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Yi-Long Wu
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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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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: 5
- 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 01.10 - The Main Treatment Failure Pattern for Completely Resected Stage II–IIIA (N1–N2) EGFR-Mutation Positive Lung Cancer (ID 10904)
10:05 - 10:20 | Author(s): Yi-Long Wu
- 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 01.21 - Combination of Biomarker and Clinicopathologic Characters May Circle out Beneficiaries through Second-Line Immunotherapy: A Meta Analyse (ID 10917)
11:30 - 11:30 | Author(s): 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 01.24 - 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 | Author(s): 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 | Author(s): 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 | Author(s): 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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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M.I. Abdul Wahid, Martin Reck
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 313 + 314
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MA 11.03 - Gefitinib as First-Line Treatment of Plasma CtDNA EGFR Mutation-Positive NSCLC Detected by DdPCR: BENEFIT Study (CTONG1405) (ID 9278)
11:10 - 11:15 | Author(s): Yi-Long Wu
- Abstract
- Presentation
Background:
EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).
Method:
Patients with stage IV lung adenocarcinoma and plasma ctDNA EGFR-sensitizing mutations (exon 19 del or exon 21 L858R; by ddPCR) received first-line gefitinib (250 mg once-daily) until progressive disease (PD). Blood samples were collected every 8 weeks for dynamic EGFR analysis until PD. Primary endpoint was ORR. Secondary endpoints included PFS, DCR (Week 8), and analysis of baseline ctDNA samples by next-generation sequencing (NGS).
Result:
From December 2014-January 2016, 426 patients from 15 Chinese centers were screened: 391 had matched tissue and blood samples; 188 had ctDNA EGFR mutation-positive NSCLC and received gefitinib; and 183 had ≥1 post-baseline tumor assessment and plasma samples every 8 weeks until PD. At data cutoff (January 31, 2017), 152 patients had progressed. ORR was 72.1% (95% CI 65.0%,78.5%); DCR (Week 8) was 92.3% (95% CI 87.5%,95.8%); and median PFS was 9.5 months (95% CI 9.07,11.04). PFS was significantly shorter in the subgroup with baseline ctDNA de novo T790M mutations (5.0%, n=9) versus the EGFR-sensitizing mutations subgroup (5.6 vs 9.6 months, HR=2.60; 95% CI 1.32,5.12, p=0.004). In patients with Week 8 on-treatment plasma samples (n=167), the subgroup who showed EGFR mutation clearance in ctDNA by ddPCR (88%, 147/167) had longer PFS compared with those who did not (11.0 vs 2.1 months, HR=7.28; 95% CI 4.35,12.18, p<0.0001). The median time to emergence of acquired T790M mutation in plasma was 7.6 months. The T790M-positive rate increased from Week 24 (15.7%) to Week 48 (32.6%), with a corresponding increase in PD rate (24.7% at Week 24, 56.9% at Week 48). Among 180 patients with baseline NGS data, 21 (11.7%) harbored aberrations in additional oncogenic drivers (MET, ERBB2, KRAS, BRAF, RET, or ROS1) and tumor suppressors (TP53, RB1, and PTEN). This subgroup had worse PFS versus those with EGFR-sensitizing mutations alone (3.9 vs 13.0 months, HR=2.83; 95% CI 1.65,4.87, p=0.00016).
Conclusion:
The BENEFIT study prospectively demonstrated that ctDNA-based EGFR mutation detection can be used to select patients for treatment with first-line gefitinib. Dynamic alterations in EGFR mutations could be used to predict efficacy and disease progression, ahead of radiological results.
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MS 12 - Sustainable Care System in Each Region (ID 534)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
- Moderators:Yasushi Goto, M.E. Hand
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 501
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MS 12.03 - Sustainable Care System in China (ID 7869)
11:30 - 11:45 | Presenting Author(s): Yi-Long Wu
- Abstract
- Presentation
Abstract not provided
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.01 - First-Line Dacomitinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer with EGFR Mutation Subgroups (ID 8555)
15:45 - 15:55 | Presenting Author(s): Yi-Long Wu
- Abstract
- Presentation
Background:
The ARCHER 1050 study (NCT01774721) demonstrated benefits of dacomitinib compared with gefitinib as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutation. Here, we present the results of a prospective subgroup analysis by EGFR mutation subtype.
Method:
In this ongoing phase 3, open-label study, eligible patients with newly diagnosed stage IIIb/IV or recurrent NSCLC and EGFR-activating mutation (exon 19 deletion or L858R mutation ± T790M mutation) with an Eastern Cooperative Oncology Group performance status of 0–1 were randomized (1:1) to receive dacomitinib or gefitinib, stratified by race and EGFR mutation subtype. The primary endpoint was progression-free survival (PFS) by blinded independent radiologic central (IRC) review. Secondary endpoints included overall survival and objective response rate (ORR), as determined by IRC and investigators’ assessments.
Result:
A total of 452 patients were randomized (dacomitinib, n=227; gefitinib, n=225). Among the dacomitinib and gefitinib arms, respectively, 134 (59%) and 133 (59%) had exon 19 deletions and 93 (41%) and 92 (41%) had L858R mutations. The Table shows PFS, ORR, and duration of response by EGFR mutation per IRC. Results based on investigators’ assessments were consistent with those based on IRC review. Overall survival data are immature.Exon 19 Deletion L858R Mutation Dacomitinib (n=134) Gefitinib (n=133) Dacomitinib (n=93) Gefitinib(n=92) PFS per IRC Median, months (95% CI) 16.5 (11.3–18.4) 9.2 (9.1–11.0) 12.3 (9.2–16.0) 9.8 (7.6–11.1) Hazard ratio (95% CI) 1-sided P value 0.551 (0.408–0.745) <0.0001 0.626 (0.444–0.883) 0.0034 ORR per IRC CR, n (%) 7 (5.2) 3 (2.3) 5 (5.4) 1 (1.1) PR, n (%) 95 (70.9) 90 (67.7) 63 (67.7) 67 (72.8) ORR (CR + PR), n (%) (95% CI) 102 (76.1) (68.0–83.1) 93 (69.9) (61.4–77.6) 68 (73.1) (62.9–81.8) 68 (73.9) (63.7–82.5) 1-sided P value 0.1143 0.5395 DoR in responders per IRC Median, months (95% CI) 15.6 (13.1–19.6) 8.3 (7.9–10.1) 13.7 (9.2–17.4) 7.5 (6.5–10.2) Hazard ratio (95% CI) 1-sided P value 0.454 (0.319–0.645) <0.0001 0.403 (0.267–0.607) <0.0001 CI, confidence interval; CR, complete response; DoR, duration of response; PR, partial response.
Conclusion:
By IRC and investigators’ assessments, PFS with dacomitinib was superior to that with gefitinib in patients with either EGFR mutation. Despite a similar ORR among the treatment and EGFR mutation subgroups, duration of response was longer with dacomitinib for both mutations.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.06 - A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC (ID 8995)
11:55 - 12:05 | Author(s): Yi-Long Wu
- Abstract
- Presentation
Background:
EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).
Method:
This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.
Result:
As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.
Conclusion:
These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.02 - Unique Genetic Profiles from Circulating Cell-Free DNA of Cerebrospinal Fluid in Leptomeningeal Metastases of EGFR Mutant NSCLC (ID 8258)
11:10 - 11:20 | Author(s): Yi-Long Wu
- Abstract
- Presentation
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM 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 with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available
Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.
Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 5
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-009 - Clinically Primary and Secondary Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer (ID 8739)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Crizotinib is a standard of care in anaplastic lymphoma kinase(ALK)-positive advanced non-small-cell lung cancers (NSCLC).Undoubtedly,the resistance to crizotinib is a current bottleneck.Hence,it is necessary to explore the resistance mechanisms to ALK inhibitors.
Method:
From October 2010 to May 2017,225 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China.The status of ALK rearrangement was assessed by Lysis ALK Break Apart fluorescence in situ hybridization,reverse transcription polymerase chain reaction,or Ventana ALK immunohistochemistry.Next generation sequencing(NGS) was used to test the tissue or plasma from patients with resistance to crizotinib.Primary resistance to crizotinib occurred when Progression-free survival was less than 3 months for the patients treated with crizotinib.
Result:
Among enrolled patients,72.4%(163/225) gained secondary resistance,and 8.9%(20/225) had primary resistance.Molecular mechanisms of clinically primary resistance were shown in Figure a.The variants of ALK fusion were different between primary and secondary resistance patients.There were more variants of ALK fusion appeared in the group with primary resistance except E6-A20 and E13-A20.Among secondary resistant patients，non-EML4 partners fusion,such as DMD-ALK fusion,YWHAQ&TAF1B-ALK fusion,GALNT14-ALK fusion and SLC19A3-CCL20-ALK fusion were found,which responsed to crizotinib treatment.Acquired ALK L1196M/G1269A mutations were found in both primary and secondary resistant patients,and while ALK I1171T mutation was only found in secondary resistantpatients.Wnt signaling pathway was activated significantly after the treatment of crizotinib according to Kyoto Encyclopedia of Genes and Genomes(KEGG) and GeneOntology(GO) analyses.Moreover, AMER1 aberrance was inclined to appear in the primary resistance patients, which was significant different between the two groups in KEGG and GO analyses.Figure 1
Conclusion:
ALK mutations could exist in both primary and secondary resistance to crizotinib in ALK-rearranged NSCLC. Response to crizotinib was also observed in ALK-rearranged NSCLC patients with non-EML4 partners. NGS may facilitate precision treatment for both primary and secondary resistant patients though they have a few differences in molecular mechanisms of resistance.
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P1.01-010 - Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC (ID 8754)
09:30 - 09:30 | Author(s): 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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P1.01-018 - Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression (ID 10014)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression.
Method:
This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response . MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and ≥50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, ≥5 copies were positive or MET/CEP7 ratio ≥1.8 (low ≥1.8-≤2.2, Intermediate >2.2-<5 and High ≥5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance.
Result:
Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression , and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++~100%+++) 1.9m (95% CI 0.9-2.9,P=0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p=0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%×3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100%×3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient acheived PR with subsequent treatment of cetuximab plus Taxel.
Conclusion:
Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor.
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P1.01-027 - Combination of Biomarker and Clinicopathologic Characters May Circle out Beneficiaries through Second-Line Immunotherapy: A Meta Analyse (ID 8265)
09:30 - 09:30 | Author(s): 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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P1.01-032 - Detection of EGFR, ALK and Other Driver Oncogenes from Plasma cfDNA by Single Molecule Amplification and Re-sequencing Technology (cSMART) (ID 8603)
09:30 - 09:30 | Author(s): 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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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-010 - CheckMate 870: An Open-label Safety Study of Nivolumab in Previously Treated Patients With Non-Small Cell Lung Cancer in Asia (ID 8231)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2, which are expressed on tumor cells. Nivolumab, an anti–PD-1 antibody, showed durable antitumor activity and a favorable safety profile compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) in 2 global phase 3 studies (CheckMate 017 and CheckMate 057). Data from these trials led to the approval of weight-based nivolumab 3 mg/kg administered as a 60-minute infusion every 2 weeks (Q2W) in previously treated patients with NSCLC. Data from exposure-response simulations indicated that flat-dose nivolumab 240 mg Q2W has comparable pharmacokinetic, safety, and efficacy profiles to the weight-based dose, and data from CheckMate 153 demonstrated that nivolumab 3 mg/kg can be safely infused over 30 minutes. CheckMate 078 is an ongoing phase 3 registrational trial evaluating second-line nivolumab 3 mg/kg as 60-minute infusions Q2W versus docetaxel in patients with advanced NSCLC in a predominantly Chinese population. CheckMate 078 excludes patients with hepatitis B virus (HBV) infection, which represent a clinically relevant subgroup of patients in Asia; approximately 15% of patients with lung cancer in China are seropositive for HBV surface antigens. CheckMate 870 is an open-label, single-arm phase 3b study evaluating the safety and tolerability of flat-dose nivolumab 240 mg infused over 30 minutes Q2W in Asian patients with advanced or metastatic NSCLC, with or without HBV infection.
Method:
Approximately 400 patients in Asia with advanced or metastatic NSCLC and disease progression during or after 1 prior systemic platinum-based therapy will be enrolled; those with EGFR mutations (maximum of 40 patients) or ALK translocations should have received 2 prior systemic treatments including a tyrosine kinase inhibitor and chemotherapy. Nivolumab will be administered 240 mg over 30 minutes Q2W until disease progression or unacceptable toxicity, for a maximum of 24 months. Nivolumab may be reinitiated for subsequent disease progression and administered for up to 1 additional year. The primary objective is to evaluate the safety and tolerability of nivolumab in non–HBV-infected patients with NSCLC. The secondary objective is to assess safety and tolerability in all patients and in HBV-infected patients. Exploratory objectives include efficacy, patient-reported outcomes, health care resource utilization and direct medical costs, biomarker characterization in all patients, and viral load change and HBV reactivation rate in HBV-infected patients.
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-042 - PD-L1 and CD8 Expression in EGFR-Mutant or ALK-Rearranged Patients with Lung Cancer (ID 10407)
09:30 - 09:30 | Presenting Author(s): Yi-Long Wu
- Abstract
Background:
Several studies indicate no response to check-point inhibitors on non-small-cell lung cancer with either EGFR-mutant or ALK-rearranged patients,of whom majority of international clinical trials involving PD-1/L1 inhibitors excluded. No solid evidences to interpret the underlying mechanism of poor clinical benefit to patients through PD-1/L1 inhibitors with driver genes mutation.
Method:
From 2010 to 2016, 482 patients and 263 patients with clinically operable lung cancer and advanced lung cancer respectively were collected at Guangdong Lung Cancer Institute (GLCI). All patients have detected for EGFR as well as ALK status. CD8 and PD-L1 expression was scored by immunohistochemistry with SP142 antibody. Five years survival rate was also analyzed.
Result:
Patients were assigned to EGFR/ALK positive group (344 cases) or negative group (401 cases). EGFR/ALK positive group contains 5.52% PD-L1+/CD8+; 11.92% PD-L1-/CD8+; 18.90% PD-L1+/CD8- and 63.66% PD-L1-/CD8-. EGFR&ALK negative group contains 13.97% PD-L1+/CD8+; 6.98% PD-L1-/CD8+; 30.42% PD-L1+/CD8- and 48.63% PD-L1-/CD8-. In EGFR/ALK positive group, PD-L1+/CD8+ is lower but PD-L1-/CD8- is higher than that of EGFR&ALK negative group (P<0.001). Significant statistical differences of 5 years survival rate were observed between four subgroups in EGFR/ALK positive group (PD-L1+/CD8+:41.9%, PD-L1-/CD8+: 91.0%, PD-L1+/CD8-: 75.4%, PD-L1-/CD8-: 69.7%; P=0.003). And there were no survival differences in EGFR&ALK negative group((PD-L1+/CD8+: 66.5%, PD-L1-/CD8+: 76.9%, PD-L1+/CD8-: 62.3%, PD-L1-/CD8-: 70.6%; P=0.341).
Conclusion:
Immunotherapy with PD-1/L1 inhibitors may not be suitable for EGFR-mutant or ALK-rearranged lung cancer patients with little co-expression of PD-L1 and CD8. However, these patients with such diver genes mutation reveal the best survival in PD-L1-/CD8+ subgroup and the worst survival in PD-L1+/CD8+ subgroup. Figure 1
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P1.13 - Radiology/Staging/Screening (ID 699)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.13-001 - T1 Tumor(≪3cm) with Visceral Pleural Invasion Should Be Classified as T2a in the 8th TNM Classification for Lung Cancer (ID 9004)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
The eighth edition TNM classification for lung cancer subclassified T2 into T2a (>3 to ≤4cm) and T2b (>4 to ≤5cm). T1 tumor(<3cm) with visceral pleural invasion(VPI) should be classified as T2a or T2b remain unclear. To elucidate this, we analyzed the survival of non–small-cell lung cancer(NSCLC) patients from Surveillance, Epidemiology and End Results (SEER) registry and our institute.
Method:
Within the SEER database, we selected 24245 resected pN0 NSCLC patients from 2010 to 2013 with a special interest in the prognostic impact of VPI. The VPI was defined as including PL1 and PL2 according to the TNM system. The classification of T1 tumor with VPI was investigated via discriminative power of survival curves. The further validation set was selected from Guangdong Lung Cancer Institute (GLCI).
Result:
The overall survival (OS) and lung cancer specific survival (LCSS) of T1-VPI and each stage (size only) were compared. The survival differences were statistically significant between T1-VPI and T1c, as well as T1-VPI and T2b. There were no significant survival differences between T1-VPI and T2a (OS: p=0.706; LCSS: p=0.792). And we retrospectively collected pN0 NSCLC patients between 2011-2013 from GLCI. The progression-free survival(PFS) and OS differences were also observed between T1-VPI and other groups except T2a (PFS: p=0.852; OS: p=0.970).
Conclusion:
In the 8th TNM classification for lung cancer, in which T1 tumors with VPI are upgraded to T2a, rather than T2b. Figure 1
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-047 - The Main Treatment Failure Pattern for Completely Resected Stage II–IIIA (N1–N2) EGFR-Mutation Positive Lung Cancer (ID 9743)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
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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P2.03-054 - EGFR Mutation with Acquired C-MET Positive Reveals Potential Immunotherapeutic Vulnerabilities (ID 10436)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
There are few effective strategies for C-MET positive advance non-small-cell lung cancer(NSCLC) patients with epidermal growth factor receptor(EGFR) inhibitor resistance.The efficacy of PD-1 blockade immunotherapy and even the status of PD-L1 expression in such population is unclear.
Method:
Patients diagnosed as advanced NSCLC synchronously tested for EGFR status, expression of PD-L1 and C-MET at the Guangdong Lung Cancer Institute (GLCI) from 2015 to 2017 were collected.PD-L1 expression on tumor cells and immune cell was evaluated using a three-tiered grading system. C-MET positive was define as immunohistochemistry staining (2+/3+) in ≥ 50% of tumor cells. A chi-squared test was used to assess the relationships between C-MET positive and PD-L1 expression.
Result:
A total of 487 eligible cases were selected including 166 EGFR mutant and 321 wild type patients.In the general population(n=487),the difference of PD-L1 expression were observed between C-MET positive group and C-MET negative group (65.3% vs 31.7%, P=0.001),which was in accordance with the result from the Cancer Genome Atlas (TCGA) dataset (n=512,P<0.001).Furthermore,among the EGFR mutant patients (n=166), PD-L1 expression was showed in 58.1% of C-MET positive group and 28.5% of C-MET negative group,P value <0.001. Subsequently,T790M negative was identified in 55%(47/86) of EGFR TKI resistant patients (n=86).In this subgroup,a significant increase of PD-L1 expression was demonstrated in C-MET positive group compared to C-MET negative group(66.7% vs 34.6%,P=0.027).Finally, clinical efficacy of immunotherapy was further confirmed in 2 C-MET positive advanced lung adenocarcinoma patients with remarkable response to PD-1 blockade immunotherapy who had disease progression after C-MET inhibitors.Figure 1
Conclusion:
C-MET positive maybe associated with high PD-L1 expression in advanced NSCLC providing therapeutic insight into targeting the PD-1/PD-L1 pathway in EGFR inhibitor-resistant NSCLC with C-MET positive and T790M negative.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-006 - ADAURA: PhIII, Double-Blind, Randomized Study of Osimertinib vs Placebo in EGFR Mutation-Positive NSCLC Post-Tumor Resection (ID 8989)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
EGFR-TKIs are standard first-line therapy in patients with EGFR sensitizing mutation (EGFRm)-positive advanced NSCLC. EGFR T790M resistance mutation is observed in >50% of patients with acquired resistance to EGFR-TKIs. Osimertinib is a third-generation, irreversible, CNS-active EGFR-TKI selective for EGFRm and T790M, recommended in patients with T790M-positive advanced NSCLC who have progressed on first-line EGFR-TKIs. In a recent study (NCT01405079), gefitinib treatment in patients with resected EGFRm-positive NSCLC significantly increased disease-free survival (DFS) vs vinorelbine+cisplatin: median 28.7 vs 18.0 months (hazard ratio 0.60 (95% CI 0.42–0.87), p=0.005), warranting further investigation of EGFR-TKIs in this setting (Wu et al, J Clin Oncol 2017;35:suppl;abs8500). Osimertinib may prolong DFS in adjuvant EGFRm-positive NSCLC.
Method:
Trial Design ADAURA (NCT02511106) is a global, Phase III, double-blind, randomized study, assessing efficacy and safety of osimertinib vs placebo in patients with stage IB–IIIA non-squamous EGFRm-positive NSCLC with complete tumor resection. Approximately 700 patients from 210 sites will be randomized. A planned 60% of patients will be recruited from Asia, 40% from non-Asian countries; 70% stage II–IIIA, 30% stage IB. Patients must be adults ≥18 years (Japan/Taiwan: ≥20) with primary NSCLC staged post-operatively as IB/II/IIIA, and central confirmation of Ex19del or L858R (alone or combined with other EGFR mutations including T790M). Complete surgical resection of the primary NSCLC is mandatory; patients will have baseline CT scans within 28 days prior to treatment confirming radiographic absence of residual disease. Complete surgical recovery is required for randomization; treatment to start at least 4 weeks following surgery. Patients who have received radiation therapy, pre-operative chemotherapy, prior anticancer therapy or neoadjuvant/adjuvant EGFR-TKI treatment are exempt. Standard post-operative adjuvant chemotherapy, consisting of a platinum-based doublet for 4 cycles maximum, is allowed; no more than 10 and 26 weeks may have elapsed between surgery and randomization for patients who have not or have received adjuvant chemotherapy, respectively. Patients will be randomized 1:1 to once-daily osimertinib 80 mg or placebo and stratified by stage (IB/II/IIIA), mutation type (Ex19Del/L858R) and race (Asian/non-Asian). Treatment may continue for 3 years in absence of discontinuation criteria including disease recurrence. Primary objective is to assess the efficacy of osimertinib vs placebo, measured by investigator-assessed DFS. Secondary objectives include assessment of the safety profile of osimertinib vs placebo; DFS rate at 2, 3, 5 years; overall survival (OS); 5-year OS rate; health-related quality of life; pharmacokinetics. Estimated primary completion date (final DFS data collection date): July 2021.
Result:
Section not applicable.
Conclusion:
Section not applicable.
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P2.04-012 - First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study (ID 8841)
09:30 - 09:30 | Presenting Author(s): Yi-Long Wu
- Abstract
Background:
Ensartinib (X-396) is a novel, potent ALK TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Its phase 1/2 study (NCT01625234) demonstrated that ensartinib is well-tolerated and induces favorable responses in both crizotinib-naïve (ORR 80%) and crizotinib-resistant ALK+ NSCLC patients (ORR 71%), as well as those with CNS metastases.
Method:
In this global, phase 3, open-label, randomized study (eXalt3), approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia Pacific/other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity. Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint was progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.
Result:
Progress report Phase 3 recruitment began in June, 2016 and currently has 66 active sites in 21 countries. The duration of recruitment will be approximately 24 months. This study is registered with ClinicalTrials.Gov as NCT02767804.
Conclusion:
Section not applicable
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P2.08 - Locally Advanced Nsclc (ID 709)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.08-002 - A Nomogram for Predicting Underlying Beneficiaries for Resectable IIIA/N2 NSCLC Patients (ID 9260)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Stage IIIA/N2 non-small-cell lung cancer (NSCLC) is a heterogeneous condition with multidisciplinary approaches involved. For operable IIIA/N2 NSCLC, surgery combined with chemotherapy is considered as an optimal management. Yet no solid evidences to conduct appropriate treatment modality for operable IIIA/N2 NSCLC and patients through curative treatment still surfer unsatisfactory prognosis.
Method:
329 pathologically confirmed IIIA/N2 NSCLC patients through curative treatment were enrolled. Multivariate analysis was performed to select highly correlated clinical characters for nomogram. C-index and further survival analysis were given to validate the efficacy of the model.
Result:
Multivariate analysis indicate independent factors for overall survival including clinical stage, T stage, N stage, N2 status and tumor position which were then integrated into the model. The calibration curves showed moderate concordance between nomogram prediction and actual observation. Linear predictor of 3.5 was set to be the cutoff of the model through X-tile plot, and patients with linear predictor over 3.5 revealed significant longer median survival than those under 3.5 (59.90 vs. 24.90, log-rank P=0.0005). Figure 1Figure 2
Conclusion:
We established a nomogram that may well distinguish the potential subgroup of patients benefit from curative treatment modalities. Further perspective study should rigorously clarify the issue of which multimodality treatment to be chosen for IIIA/N2 NSCLC patients.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-005 - ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis (ID 7884)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).
Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.
Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).
Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.
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P3.01-012 - Symptom Impact of First-Line Dacomitinib versus Gefitinib in EGFR-Positive NSCLC: Results from a Randomized Phase 3 Study (ID 8569)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Patients with non-small-cell lung cancer (NSCLC) experience high disease burden due to many cancer-related symptoms (eg, cough, dyspnea, pain, and fatigue). Decreasing tumor burden may reduce/delay symptoms and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible, small-molecule inhibitor of EGFR/HER-1, HER-2, and HER-4 tyrosine kinases. In a global, multicenter, randomized, open-label phase 3 study (NCT01774721) for first-line treatment of NSCLC, dacomitinib improved the primary objective of progression-free survival per independent radiologic review (median, 14.7 vs 9.2 months; hazard ratio, 0.59; 95% confidence interval [CI], 0.47–0.74; P<0.0001) over gefitinib. Median duration of treatment was longer with dacomitinib than with gefitinib (67 vs 52 weeks, respectively).[1] A secondary objective was to explore HRQoL. Here, we report the impact of dacomitinib and gefitinib treatment on core lung cancer symptoms.
Method:
Patients were randomized 1:1 to receive oral dacomitinib (45 mg) or gefitinib (250 mg) once daily. Disease-related symptoms were measured using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13). Scores were summarized by the mean and 95% CI for each group and plotted over 30 cycles and at the end of treatment; the number of cycles (n=30) chosen for this analysis was not prespecified. Mean changes from baseline (cycle 1, day 1 [C1D1]) were reported for each group.
Result:
Between 9-May-2013 and 20-March-2015, 452 patients were randomly assigned to dacomitinib (n=227) or gefitinib (n=225). Baseline scores were similar between treatment arms. On-study completion rates were high, with >90% of patients answering all questions for most treatment cycles. Statistically significant improvements from baseline (95% CI excludes 0; no adjustment for multiplicity) for most cycles were seen in fatigue, pain, dyspnea, and cough in both arms. Improvements were reported as early as C1D8. Clinically meaningful improvements (≥10 points score change) were recorded for pain in chest (23/30 cycles) and cough (28/30 cycles) with dacomitinib and for cough (22/30 cycles) with gefitinib; hence, improvements appear to be more frequent with dacomitinib. Symptom burden at end of treatment was generally higher than during treatment. As treatment duration was longer with dacomitinib, key lung cancer symptom improvements were seen for a longer time in patients treated with dacomitinib.
Conclusion:
Dacomitinib, along with gefitinib, demonstrated favorable clinical benefit and improvements in key NSCLC symptoms. These findings are important when considering choice of therapy. Reference 1. Mok T, et al. J Clin Oncol. 2017;35(Suppl):abstract LBA9007.
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-036 - A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 9251)
09:30 - 09:30 | Presenting Author(s): Yi-Long Wu
- Abstract
Background:
In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR=0.58; p=0.001; LL6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR=0.73; p=0.017; TTF: 13.7 vs 11.5 months, HR=0.73, p=0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC.
Method:
In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review).
Result:
At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/≥2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2–38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade ≥3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n=50; 10.4%) and rash/acne (n=38; 7.9%) were the most common (≥5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4–17.5]) was 3 months longer than PFS (12.1 months [10.8–13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months).
Conclusion:
The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinib-related AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyses of this trial.
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P3.01-044 - Erlotinib vs Chemotherapy in EGFR Mut+ NSCLC: OS in Three Phase III Trials Adjusting for Post-Progression Treatment Crossover (ID 9462)
09:30 - 09:30 | Presenting Author(s): Yi-Long Wu
- Abstract
Background:
In EURTAC, ENSURE and OPTIMAL, first-line erlotinib was associated with higher response rates and improved PFS versus chemotherapy in EGFR Mut+ NSCLC. OS benefit was not observed, possibly due to high crossover. We present statistical analyses of OS adjusting for crossover in the three studies.
Method:
Rank Preserving Structural Failure Time (RPSFT) analysis is a retrospective statistical methodology that estimates the effect of active treatment and then removes that effect from the control patients, during the period of active treatment. Separately, post-hoc OS analyses were conducted on non-randomized subgroups of patients who received a single line of therapy, chemotherapy only or erlotinib only; or a sequence, chemotherapy followed by TKI or erlotinib followed by chemotherapy. Impact of sequencing on OS was evaluated (Kaplan-Meier methodology).
Result:
RPSFT analyses (Table) show OS was numerically longer with erlotinib versus chemotherapy in EURTAC and ENSURE. OS was not longer with erlotinib in OPTIMAL, possibly due to low treatment adherence in the erlotinib arm, where >50% of patients refused chemotherapy or did not complete four cycles. In the non-randomized analyses, patients receiving erlotinib as the sole treatment had longer OS versus patients treated with only chemotherapy, in all three studies. Patients who received erlotinib followed by chemotherapy had longer OS versus patients who received chemotherapy followed by erlotinib in EURTAC and ENSURE. Patients who received chemotherapy followed by erlotinib in OPTIMAL had longer OS than patients who received erlotinib then chemotherapy, again possibly due to erlotinib patients refusing the full extent of post-progression chemotherapy.
Conclusion:
RPSFT analysis showed increased OS between erlotinib and chemotherapy in EURTAC and ENSURE versus the original ITT analysis. Similar impact in OPTIMAL was not apparent. Post-hoc analysis of non-randomized subgroups (patients treated with a single therapy) showed longer OS for erlotinib versus chemotherapy, notwithstanding caveats of such an approach.OS (RPSFT analysis) Study Treatment Group N Median OS, months HR (95% CI) EURTAC Erlotinib 86 22.9 0.64 (0.44, 0.95) Chemo 88 15.4 ENSURE Erlotinib 110 26.3 0.47 (0.32, 0.69) Chemo 107 17.1 OPTIMAL Erlotinib 82 22.7 1.78 (1.21, 2.64) Chemo 72 30.5 Influence of sequencing on OS in patients who crossed over (Kaplan-Meier analysis) Study Treatment Group N Patients crossing over, % Median OS, months EURTAC Erlotinib/chemo 49 57 24.9 Chemo/TKI 72 82 22.6 Erlotinib alone 37 17.2 Chemo alone 16 1.6* ENSURE Erlotinib/Chemo 69 63 27.0 Chemo/TKI 89 83 25.6 Erlotinib alone 41 23.2 Chemo alone 18 22.9 OPTIMAL Erlotinib/ Chemo 49 60 26.8 Chemo/TKI 52 72 31.4 Erlotinib alone 33 18.6 Chemo alone 20 11.2 *There were 5 deaths and 5 censored observations that occurred in the first two months
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P3.01-051 - Dramatic Response to Afatinib in EGFR-Mutant Lung Adenocarcinomas After Resistance to First-Generation EGFR Inhibitors: A Brief Report (ID 9706)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
T790M inhibitor, a third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was significantly superior to chemotherapy for EGFR-mutant patients with advanced non-small-cell lung cancer (NSCLC) harboring T790M mutation after resistance to the first-generation EGFR-TKIs. However, for those without acquired T790M mutations or MET amplification, few data showed whether the second-generation EGFR-TKI could overcome resistance to the first-generation EGFR-TKIs.
Method:
EGFR mutation was detected by amplification refractory mutation system (ARMS) technology. Overexpression of MET was determined by immunohistochemistry (IHC), and MET amplification was detected by FISH. Next generation sequencing (NGS) was used to test tumor tissues before and after resistance to TKIs.
Result:
Patient 1 was a 53-year-old Asian male, who underwent surgery followed by adjuvant chemoradiotherapy with an 11 months of disease-free survival. A biopsy was performed and revealed an activating deletion mutation in exon 19 of the EGFR. He started gefitinib 250mg once daily and achieved an initially good partial response (PR) followed by continuously stable disease for a progression-free-survival (PFS) about 29 months. A rebiopsy showed that exon 19 deletion mutation still existed without an acquired T790M mutation or MET amplification. He refused to receive chemotherapy so we prescribed afatinib 40mg daily. He then achieved a dramatic PR 23 days later which was confirmed 1.5 months after that. We sent tumor tissue of the patient before and after TKI therapy for NGS, the result showed a decreasing abundance of EGFR exon 19 deletion without T790M mutation, MET amplification and Her2 mutation/amplification. Patient 2 was a 63-year-old Asian female harboring EGFR exon 20 insertion (A763-Y764 ins), who received first and second lines of chemotherapy with short PFSs. He was enrolled in the trial of allitinib (AST-1306) as the third line therapy with the best response of stable disease(SD) and the PFS of 7 months. A later rebiopsy showed the strong overexpression of MET, but the forth-line therapy crizotinib failed. He then received chemotherapy as the-fifth line therapy, 4 cycles later he progressed. So he started afatinib 40mg daily. His symptoms were relieved significantly 5 days later, and PR was confirmed 1.5 months later.
Conclusion:
Afatinib might overcome resistance to the first-generation EGFR-TKIs for EGFR-mutant patients with advanced NSCLC without acquired T790M mutation or MET amplification. Further investigations are warranted.
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P3.01-063 - Concomitant EGFR Mutation and ALK Rearrangement in Non-Small-Cell Lung Cancer (ID 10058)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
The concomitance of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). We investigated the factors associated with the efficacy of targeted therapy and resistance mechanisms in EGFR/ALK co-altered NSCLCs.
Method:
EGFR mutation was identified with direct sequencing or Scorpion amplification refractory mutation system (ARMS). Relatively low EGFR-mutant abundance is considered as sequencing (-)/ARMS (+), while high abundance as sequencing (+). ALK-positive is assessed with any of the 3 methods: fluorescence in situ hybridization (FISH), rapid amplification of cDNA ends -coupled polymerase chain reaction and sequencing or Ventana immunohistochemistry (IHC). Next-generation sequencing was employed to analyze genetic profiles in patients with specimens before and after targeted therapy.
Result:
From December 2011 to December 2016, sixteen patients were identified with concomitant EGFR/ALK co-alterations, accounting for 0.6% (16/2632) in NSCLC patients, 1.8% (16/867) in EGFR-mutant and 8.6% (16/185) in ALK-positive patients. Five ALK-IHC (-)/FISH (+)/EGFR (+) patients with EGFR-TKIs experienced 3 PR, 1 SD and 1 waitiing for response evaluation, with median PFS of 11 months. Three with relatively low EGFR-mutant abundance achieved PR with crizotinib, while three with relatively high EGFR-mutant abundance obtained 2 PR and 1 SD with EGFR-TKIs. Spatial and inter-tumoral heterogeneity was observed in one EGFR/ALK co-altered patient. (Figure 1B) Two patients with T790M, one with Met pathway activation and two with loss of EGFR mutation were found after resistance to EGFR-TKIs. One with KRAS mutation was found pre- and post-EGFR-TKIs. ALK_F1174C mutation was observed in one patient after progression to crizotinib and ALK_G1202R mutation after resistance to ceritinib.Figure 1
Conclusion:
ALK protein expression, EGFR mutation abundance and tumor heterogeneity were associated with efficacy of targeted treatment for EGFR/ALK co-altered patients. Most mechanisms resistance to EGFR-TKIs and crizotinib were similar to those in typical EGFR mutation and ALK rearrangement respectively.
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P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 09:30 | Author(s): Yi-Long Wu
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
