018) 149-161.

-p

[7] D. Westover, J. Zugazagoitia, B.C. Cho, C.M. Lovly, L. Paz-Ares, Mechanisms of acquired

re

resistance to first- and second-generation EGFR tyrosine kinase inhibitors, Annals of oncology : official journal of the European Society for Medical Oncology 29(suppl_1) (2018) i10-i19.

lP

[8] C.H. Yun, K.E. Mengwasser, A.V. Toms, M.S. Woo, H. Greulich, K.K. Wong, M. Meyerson, M.J. Eck, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity

ur na

for ATP, Proceedings of the National Academy of Sciences of the United States of America 105(6) (2008) 2070-5.

[9] G.R. Oxnard, M.E. Arcila, C.S. Sima, G.J. Riely, J. Chmielecki, M.G. Kris, W. Pao, M.

Jo

Ladanyi, V.A. Miller, Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation, Clinical cancer research : an official journal of the American Association for Cancer Research 17(6) (2011) 1616-22. [10] D.A. Cross, S.E. Ashton, S. Ghiorghiu, C. Eberlein, C.A. Nebhan, P.J. Spitzler, J.P. Orme,

M.R. Finlay, R.A. Ward, M.J. Mellor, G. Hughes, A. Rahi, V.N. Jacobs, M. Red Brewer, E. Ichihara, J. Sun, H. Jin, P. Ballard, K. Al-Kadhimi, R. Rowlinson, T. Klinowska, G.H. Richmond, M. Cantarini, D.W. Kim, M.R. Ranson, W. Pao, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer discovery 4(9) (2014) 1046-61. [11] T.S. Mok, Y.L. Wu, M.J. Ahn, M.C. Garassino, H.R. Kim, S.S. Ramalingam, F.A. Shepherd,

ro of

Y. He, H. Akamatsu, W.S. Theelen, C.K. Lee, M. Sebastian, A. Templeton, H. Mann, M. Marotti, S. Ghiorghiu, V.A. Papadimitrakopoulou, Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer, The New England journal of medicine 376(7) (2017) 629-640.

-p

[12] H. Greulich, B. Kaplan, P. Mertins, T.H. Chen, K.E. Tanaka, C.H. Yun, X. Zhang, S.H. Lee,

re

J. Cho, L. Ambrogio, R. Liao, M. Imielinski, S. Banerji, A.H. Berger, M.S. Lawrence, J. Zhang, N.H. Pho, S.R. Walker, W. Winckler, G. Getz, D. Frank, W.C. Hahn, M.J. Eck, D.R. Mani, J.D.

lP

Jaffe, S.A. Carr, K.K. Wong, M. Meyerson, Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2,

ur na

Proceedings of the National Academy of Sciences of the United States of America 109(36) (2012) 14476-81.

[13] D. Planchard, S. Popat, K. Kerr, S. Novello, E.F. Smit, C. Faivre-Finn, T.S. Mok, M. Reck,

Jo

P.E. Van Schil, M.D. Hellmann, S. Peters, Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Annals of oncology : official journal of the European Society for Medical Oncology

(2019).

[14] H. Yasuda, S. Kobayashi, D.B. Costa, EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications, The Lancet. Oncology 13(1) (2012) e23-

31. [15] P. Tian, Y. Wang, W. Wang, Y. Li, K. Wang, X. Cheng, Y. Tang, H. Han-Zhang, J. Ye, S. Chuai, W. Li, High-throughput sequencing reveals distinct genetic features and clinical implications of NSCLC with de novo and acquired EGFR T790M mutation, Lung cancer (Amsterdam, Netherlands) 124 (2018) 205-210. [16] E. Massarelli, F.M. Johnson, H.S. Erickson, Wistuba, II, V. Papadimitrakopoulou,

ro of

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 (Amsterdam, Netherlands) 80(3) (2013) 235-41.

-p

[17] S. Wen, L. Dai, L. Wang, W. Wang, D. Wu, K. Wang, Z. He, A. Wang, H. Chen, P. Zhang,

re

X. Dong, Y.A. Dong, K. Wang, M. Yao, M. Wang, Genomic Signature of Driver Genes Identified

oncologist

(2019).

lP

by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer, The

[18] J.Y. Wu, C.J. Yu, Y.C. Chang, C.H. Yang, J.Y. Shih, P.C. Yang, Effectiveness of tyrosine

ur na

kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clinical cancer research : an official journal of the American Association for Cancer Research 17(11) (2011) 3812-21.

Jo

[19] M. Beau-Faller, N. Prim, A.M. Ruppert, I. Nanni-Metellus, R. Lacave, L. Lacroix, F. Escande, S. Lizard, J.L. Pretet, I. Rouquette, P. de Cremoux, J. Solassol, F. de Fraipont, I. Bieche, A. Cayre, E. Favre-Guillevin, P. Tomasini, M. Wislez, B. Besse, M. Legrain, A.C. Voegeli, L. Baudrin, F. Morin, G. Zalcman, E. Quoix, H. Blons, J. Cadranel, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study

by the French ERMETIC-IFCT network, Annals of oncology : official journal of the European Society for Medical Oncology 25(1) (2014) 126-31. [20] L.C. Chang, C.K. Lim, L.Y. Chang, K.Y. Chen, J.Y. Shih, C.J. Yu, Non-small cell lung cancer harbouring non-resistant uncommon EGFR mutations: Mutation patterns, effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors and prognostic factors, European journal of cancer (Oxford, England : 1990) 119 (2019) 77-86.

ro of

[21] G.M. O'Kane, P.A. Bradbury, R. Feld, N.B. Leighl, G. Liu, K.M. Pisters, S. Kamel-Reid, M.S. Tsao, F.A. Shepherd, Uncommon EGFR mutations in advanced non-small cell lung cancer, Lung cancer (Amsterdam, Netherlands) 109 (2017) 137-144.

-p

[22] A. Passaro, A. Prelaj, L. Bonanno, M. Tiseo, A. Tuzi, C. Proto, R. Chiari, D. Rocco, C.

re

Genova, C. Sini, D. Cortinovis, S. Pilotto, L. Landi, C. Bennati, A. Camerini, L. Toschi, C. Putzu, G. Cerea, G. Spitaleri, F. Cappuzzo, F. de Marinis, Activity of EGFR TKIs in Caucasian Patients

20(2) (2019) e186-e194.

lP

With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations, Clinical lung cancer

ur na

[23] J.C. Yang, L.V. Sequist, S.L. Geater, C.M. Tsai, T.S. Mok, M. Schuler, N. Yamamoto, C.J. Yu, S.H. Ou, C. Zhou, D. Massey, V. Zazulina, Y.L. Wu, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined

Jo

post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, The Lancet. Oncology 16(7) (2015) 830-8.

[24] X. Li, W. Cai, G. Yang, C. Su, S. Ren, C. Zhao, R. Hu, X. Chen, G. Gao, Z. Guo, W. Li, C. Zhou, F.R. Hirsch, Comprehensive Analysis of EGFR-Mutant Abundance and Its Effect on Efficacy of EGFR TKIs in Advanced NSCLC with EGFR Mutations, Journal of thoracic oncology :

official publication of the International Association for the Study of Lung Cancer 12(9) (2017) 1388-1397. [25] L. Zhang, T. Jiang, X. Li, Y. Wang, C. Zhao, S. Zhao, L. Xi, S. Zhang, X. Liu, Y. Jia, H. Yang, J. Shi, C. Su, S. Ren, C. Zhou, Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer, Cancer 123(15) (2017) 2927-2935.

ro of

[26] S. Zhao, X. Li, C. Zhao, T. Jiang, Y. Jia, J. Shi, Y. He, J. Li, F. Zhou, G. Gao, W. Li, X. Chen, C. Su, S. Ren, C. Zhou, Loss of T790M mutation is associated with early progression to

cancer (Amsterdam, Netherlands) 128 (2019) 33-39.

-p

osimertinib in Chinese patients with advanced NSCLC who are harboring EGFR T790M, Lung

re

[27] D.R. Camidge, W. Pao, L.V. Sequist, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nature reviews. Clinical oncology 11(8) (2014) 473-81.

lP

[28] E.E. Ke, Q. Zhou, Q.Y. Zhang, J. Su, Z.H. Chen, X.C. Zhang, C.R. Xu, J.J. Yang, H.Y. Tu, H.H. Yan, Y.C. Zhang, F.Y. Niu, Y.L. Wu, A Higher Proportion of the EGFR T790M Mutation

ur na

May Contribute to the Better Survival of Patients with Exon 19 Deletions Compared with Those with L858R, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 12(9) (2017) 1368-1375.

Jo

[29] S. Wang, B. Yan, Y. Zhang, J. Xu, R. Qiao, Y. Dong, B. Zhang, Y. Zhao, L. Zhang, J. Qian, J. Lu, R. Zhao, B. Han, Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation, International journal of cancer 144(11) (2019) 2880-2886. [30] J.Q. Zhu, W.Z. Zhong, G.C. Zhang, R. Li, X.C. Zhang, A.L. Guo, Y.F. Zhang, S.J. An, T.S.

Mok, Y.L. Wu, Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals, Cancer letters 265(2) (2008) 307-17. [31] J. Zhou, S. Ben, Comparison of therapeutic effects of EGFR-tyrosine kinase inhibitors on 19Del and L858R mutations in advanced lung adenocarcinoma and effect on cellular immune function, Thoracic cancer 9(2) (2018) 228-233.

ro of

[32] Y. Zhang, Y. Ma, Y. Li, X. Shen, Y. Yu, Y. Pan, Y. Zhang, S. Yu, D. Zheng, Y. Zhao, H. Hu, Y. Sun, Y. Zhang, J. Xiang, H. Chen, Are exon 19 deletions and L858R different in early stage lung adenocarcinoma?, Journal of cancer research and clinical oncology 144(1) (2018) 165-

-p

171.

re

[33] M. Maemondo, A. Inoue, K. Kobayashi, S. Sugawara, S. Oizumi, H. Isobe, A. Gemma, M. Harada, H. Yoshizawa, I. Kinoshita, Y. Fujita, S. Okinaga, H. Hirano, K. Yoshimori, T. Harada,

lP

T. Ogura, M. Ando, H. Miyazawa, T. Tanaka, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa, Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR, New England

ur na

Journal of Medicine 362(25) (2010) 2380-2388.

[34] A. Hata, N. Katakami, H. Yoshioka, R. Kaji, K. Masago, S. Fujita, Y. Imai, A. Nishiyama, T. Ishida, Y. Nishimura, Y. Yatabe, Spatiotemporal T790M Heterogeneity in Individual Patients

Jo

with EGFR-Mutant Non–Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI, Journal of Thoracic Oncology 10(11) (2015) 1553-1559. [35] Y. Oya, T. Yoshida, H. Kuroda, J. Shimizu, Y. Horio, Y. Sakao, Y. Inaba, T. Hida, Y. Yatabe, Association Between EGFR T790M Status and Progression Patterns During Initial EGFR-TKI Treatment in Patients Harboring EGFR Mutation, Clinical lung cancer 18(6) (2017) 698-705.e2.

[36] T. Kawamura, H. Kenmotsu, S. Omori, K. Nakashima, K. Wakuda, A. Ono, T. Naito, H. Murakami, K. Omae, K. Mori, Y. Tanigawara, T. Nakajima, Y. Ohde, M. Endo, T. Takahashi, Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non– small-cell Lung Cancer, Clinical lung cancer 19(2) (2018) e247-e252. [37] H.Y. Tu, E.E. Ke, J.J. Yang, Y.L. Sun, H.H. Yan, M.Y. Zheng, X.Y. Bai, Z. Wang, J. Su, Z.H. Chen, X.C. Zhang, Z.Y. Dong, S.P. Wu, B.Y. Jiang, H.J. Chen, B.C. Wang, C.R. Xu, Q.

ro of

Zhou, P. Mei, D.L. Luo, W.Z. Zhong, X.N. Yang, Y.L. Wu, A comprehensive review of

uncommon EGFR mutations in patients with non-small cell lung cancer, Lung cancer (Amsterdam, Netherlands) 114 (2017) 96-102.

-p

[38] E. Banno, Y. Togashi, Y. Nakamura, M. Chiba, Y. Kobayashi, H. Hayashi, M. Terashima,

re

M.A. de Velasco, K. Sakai, Y. Fujita, T. Mitsudomi, K. Nishio, Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor

lP

mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?, Cancer science 107(8) (2016) 1134-40.

ur na

[39] Y. Kobayashi, T. Mitsudomi, Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy, Cancer science 107(9) (2016) 1179-86.

Jo

[40] A. Masood, R.K. Kancha, J. Subramanian, Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer harboring uncommon EGFR mutations: Focus on afatinib, Seminars in oncology

(2019).

[41] J.H. Cho, J. Sun, S. Lee, J.S. Ahn, K. Park, K.U. Park, E.J. Kang, Y.H. Choi, K.H. Kim, H.J.A. An, H.W. Lee, M. Ahn, OA10.05 An Open-Label, Multicenter, Phase II Single Arm Trial

of Osimertinib in NSCLC Patients with Uncommon EGFR Mutation(KCSG-LU15-09), Journal of Thoracic Oncology 13(10, Supplement) (2018) S344. [42] J.C. Soria, Y. Ohe, J. Vansteenkiste, T. Reungwetwattana, B. Chewaskulyong, K.H. Lee, A. Dechaphunkul, F. Imamura, N. Nogami, T. Kurata, I. Okamoto, C. Zhou, B.C. Cho, Y. Cheng, E.K. Cho, P.J. Voon, D. Planchard, W.C. Su, J.E. Gray, S.M. Lee, R. Hodge, M. Marotti, Y. Rukazenkov, S.S. Ramalingam, Osimertinib in Untreated EGFR-Mutated Advanced Non-

ro of

Small-Cell Lung Cancer, The New England journal of medicine 378(2) (2018) 113-125.

[43] P.A. Janne, J.C. Yang, D.W. Kim, D. Planchard, Y. Ohe, S.S. Ramalingam, M.J. Ahn, S.W. Kim, W.C. Su, L. Horn, D. Haggstrom, E. Felip, J.H. Kim, P. Frewer, M. Cantarini, K.H. Brown,

-p

P.A. Dickinson, S. Ghiorghiu, M. Ranson, AZD9291 in EGFR inhibitor-resistant non-small-cell

re

lung cancer, The New England journal of medicine 372(18) (2015) 1689-99. [44] T. Hakozaki, M. Yomota, Acquisition of T790M resistance mutation in a patient with

lP

advanced adenocarcinoma harbouring uncommon EGFR mutations: a case report and literature review, OncoTargets and therapy 12 (2019) 745-748.

ur na

[45] H. Niwa, Y. Nakahara, J. Sasaki, N. Masuda, A promising response to osimertinib in a patient with erlotinib-resistant lung adenocarcinoma with an uncommon EGFR mutation, BMJ case reports 2018 (2018).

Jo

[46] S. Nasu, T. Shiroyama, S. Morita, S. Takata, H. Takada, K. Masuhiro, A. Tanaka, N. Morishita, H. Suzuki, N. Okamoto, T. Hirashima, Osimertinib Treatment Was Unsuccessful for Lung Adenocarcinoma with G719S, S768I, and T790M Mutations, Internal medicine (Tokyo, Japan) 57(24) (2018) 3643-3645. [47] J.Y. Wu, J.Y. Shih, Effectiveness of tyrosine kinase inhibitors on uncommon E709X

epidermal growth factor receptor mutations in non-small-cell lung cancer, OncoTargets and therapy 9 (2016) 6137-6145. [48] Y. Kobayashi, Y. Togashi, Y. Yatabe, H. Mizuuchi, P. Jangchul, C. Kondo, M. Shimoji, K. Sato, K. Suda, K. Tomizawa, T. Takemoto, T. Hida, K. Nishio, T. Mitsudomi, EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs, Clinical cancer research : an

ro of

official journal of the American Association for Cancer Research 21(23) (2015) 5305-13.

[49] M. Yang, X. Tong, X. Xu, E. Zheng, J. Ni, J. Li, J. Yan, Y.W. Shao, G. Zhao, Case Report: Osimertinib achieved remarkable and sustained disease control in an advanced non-small-cell

-p

lung cancer harboring EGFR H773L/V774M mutation complex, Lung cancer (Amsterdam,

re

Netherlands) 121 (2018) 1-4.

[50] S.V. Sharma, D.W. Bell, J. Settleman, D.A. Haber, Epidermal growth factor receptor

Jo

ur na

lP

mutations in lung cancer, Nature reviews. Cancer 7(3) (2007) 169-81.

Figure Legends

re

-p

ro of

Figure 1. Patient distribution of this study. Total 754 patients enrolled for T790M mutation rate comparison (No difference of sample type used for T790M mutation was observed among mutation variants, p=0.110). Among 341 patients identified with positive T790M mutation, 236 patients received subsequent osimertinib treatment and enrolled for osimertinib efficacy comparison. TKI, tyrosine kinase inhibitor.

Jo

ur na

lP

Figure 2. Distribution of mutation variant and T790M mutation within EGFR mutations. A. EGFR mutation variant distribution of total 754 patients. Left pie chart, dark grey indicated 19del, light grey indicated L858R, while blue indicated uncommon mutations. Right pie chart, details within uncommon EGFR mutations. Blue indicated single uncommon EGFR mutation, grey indicated compound uncommon EGFR mutation, while green indicated uncommon EGFR mutation compound with 19del or L858R. B. Comparison of the incidence of T790M mutation within EGFR mutations. Total 754 patients enrolled for analysis, including 48 with uncommon mutation, 362 with 19del and 344 with L858R. EGFR, epidermal growth factor receptor.

lP

re

-p

ro of

Figure 3. Treatment efficacy comparison of subsequent osimertinib within uncommon sensitive mutations, 19del and L858R. A, B. Progression free survival (PFS) and Overall survival (OS) of osimertinib comparison within mutation variants. C, D. Objective Response Rate (ORR) and Disease Control Rate (DCR) comparison within mutation variants. PFS, progression free survival; OS, overall survival; ORR, objective response rate; DCR, disease control rate.

Jo

ur na

Supplementary figure 1. Treatment efficacy comparison of subsequent osimertinib within uncommon sensitive mutations and common mutations. A, B. Progression free survival (PFS) and Overall survival (OS) of osimertinib comparison within mutation variants. C, D. Objective Response Rate (ORR) and Disease Control Rate (DCR) comparison within mutation variants. PFS, progression free survival; OS, overall survival; ORR, objective response rate; DCR, disease control rate.

ro of

Table 1. Clinicopathological characteristics and responses to second-line Osimertinib treatment of patients enrolled for efficacy analysis. Sensitizing mutations

total (n=224)

19del (n=145)

21L858R (n=79)

p value

4 (33.3) 8 (66.7)

94 (42.0) 130 (58.0)

62 (42.8) 83 (57.2)

32 (40.5) 47 (59.5)

0.789

62 (31-83) 157 (66.5)

68 (51-83) 5 (41.7)

62 (31-79) 152 (67.9)

60 (31-79) 101 (69.7)

63.5 (35-79) 51 (64.6)

0.002 0.127

79 (33.5)

7 (58.3)

72 (32.1)

44 (30.3)

28 (35.4)

adenocarcinoma non-adenocarcinoma ECOG PS, No (%)

218 (92.4) 18 (7.6)

10 (83.3) 2 (16.7)

134 (92.4) 11 (7.6)

74 (93.7) 5 (6.3)

0.342

0-1 2-3 Smoking histology, No (%) never smoker ever smoker Line of prior TKI, No (%) 1st line

230 (97.5) 6 (2.5)

10 (83.3) 2 (16.7)

77 (97.5) 2 (2.5)

0.023

4 (1.8)

143 (98.6) 2 (1.4)

245 (80.6) 59 (19.4)

78 (76.5) 24 (23.5)

167 (82.7) 35 (17.3)

83 (82.2) 18 (17.8)

84 (83.2) 17 (16.8)

0.437

189 (80.1)

8 (66.7)

181 (80.8)

118 (81.4)

63 (79.7)

0.459

na

≥65

lP

98 (41.5) 138 (58.5)

ur

Gender, No (%) male female Age, yr, No (%) median (range) <65

re

Characteristics

Uncommon mutations (n=12)

-p

Total (n=236)

Jo

Histology, No (%)

208 (92.9） 16 (7.1)

220 (98.2）

43 (19.2)

27 (18.6)

16 (20.3)

231 (97.9) 5 (2.1)

10 (83.3) 2 (16.7)

-p

221 (98.7) 3 (1.3)

144 (99.3) 1 (0.7)

77 (97.5) 2 (2.5)

0.014

172 (72.9) 64 (27.1)

9 (75.0) 3 (25.0)

163 (72.8) 61 (27.2)

111 (76.6) 34 (23.4)

52 (65.8) 27 (34.2)

0.233

143 (60.6)

7 (58.3)

136 (60.7)

93 (64.1)

43 (54.4)

0.365

93 (39.4)

5 (41.7)

88 (39.3)

52 (35.9)

36 (45.6)

131 (55.5) 81 (34.3) 24 (10.2)

5 (41.7) 7 (58.3) 0 (0.0)

126 (56.3) 74 (33.0) 24 (10.7)

82 (56.6) 48 (33.1) 15 (10.3)

44 (55.7) 26 (32.9) 9 (11.4)

0.52

0 (0.0) 140 (59.3) 71 (30.1) 18 (7.6) 7 (3.0)

0 (0.0) 5 (41.7) 3 (25.0) 3 (25.0) 1 (8.3)

0 (0.0) 135 (60.3) 68 (30.4) 15 (6.7) 6 (2.7)

0 (0.0) 94 (64.8) 38 (26.3) 9 (6.2) 4 (2.8)

0 (0.0) 41 (51.9) 30 (38.0) 6 (7.6) 2 (2.5)

0.077

lP

≥3nd line

ur

Sample type for positive T790M detection, No (%) tissue-based plasma-based both tissue and plasma-based Response to second-line Osimertinib, No (%) CR PR SD PD NE

Jo

ro of

4 (33.3)

na

Type of prior TKI, No (%) non-covalent covalent Last treatment before Osimertinib, No (%) prior TKI chemotherapy Line of Osimertinib, No (%) 2nd line

47 (19.9)

re

≥2nd line

ro of

Jo

ur

na

lP

re

-p

ORR 140 (61.1) 5 (45.5) 135 (61.9) 94 (66.7) 41 (53.2) DCR 211 (92.1) 8 (72.7) 203 (93.1) 132 (93.6) 71 (92.2) Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status; TKI, tyrosine kinase inhibitor

0.085 0.074

ro of

Table 2. Multivariate cox regression analysis of PFS and OS to second-line Osimertinib treatment.

95%CI

p value

1.00

female

1.11

0.82-1.50

＜65

1.00

≥65

adenocarcinoma

1.00

non-adenocarcinoma

1.39

ur

EGFR mutation

0.66-1.26

na

0.91

0.77-2.51

1.00

L858R

1.02

0.73-1.42

4.07

2.20-7.53

Jo

19del

uncommon

0.518

lP

Age

HR

re

male

-p

HR

Gender

Histology

Multivariate analysis for PFS

Univariate analysis for PFS

factors

0.567

-

95%CI

-

p value

Univariate analysis for OS

Multivariate analysis for OS

HR

HR

95%CI

p value

1.00 -

1.37

95%CI

p value

1.00 0.86-2.17

0.182

1.45

0.910-2.321

0.117

0.56-1.47

0.697

-

-

-

0.69-3.29

0.298

-

-

-

1.00

-

-

-

0.91

1.00 0.274

-

-

-

1.00 0.932 ＜0.001

1.51

1.00

0.96

0.69-1.35

3.44

1.79-6.58

0.832 ＜0.001

1.00

1.37

0.85-2.23

0.199

1.30

0.80-2.11

0.294

3.79

1.78-8.10

0.001

3.64

1.66-7.99

0.001

ECOG PS

0-1

1.00

2-3

1.73

1.00 0.77-3.92

0.187

1.69

1.00 0.74-3.87

0.214

2.309

1.00 0.73-7.35

0.157

1.83

0.55-6.08

0.322

0.54-1.80

0.965

-

-

-

Smoking history never-smoker

1.00

ever-smoker

0.88

1.00 0.59-1.30

0.514

-

-

-

0.99

covalent

5.77

1.00

2.32-14.33

Last treatment before Osimertinib 1.00

chemotherapy

1.17

Line of Osimertinib second line

1.00

third line and beyond

1.05

0.84-1.65

＜0.001

3.87

0.356

lP

prior TKI

0.77-1.43

1.00

-p

1.00

re

non-covalent

ro of

Type of prior TKI

0.749

-

1.47-10.15

0.006

4.28

1.00

1.03-17.83

0.046

1.00 -

-

1.59

2.91

0.66-12.82

0.157

1.00 0.99-2.54

0.053

1.55

0.96-2.50

0.074

0.83-2.04

0.244

-

-

-

1.00 -

-

-

1.30

na

Abbreviations: PFS, progression-free survival; OS, overall survival; HR, hazard rate; CI, confidence interval; EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative

Jo

ur

Oncology Group; PS, performance status; TKI, tyrosine kinase inhibitor