1. Fig 1A. Patient enrollment flow chart
Association of plasma EGFR T790M ctDNA status with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Di Zheng1; Xin Ye2Meizhuo Zhang2; Yun Sun2; Jiying Wang1; Jian Ni1; Haiping Zhang1; Ling Zhang1; Jie Luo1; Jie Zhang1; Liang Tang1; Bo Su1; Gang Chen1;Guanshan Zhu2;Yi Gu2; Jianfang Xu1. 1Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China 2Asia & Emerging Markets Innovative Medicine, AstraZeneca R&D, Shanghai, China
Fig 3. Forest plot of hazard ratios (HR) for OS according to clinical characteristics, T790M ctDNA status and post TKI PD therapies.
Objective
Results
Fig 2A. Dynamic monitoring of EGFR mutant ctDNA status in plasma from 117 patients before and after EGFR-TKI progression.
Factors HR
95% CI
p-value
T790M - Positive
1.716
0.0443*
Age > 60
0.8806
0.639
Sex - Male
0.8893
0.681
Histopathological Type - Non-Adeno
1.623
0.265
Clinical Stage - IIIb
0.7943
0.751
Clinical Stage - Postoperative Metastasis
0.5751
0.146
Smoking - No
0.9085
0.762
TKI Line of Treatment - Second Line or after
1.01
0.973
Post TKI PD Therapy - TKI + Chemo
1.2396
0.441
Post TKI PD Therapy - Others
0.7205
0.546
EGFR T790M mutation occurs in around half of non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI (TKI) resistance, based on tumor tissue re-biopsies using an invasive clinical procedure. Here, we evaluated the feasibility of detecting T790M mutation in circulating tumor DNA (ctDNA), using serial plasma samples from NSCLC patients receiving TKI to further investigate its association with clinical outcome.
Table 1. Clinical characteristics and EGFR T790M ctDNA status in plasma of 117 patients
Total
T790M ctDNA in plasma
p-value
T790M +ve
T790M –ve N
117 55 62
Age 1
<= 60 66 31 35
> 60 51 24 27
Sex
0.1293
Female 71 29 42
Male 46 26 20
Histopathological type
0.1698
Adenocarcinoma
108 53
Non-adeno 9 2 7
Clinical stage
0.0677
Recurrent 21 6 15
Stage IV 91 48 43
Stage IIIb 5 4
Smoking
0.3918
Yes 16 13 No 88 39 49
TKI line of treatment
0.6688
First line 14
Second line or after 40
Post TKI PD therapy
0.6467
TKI alone
TKI + chemo 52 25
Others 10
Materials & Methods
Patients with advanced or recurrent NSCLC who had been receiving (or were about to receive) TKI treatment since May 2013 at Shanghai Pulmonary Hospital were enrolled consecutively. Following informed consent, blood samples were drawn every 2 months during TKI treatment and beyond PD. Pleural effusion (PE) or tumor re-biopsy samples were collected when available from patients with acquired TKI resistance. Patients who met the following criteria for acquired resistance to TKI were included for analysis: patients showing response or durable stable disease (>6 months) on TKI followed by progression whilst receiving TKI; or patients with documented EGFR activating mutation who developed PD during TKI treatment. Patients received TKI alone continuation therapy or TKI plus chemotherapy upon TKI failure at the physicians’ discretion.
Fig4. Overall survival in the TKI 2nd line or after subgroup, according to T790M ctDNA status in plasma.
Subgroups
Median (95% CI)
T790M+ve
808(674 – 1077)
T790M -ve
1083(845 – NA)
Fig1B. Distribution of plasma sample collection from different time period against 1st TKI-PD.
Log-rank P value =
Fig2B. Monitoring of response and resistance to clinical treatments by serial measurement of plasma EGFR ctDNA.
1st TKI PD
2nd PD
TKI + chemo
stop chemo
TKI alone
Fig 1A. Patient enrollment flow chart
318 consecutive NSCLC patients receiving EGFR-TKI
15 patients disqualified for the resistance criteria
177 patients without PD occurred before the analysis
Conclusions
124 patients acquired resistance to EGFR-TKI (1st PD)
Table 2. Comparison of EGFR T790M detected in plasma versus the status detected in paired tumor tissue
Tumor tissue
Plasma
Total + - 13 3 16 9 12 25
In summary, we have demonstrated the feasibility of monitoring EGFR mutation dynamics in serial plasma samples from NSCLC patients receiving TKI therapy in real-world clinical practice. We also showed that detection of plasma T790M ctDNA in patients with acquired TKI-resistance is a poor prognostic factor, especially in those patients receiving TKI as the second line or after treament. Our results highlight the clinical utility of plasma T790M ctDNA detection in guiding TKI therapies in NSCLC patients and support further validation of this approach in prospective interventional multi-center clinical studies in the future.
7 patients without post-PD blood samples
117 patients eligible for the analysis
Post-PD therapy based on the physicians’ discretion
55 patients received EGFR-TKI alone continuation therapy
52 patients received EGFR-TKI plus chemotherapy
10 patients received other regimens
Printed by