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 1.014 - 2.903 0.0443* Age > 60 0.8806 0.5181 - 1.497 0.639 Sex - Male 0.8893 0.5085 - 1.555 0.681 Histopathological Type - Non-Adeno 1.623 0.6929 - 3.804 0.265 Clinical Stage - IIIb 0.7943 0.1919 - 3.287 0.751 Clinical Stage - Postoperative Metastasis 0.5751 0.2728 - 1.212 0.146 Smoking - No 0.9085 0.4883 - 1.69 0.762 TKI Line of Treatment - Second Line or after 1.01 0.5584 - 1.828 0.973 Post TKI PD Therapy - TKI + Chemo 1.2396 0.7175 - 2.142 0.441 Post TKI PD Therapy - Others 0.7205 0.2486 - 2.088 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 = 0.0418 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 Email: zhengdiok@hotmail.com Printed by