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C. Bai
Moderator of
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 21
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.03 - The Science of Immunotherapy (ID 8220)
08:00 - 08:20 | Presenting Author(s): Roy S. Herbst
- Abstract
- Presentation
Abstract not provided
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JCSE 01.05 - PD-1+CD8+ T and iNKT Cell Based Immunotherapy on Lung Cancer (ID 8224)
08:20 - 08:40 | Presenting Author(s): Jianqing Xu
- Abstract
- Presentation
Abstract not provided
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JCSE 01.06 - ctDNA Based Tumor Mutation Burden Evaluation for Predicting Immunotherapy Effect (ID 8225)
08:40 - 09:00 | Presenting Author(s): Jie Hu
- Abstract
- Presentation
Abstract not provided
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JCSE 01.07 - Ongoing Trials in China on Checkpoint Inhibitors and Other Immunotherapies (ID 8226)
09:00 - 09:20 | Presenting Author(s): Qing Zhou
- Abstract
- Presentation
Abstract:
Immunotherapy gets the breakthrough after almost 100 years of silence. PD1/PD-L1 inhibitors as the representative has been extensively studied in various human malignant tumors and get promising long term response with relatively fewer adverse event. The first PD1 inhibitor indication was approved for melanoma in Japan on July 2014. By the end of December 2016, the US Food and Drug Administration had approved several PD-1 pathway blockade treatments including nivolumab, pembrolizumab and atezolizumab using in first line and second line of NSCLC. But In China, no PD-1 or PD-L1 inhibitors have received marketing approval from the Chinese Food and Drug Administration (CFDA) until July 2017. One sides, IO arena faces intense in-class competition from both MNC (Multi-National Corporation) and domestic pharmaceutical company in China. Now there are 20 IO antibodies from 7 MNCs and 10 pharmaceutical companies in China. But all the antibodies only confined to PD1/PD-L1 and CTLA4, no other hot IO drugs such as IDO or Lag3 et al. In the field of innovation, China is several years behind research in other areas of the world. The other sides various clinical trials are actively investigating MNC and domestic drugs in China. Between January 1, 2013 and April 6, 2017, Clinical Trials.-gov registered 270 international clinical trials using PD-1/PD-L1 therapies for NSCLC (e.g.nivolumab,pembrolizumab,atezolizumab,and durvalumab). These 270 trials included 61 studies that involved East Asian sites and 14studies that involved Chinese sites (12 multinational trials and 2 trials that only evaluated Chinese patients). These trials cover from second line and first line to adjuvant therapy in NSCLC. Most of the ongoing MNC NSCLC clinical trials joined in global study design that may accelerate the patient access to PD1/PD-L1. But Chinese population has relatively high rates of hepatitis B virus infection and much higher proportion of EGFR mutation. The delightful changing recently is some studies emerging to consider the characteristics of the Chinese or Asian populations. Domestic company clinical trials focus on GI (Gastrointestinal) and only 1 NSCLC study in China. Chinese clinical trials using IO remain in their early stages, and further efforts are needed to improve the design of future clinical trials. Meanwhile, the other hot IO drug phase I study need speed up in China.
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JCSE 01.09 - Therapeutic Practices in Europe for Immunotherapy, including Biomarkers (ID 8228)
09:45 - 10:05 | Presenting Author(s): Solange Peters
- Abstract
- Presentation
Abstract not provided
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JCSE 01.10 - The Main Treatment Failure Pattern for Completely Resected Stage II–IIIA (N1–N2) EGFR-Mutation Positive Lung Cancer (ID 10904)
10:05 - 10:20 | Presenting Author(s): Songtao Xu | Author(s): W. Zhong, Y. Zhang, W. Mao, L. Wu, Y. Shen, Y. Liu, C. Chen, Ying Cheng, L. Xu, J. Wang, K. Fei, X. Li, J. Li, C. Huang, Z. Liu, S. Xu, K. Chen, S. Xu, L. Liu, P. Yu, B. Wang, H. Ma, H. Yan, X. Yang, Yi-Long Wu, Q. Wang
- Abstract
- Presentation
Background:
ADJUVANT (CTONG 1104) is the first randomized trial shows significantly prolonged disease-free survival (DFS) in completely resected stage II-IIIA (N1-N2) epidermal growth factor receptor (EGFR)-mutation positive non-small-cell lung cancer (NSCLC) through adjuvant gefitinib compare with vinorelbine plus cisplatin (VP). Further we aim to analyze the treatment failure pattern in ADJUVANT study.
Method:
In the ADJUVANT trial, a total of 222 patients with completely resected stage N1–N2 EGFR-mutation positive NSCLC were randomized 1:1 into gefitinib group (250mg, QD, 24 months ) or vinorelbine (25mg/m[2] Day 1/Day 8) plus cisplatin (75mg/m[2] Day 1) group (every 3 weeks for 4 cycles) respectively. Any recurrence or metastases occurred during the follow-up period was defined as treatment failure. Recurrent pattern in both group were analyzed with follow-up data (until Mar 9[th] 2017) integrated.
Result:
At the Data cut-off date for the primary analysis of DFS, 124 progression events (55.9% maturity overall) had occurred; 114 patients had disease recurrence，10 patients died before disease recurrence. Analysed recurrent pattern include lung, brain, liver, bone adrenal gland, pleura, pericardium, spleen and regional lymph nodes metastasis. Even no significant differences were found, highest proportion of patients in both group(18.9% for VP and 26.1% for gefitinib, p=0.199) surfer brain metastasis with lung metastases being the second common recurrent site. Time to brain metastases showed no significantly difference between the two groups (not reach vs 40.8m, p>0.05). Among the 29 brain metastases patients with gefitinib, the brain metastases occurred in 17 patients during the gefitinib treament, and 12 patients relapse after the gefitnib termination. Figure 1
Conclusion:
Compared with other site metastases, lung, brain and regional lymph nodes metastases account for major proportion of recurrence in ADJUVANT study. (NCT01405079)
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JCSE 01.11 - A Multicenter, Non-Interventional Study on Real World EGFR Testing and in Patients with IIIB/IV NSCLC in Northern China (ID 10905)
10:20 - 10:35 | Presenting Author(s): Ying Cheng | Author(s): Y. Wang, J. Zhao, Y. Liu, H. Gao, K. Ma, S. Zhang, H. Xin, J. Liu, H. Chengbo, Z. Zhu, Y. Wang, J. Chen, F. Wen, J. Li, Z. Jie, Z. Zheng, Z. Dai, H. Piao, X. Li, Y. Li, M. Zhong, R. Ma, Y. Zhuang, Y. Xu, Z. Qu, H. Yang, C. Pan, F. Yang, D. Zhang, B. Li
- Abstract
- Presentation
Background:
EGFR mutation plays a dominant role in the precise treatment of non-small cell lung cancer (NSCLC), and EGFR-TKIs has been recommended for patients with positive EGFR-sensitive mutation as a standard regimen in clinical practice. In China, application of EGFR-TKIs without knowing EGFR mutation status has been a common phenomenon due to various reasons including the vast territory, uneven distribution of medical resources, differences level of testing technology and others. Therefore, we prospectively conducted a real-world investigation to understand the actual situation of EGFR testing in Northern China, and identify the underlying causes affecting EGFR detection, in order to provide references to improve the standardized treatment (NCT02620657).
Method:
The patients with IIIB/IV NSCLC who were firstly diagnosed or postoperative recurrence between 2014-1-1 and 2014-12-31 in 28 research centers of Northern China were analyzed. The primary endpoint was testing rate，the secondary endpoints were factors affecting EGFR testing, EGFR mutation status, detection methods and the survival outcomes of patients.
Result:
Among 2809 patients, 2250 (90.78%) were adenocarcinoma, 208 (7.40%) were squamous carcinoma, 51 (1.82%) were other pathologic types. Testing rate was 42.54% (1195/2809) and was significantly related to city level (first-tier cities vs. new first-tier cities vs. second-tier cities vs. third-tier and above cities : 69.04% vs. 38.08% vs. 34.05% vs. 14.11%, P < 0.001, smoking status (never smoking vs. ever smoking vs. smoking: 45.42% vs. 51.10% vs. 33.37%, P<0.001, ECOG PS (0 vs.1vs.2vs.≥3:47.93%vs. 44.48vs.34.89%vs.20.37%, P=0.011), pathological type (adenocarcinoma vs. squamous carcinoma: 44.94% vs.19.23%, P=0.003 and medical insurance situation (social basic medical insurance vs. new rural cooperative medical insurance vs. own expense: 44.98% vs. 36.49% vs. 29.55%, P=0.001. EGFR sensitive mutation rate was 46.44%, the most common subtype was 19Del (42.16%), followed by L858R(40.00%), Exon 20 insertions (1.62%) and other subtypes (16.20%). The most common methodology is ARMS (63.77%), the second common one is DNA sequencing (5.36%). The 1-year and 2-year survival rate in patients receiving EGFR testing was 73.6% and 51.9%, compared with 64.3% and 43.7% respectively in patients without EGFR testing.
Conclusion:
There were regional differences in EGFR testing rates among IIIB/IV NSCLC patients in Northern China. The intention of doctors and patients, medical insurance coverage and differences technical level are major factors affecting the testing rate of EGFR. Approaches should be taken to improve the situation, such as strengthening the training, expanding the coverage of medical insurance, and relying on commercial gene detection companies, and further standardize the molecularly pathological diagnosis and treatment of NSCLC.
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- Abstract
- Presentation
Background:
Seveal studies have demonstrated targeting EGFR mutations and tumor angiogenesis simultaneously has synergistic effect in the 1[st] line setting in EGFR mutant NSCLC. However, in JO25567 trial, the ≥grade 3 hypertension incidence with combination therapy was much higher (60%) when compared to historic incidence of hypertension with bevacizumab (10-15%). Considering relatively shorter half-lives for small molecule tyrosine kinase inhibitors, it might be a better choice to combine EGFR TKI and VEGFR TKI when it comes to hypertension management. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting VEGFR and it has demonstrated favorable benefit-to-risk profile in third line treatment in NSCLC patients.Thus it is important to assess safety, tolerability and efficacy of this new combination in the 1[st] line setting in EGFR mutant NSCLC patients. NCT02976116
Method:
This is a single arm, open-label, multi-center study. All patients will receive gefitinib continuously at 250 mg qd. Fruquintinib will be given at 4 mg as starting dose for 3 weeks followed by 1 week off in the first 4-week cycle. Fruquintinib dose can be escalated to 5 mg with the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. The primary objective is to assess the safety and tolerability of this combination. Key eligibility criteria include: histologically or cytologically confirmed NSCLC, ECOG PS 0-1, no prior systematic treatment, no brain metastasis. Key exclusion criteria include: known T790M mutation and bleeding history within 1 month before enrollment.
Result:
As of Jun 20, 2017, 9 patients have been enrolled and received at least one dose of fruquintinib and gefitinib. Six patients had L858R mutations, and three patients had exon 19 deletions. All patients reported AEs, but only one patient (11.1%) had grade 3 proteinuria. No SAE was reported. The most common AEs were increased ALT (3 [33.3%] patients), increased AST (3 [33.3%] patients), increased TBIL (3 [33.3%] patients), proteinuria (3 [33.3%] patients) and rash (3 [33.3%] patients). Fruquintinib dose reduction occurred in 3 patients due to grade 3 proteinuria, grade 2 increased ALT and grade 2 hemoptysis, respectively.
Conclusion:
The study is ongoing. As of the cut-off date, no unexpected toxicities were identified. The combination of fruquintinib and gefitinib showed an expected and manageable preliminary safety profile. Additional patients and follow-up data are required to further confirm the full potential of this combination treatment.
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JCSE 01.13 - Discussant Oral Abstracts - JCSE 01.10, JCSE 01.11, JCSE 01.12 (ID 10909)
10:50 - 11:10 | Presenting Author(s): Joel W. Neal
- Abstract
- Presentation
Abstract not provided
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JCSE 01.14 - Discussant Poster Abstracts (ID 10908)
11:10 - 11:30 | Presenting Author(s): Bob T. Li, Jonathan W Riess
- Abstract
- Presentation
Abstract not provided
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- Abstract
Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.
Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.
Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.
Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.
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- Abstract
Background:
Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.
Method:
A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).
Result:
No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1
Conclusion:
Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.
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- Abstract
Background:
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 these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.
Method:
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.
Result:
Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment 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. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p=0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios=0.31; 95% confidence intervals: 0.11-0.90; p=0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p=0.021; 10.1 verse 8.6 months, p=0.232).
Conclusion:
Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients.
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- Abstract
Background:
To evaluate (1) the potential effect of primary tumor resection, an aggressive local consolidative therapy, for patients with oligometastatic NSCLC on 3 year overall survival; (2) the surgical outcomes in the treatment of patients with oligometastatic NSCLC; (3) the potential clinical factors predicting survival in order to better select patients for surgery.
Method:
According to the extent of pulmonary resection, the patients were divided into two subgroups. A. intent to cure (ITC: removal of total or primary pulmonary lesions); B. intent to biopsy (ITB: preservation of major lesions, only diagnostic biopsy via minimally invasive approach). M stage classified based on 8th UICC/AJCC TNM M categories.
Result:
From Jan 2002 through Dec 2015, a total of 115 consecutive metastatic NSCLC patients were enrolled from Peking University Cancer Hospital. The 3-year overall survival (OS) of ITC and ITB were 64.3% and 34.9% (log-rank p = 0.0009), respectively. Multivariate cox proportional regression analysis identified multiple station lymph nodes (LN) and bone involvement may be prognostic indicators. Figure 1Figure 2
Conclusion:
The current findings suggest that aggressive surgical therapy can extend the survival in selected stage IV NSCLC patients, and should be further explored in phase 3 trials as a standard treatment option in this clinical scenario.
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JCSE 01.21 - Combination of Biomarker and Clinicopathologic Characters May Circle out Beneficiaries through Second-Line Immunotherapy: A Meta Analyse (ID 10917)
11:30 - 11:30 | Presenting Author(s): Si-Yang Liu | Author(s): Z. Dong, C. Zhang, W. Zhong, Yi-Long Wu
- Abstract
Background:
Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of NSCLC. Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown.
Method:
We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1.
Result:
Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR=0.64, 95%CI=0.56-0.73, P<0.00001) and PD-L1 negative (HR=0.88, 95%CI=0.78-1.00, P=0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR=0.70, 95%CI=0.63-0.79, P<0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR=0.67, 95%CI=0.60-0.76, P<0.00001). Both KRAS mutation (HR=0.60, 95%CI=0.39-0.92, P=0.02) and wild type/unknown (HR=0.81, 95%CI=0.67-0.97, P=0.02) were apt to anti PD-1/L1. Figure 1
Conclusion:
Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.
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JCSE 01.23 - The Feasibility of Osimertinib Treatment on Brain Metastases in NSCLC Patients After 1st Generation EGFR-TKI Resistance: A Preliminary Study (ID 10919)
11:30 - 11:30 | Presenting Author(s): Lucheng Zhu | Author(s): S. Zhang, B. Xia, X. Chen, S. Ma
- Abstract
Background:
NSCLC patients with activating EGFR mutations benefit from 1[st] generation EGFR-TKIs. It eventually develops acquire resistance after 10-12 months during of response. Of note, approximately one-third of those patients develop brain metastases, which deteriorate their quality of life and survival. Few effective therapeutic options are currently available for BM patients. Several case studies have showed the well response with osimertinib in BM patients. BM model also found the high penetration rate of Osimertinib into blood-brain barrier. This study evaluated the feasibility of osimertinib treatment on BM patients after 1st generation EGFR-TKI resistance.
Method:
Patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were collected from our previous clinical trial (NCT02418234) from March 2015 to March 2016. Blood samples were drawn within two weeks from PD occurred. T790M mutations were evaluated by droplet digital PCR. We undertook follow-up every 3 months by phone until April 2017. The median follow-up time was 11 months (range, 2 to 22 months).
Result:
Fifty NSCLC patients with BM after EGFR-TKI resistance were collected from our previous trials. After TKI resistance, ten patients received subsequent osimertinib treatment. Finally, ten patients included three males and seven females were included in the study. The median age was 66.5 (56 to 73). Seven were detected acquired T790M mutation. The median survival was 15.3 months (95% CI, 10.1 to 20.6 mo), 15.3 mo for T790M negative and 12.9 mo for T790M positive patients.
Conclusion:
Our preliminary study showed the well efficacy of osimertinib on NSCLC patients with BM. It provides well survival benefit. Randomized control trials should be required before it is widely used.
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JCSE 01.24 - Detection of EGFR, ALK and Other Driver Oncogenes from Plasma cfDNA by Single Molecule Amplification and Re-sequencing Technology (cSMART) (ID 10920)
11:30 - 11:30 | Presenting Author(s): Tony SK Mok | Author(s): Shun Lu, Ying Cheng, Jie Wang, Y. Wang, T. Wang, T. Yung, X. Su, F. Sun, F. Sun, L.T. Wang, Yi-Long Wu
- Abstract
Background:
All patients with advanced stage NSCLC should have their EGFR and ALK mutation status known prior to initiation of first line therapy. Multiple plasma-based technologies such as ARMS and ddPCR are available for rapid detection of EGFR mutation, while only the more laborious Next Generation Sequencing (NGS) may cover EGFR, ALK and other uncommon mutations in a single blood test. cSMART is a novel NGS-based technology with rapid turnaround time that can detect EGFR, ALK and KRAS mutations plus others less common lung cancer specific driver oncogenes (BRAF, ROS-1, HER-2, PIK3CA, RET, MET14skipping).
Method:
Objectives of this study is to investigate the clinical application of cSMART on patients with advanced NSCLC. In cSMART assay, each cfDNA single allelic molecule is uniquely barcoded and universally amplified to make duplications. The amplified products are circularized and re-amplified with target-specific back-to-back primers. These DNA are then ligated with sequencing adapters and pair-end sequenced (>40,000x) with illumine sequencers. The original cfDNA molecules are reconstituted by multi-step bioinformatics pipeline for censor and correction. The final products are quantified for calculation of allele frequencies
Result:
Out of the 1664 samples tested, total of 1469 were of advanced stage NSCLC. We detected EGFR mutations in 758 (51.6%), ALK translocation in 34 (2.3%) and KRAS mutation in 78 (5.8%) patients. Among the patients with activating EGFR mutations, 301(39.7%) have exon 19 deletion and 279 (36.8%) have exon 21 point-mutation. Total of 6 (0.8%) patients with EGFR mutation have concurrent presence of ALK translocation. Incidence and mean allele frequency of the less common target mutation is summarized in Table. Median sample turnaround time is 7 days.Incidence (%) Median Mutation Allele frequency (%) BRAF 29 (1.97%) 0.08% ROS1 2 (0.14%) 0.77% HER-2 19 (1.29%) 0.20% PIK3CA 70 (4.77%) 0.17% RET 14 (0.95%) 0.57% MET14skipping 63 (4.29%) 0.08%
Conclusion:
cSMART is a novel plasma cfDNA-based technology that can detect the actionable target oncogenes for patients with advanced NSCLC. This is a sensitive method with capacity of detecting the uncommon targets at relatively low allele frequency.
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JCSE 01.25 - Detection of EGFR T790M Mutations by Four Testing Platforms in ctDNA from Chinese Patients with Advanced NSCLC (ID 10921)
11:30 - 11:30 | Presenting Author(s): Xu-Chao Zhang | Author(s): Z. Liang, Y. Chen, H. Zhang, W. Gang, Y. Lu, Z. Liang, Ying Cheng, Y. Hu, Jie Wang, J. Ying, W. Liu, Yi-Long Wu
- Abstract
Background:
Osimertinib is used to treat patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC). Detection of the T790M mutation in tissue samples may not be possible in some patients due to unfeasible or unsuccessful rebiopsies; detection in circulating cell-free tumor DNA (ctDNA) may represent a promising alternative. Here we evaluated four platforms to detect T790M using ctDNA in plasma from Chinese patients as part of the ADELOS study.
Method:
ADELOS is being conducted in China in 256 patients with advanced NSCLC, sensitizing mutations and progression on previous tyrosine kinase inhibitor. T790M was detected in plasma ctDNA by cobas® real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, QuantStudio3D digital PCR, and next-generation sequencing (NGS). T790M positive patients by any of the four platforms received osimertinib 80 mg/day orally. The relationship between T790M detection by each platform and objective response rate (ORR) was investigated. Concordance, sensitivity and specificity, and positive/negative predictive value between platforms were assessed. T790M mutation level in ctDNA was dynamically monitored every 6 weeks using digital PCR and NGS during osimertinib treatment, and its correlation with clinical outcome was evaluated. NGS also provided information about the heterogeneity of other genetic alterations in patients before osimertinib treatment.
Result:
Section will be completed in late-breaking abstract submission
Conclusion:
Section will be completed in late-breaking abstract submission
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JCSE 01.26 - Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC (ID 10922)
11:30 - 11:30 | Presenting Author(s): Yangsi Li | Author(s): B. Jiang, Jin -Ji Yang, X. Zhang, Z. Zhang, Qing Zhou, H. Tu, Z. Wang, H. Chen, C. Xu, B. Wang, Yi-Long Wu
- Abstract
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) patients with oncogenic drivers. Resistance mechanisms of LM with ALK rearrangement remained unclear due to limited access to leptomeningeal lesions.
Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing.
Result:
In patents with ALK rearrangement, driver genes were detected in 66.7%, 50.0% and 28.6% patients of CSF cfDNA, CSF precipitates and plasma, respectively; and all of them had much higher allele fractions in CSF cfDNA than the other two media. The diagnosis criteria of LM were positive in brain MRI or CSF cytology, and driver genes were identified in CSF cfDNA of all patients with positive CSF cytology while in those CSF cytology negative all genes were negative. Resistance mutations including gatekeeper genes ALK G1202R and ALK G1269A were identified in CSF cfDNA but they were absent in their plasma. Moreover, tailor therapy based on CSF cfDNA obtained surprising outcomes, and genetic profiles of CSF cfDNA showed dynamic changes, suggesting the potential role of CSF for follow-up studies. Figure 1
Conclusion:
CSF cfDNA could reveal the driver and resistant genes of LM, and it may function as the media of liquid biopsy for LM in NSCLC with ALK rearrangement.
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JCSE 01.27 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 10923)
11:30 - 11:30 | Presenting Author(s): Tony SK Mok | Author(s): Solange Peters, D. Ross Camidge, Shirish M Gadgeel, S.I. Ou, D. Kim, Rafal Dziadziuszko, F. De Marinis, R. Sangha, A. Zeaiter, J. Noe, E. Nueesch, T. Liu, I. Loftin, C. Williams, Alice Shaw
- Abstract
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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JCSE 01.28 - NGS Sequencing Based Liquid / Tissue Biopsy Identified Coexistence of HER2 Amplification and Mutation in Advanced NSCLC Patients (ID 10924)
11:30 - 11:30 | Presenting Author(s): Rongrong Chen | Author(s): J. Zhao, G. Lin, L. Liu, L. Chen, X. Hu, X. Ai, Z. Fan, C. Xu, W. Wang, W. Zhuang, M. Fang, Y. Zhu, G. Chen, Y. Guan, L. Yang, X. Xia, X. Yi
- Abstract
Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.
Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).
Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.
Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.
Author of
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MA 20 - Recent Advances in Pulmonology/Endoscopy (ID 685)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Pulmonology/Endoscopy
- Presentations: 1
- Moderators:C. Lee, S. Sasada
- Coordinates: 10/18/2017, 14:30 - 16:15, F205 + F206 (Annex Hall)
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MA 20.13 - etDNA: Tumor-Derived DNA from Pleural Effusion Supernatant as a Promising Source for NGS-Based Mutation Profiling in Lung Cancer (ID 10091)
15:50 - 15:55 | Author(s): C. Bai
- Abstract
- Presentation
Background:
Mutation profiling of circulating tumor DNA (ctDNA) and pleural effusion sediment containing tumor cells (ETCs) were commonly applied in clinical practice. Several studies suggested that tumor-derived DNA from pleural effusion supernatant (etDNA) might be a better candidate for detecting gene alterations in lung cancer. However, little is known regarding the abundance and diversity of tumor DNA acquired among different types of liquid biopsy.
Method:
We performed targeted next generation sequencing (NGS)-based genetic profiling on tumor tissue, pleural effusion (etDNA & ETCs) and contemporaneous ctDNA from 63 lung cancer patients (58 adenocarcinoma, 2 adenosquamous carcinoma, 2 SCLC, 1 neuroendocrine carcinoma), among which 28 patients had paired tumor tissue samples. Genomic DNA from whole blood of each patient was used for germline control. Driver mutation and rearrangement profiling was validated using ARMS-PCR, FISH, or Ventana IHC assay in tumor tissue as golden standard.
Result:
We identified tumor-specific mutations in 98%, 89%, 86%, and 100% of patients in their etDNAs, ETCs, ctDNAs and tumor tissues, respectively (p<0.01). etDNAs showed a significantly higher tumor-specific mutation number per patient (Median: 5) compared to ETCs and plasma ctDNAs (Median of 3 for both), while the median number in tumor tissues is 4 per patient. The detection sensitivity for EGFR mutations in etDNAs is 95%, higher than that in ETCs and ctDNAs (89% and 63%, respectively). Two patients detected ALK fusion in tumor tissue were also positive in etDNA, only one patient was positive in ETCs and ctDNA, respectively. A total of 298 genetic alterations, including point mutations, indels, copy number variations (CNVs) and gene fusions, were identified in etDNAs from all the patients. However, only 74% and 57% of these alterations were detected in contemporaneous ETCs and ctDNA samples, with CNVs having the lowest detection sensitivity as 49% and 11%, especially in lung cancer patients without extrathoracic metastasis, as none of the CNVs detected in etDNAs were captured in plasma ctDNAs of these patients. Furthermore, driver mutations and rearrangements in etDNA showed a strong correlation to targeted therapy efficacy.
Conclusion:
This study demonstrated that etDNA had significantly higher tumor-specific mutation detection rate and sensitivity compared to ETCs and ctDNA. etDNA from supernatant of pleural effusion is a promising source for genetic testing to guide treatment-decision making in lung cancer. This study is funded by Shanghai Science and Technology Program (15ZR1406400).
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-001 - Evaluate the Utility of the ProLung China Test in the Diagnosis of Lung Cancer (ID 9541)
09:30 - 09:30 | Author(s): C. Bai
- Abstract
Background:
This Study will assess the stability of the ProLung China Test classification algorithm when used as an adjunct to CT scan. Also, we will assess whether there are any potential safety concerns of the ProLung China Test when used to evaluate patients with a positive CT scan for lung cancer.
Method:
This study is a multicentre, prospective, open, self-control study which aims to evaluate the utility of the ProLung China Test in diagnosis of lung cancer (ClinicalTrials.gov ID: NCT02726633 ). The subject whose age is between 18 and 80 years old and CT result shows a 4 ~ 50 mm nodule within 30 days is our object. In these objects, we will exclude those people who has TB, pulmonary edema, chronic lung infection, abnormal anatomy, skin disease effecting bioconductance and other tumors.The expected sensitivity and specificity of Prolung China Test are 70 % and 61%, and non-inferiority margin is 10 %. Based on these statistical information, four clinical trial centers, in the study, will enroll at least 452 samples with 20 % dropout rate. These samples must contain at least 182 effective malignant sample and 194 benign samples.
Result:
According to the inclusion and exclusion criteria, excision biopsy or follow-up examination will perform on enrolled subjects. Before these examination, a Prolung China test will be operated on these subjects. The subject in follow-up will be followed at least 24 months. The pathology result and follow-up result will be the gold standard in this study. The diagnosis result and adverse event will be recorded during the experiment.
Conclusion:
To demonstrate safety and efficacy of the ProLung China Test in the risk stratification of patients with pulmonary lesions identified by CT that are suspicious for lung cancer.
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-037 - Deep Learning System for Lung Nodule Detection (ID 9503)
09:30 - 09:30 | Author(s): C. Bai
- Abstract
Background:
Ever since its first success in large scale image recognition problem, deep convolutional neural networks (DCNNs) have shown their capabilities in solving many challenging visual perceptual tasks, such as image classification, segmentation, object detection. In some cases, DCNNs have already achieved near-human performance. In medical image analysis, DCNNs have also been successfully applied to lesion detection, segmentation, and diagnosis. The power of DCNN lies in its ability to learn a hierarchical representation of raw input data, without hand-crafted features.
Method:
The focus of this study was to improve the performance of DCNN in automatic detection of pulmonary nodule on CT scan. In particular, nodules whose size is less than 4mm were considered. A total of 171 scans were collected at Zhongshan Hospital Fudan University, which was first process by the proposed DCNN system (12Sigma). The detection results were then carefully reviewed by an experienced physician, all false positives and missed nodules were manually labeled. To refine the system, all false positives and true nodules of sizes 4mm and under were selected.
Result:
The data set was randomly split into training and test sets, where the training set consists of 90% (154 scans) and the test set consists of 10% of data (17 scans). Figure 1 shows the FROC curves on the test set before and after re-training. Overall, the detection sensitivity were improved at all false positive levels, but the improvement was most significant at low FP rate region. For example, when FP is 0.5 per scan, the detection sensitivity increased from 0.36 to 0.49. Figure 1
Conclusion:
This improvement suggests that, even with limited data, the deep neural network can learn from its mistakes and be easily tuned to be more sensitive to small nodules. We believe that when more data is colllected, more significant improve in high FP rate region will be observed.
