Virtual Library
Start Your Search
Fred R. Hirsch
Moderator of
-
+
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)
-
+
JCSE 01.03 - The Science of Immunotherapy (ID 8220)
08:00 - 08:20 | Presenting Author(s): Roy S. Herbst
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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)
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
- 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.
-
+
- 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.
-
+
- 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.
-
+
- 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.
-
+
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.
-
+
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.
-
+
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.
-
+
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
-
+
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.
-
+
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.
-
+
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
-
+
MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
-
+
MA 05.14 - Differential Expression of IFN-Stimulating DNA Sensors STING and cGAS in Lung Cancer Subtypes (ID 9578)
17:10 - 17:15 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Background:
STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade.
Method:
Section not applicable
Result:
We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359).
Conclusion:
This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
-
+
MA 13.02 - Comprehensive Genetic Analysis Related to PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)
15:50 - 15:55 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Background:
Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).
Method:
Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.
Result:
The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.
Conclusion:
PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MS 18 - Biomarker for Anti-PD-L1 Therapy (ID 540)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichi Ishikawa, Sanja Dacic
- Coordinates: 10/17/2017, 15:45 - 17:30, Main Hall
-
+
MS 18.02 - An Update on the BLUEPRINT and Related Projects (ID 8123)
16:00 - 16:15 | Presenting Author(s): Fred R. Hirsch
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 2
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
-
+
OA 07.03a - Impact of Tumor Mutation Burden on the Efficacy of Nivolumab or Nivolumab + Ipilimumab in Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 032 (ID 11063)
16:15 - 16:25 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Background:
CheckMate 032 is a phase 1/2 clinical trial evaluating nivolumab ± ipilimumab in solid tumors, including small cell lung cancer (SCLC). Initial results have shown durable responses and encouraging survival, with benefit seen regardless of PD-L1 status. There is a need for improved biomarkers in SCLC. SCLC is nearly universally found in smokers and is characterized by high tumor mutation burden (TMB). The association of high TMB and clinical benefit from nivolumab ± ipilimumab in patients with SCLC was evaluated in an exploratory analysis of CheckMate 032.
Method:
CheckMate 032 evaluated nivolumab ± ipilimumab in non-randomized and randomized cohorts, which were pooled for this analysis. Whole exome sequencing (WES) was conducted on tumor and matched blood samples. TMB was defined as the total number of nonsynonymous somatic mutations. For the exploratory analyses, patients were equally divided into TMB tertiles (defined as low, medium, and high). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods.
Result:
Among 401 patients in the intent-to-treat (ITT) population, 211 (53%) had an evaluable TMB result for these analyses (86% of the 246 patients with tissue available to attempt WES). Baseline characteristics and outcomes were similar between the ITT and TMB-evaluable populations. In TMB-evaluable patients treated with nivolumab (n=133), objective response rate (ORR), PFS, and OS were improved in the high TMB cohort vs the medium and low TMB cohorts (ORR: 21.3% vs 6.8% and 4.8%; 1-year PFS: 21.2% vs 3.1% and not calculable; 1-year OS: 35.2% vs 26.0% and 22.1%). Similar benefits were seen in TMB-evaluable patients treated with nivolumab + ipilimumab (n=78) in the high vs medium and low TMB cohorts (ORR: 46.2% vs 16.0% and 22.2%; 1-year PFS: 30.0% vs 8.0% and 6.2%; 1-year OS 62.4% vs 19.6% and 23.4%).
Conclusion:
In patients with SCLC, efficacy with nivolumab ± ipilimumab was enhanced in those with high TMB. Among patients with high TMB, ORR and 1-year OS rates were approximately double with nivolumab + ipilimumab compared with nivolumab monotherapy. TMB has a potential role as a biomarker in lung cancer. Optimization of TMB cutoff and prospective investigation are warranted.Acknowledgements: All authors contributed to and approved the abstract; writing and editorial assistance was provided by Beth Burke, PhD, CMPP, of Evidence Scientific Solutions, funded by Bristol-Myers Squibb.Trial Registration: clinicaltrials.gov, NCT01928394
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 07.06 - Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions (ID 9102)
16:50 - 17:00 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Background:
Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.
Method:
We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.
Result:
Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1
Conclusion:
These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
-
+
OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
12:05 - 12:15 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.03-052 - Comparing EGFR-TKI with EGFR-TKI plus Chemotherapy as 1st Line Treatment in Advanced NSCLC Patients with Both Mutated EGFR and Bim Polymorphism (ID 10516)
09:30 - 09:30 | Author(s): Fred R. Hirsch
- Abstract
Background:
Not all advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations could get benefit from 1[st] line treatment of EGFR tyrosine kinase inhibitors (TKIs). Our previous study indicated that B-cell chronic lymphocytic leukemia/lymphoma-like 11 (Bim) deletion polymorphism was about 10% and was significantly associated with a poor clinical response to EGFR-TKIs in EGFR mutation-positive NSCLC. This retrospective study compared efficacy and tolerability of the EGFR-TKI alone versus EGFR-TKI plus chemotherapy as the 1[st] line treatment in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism.
Method:
Main included criterias were patients older than 18 years, histologically confirmed stage IIIB or IV NSCLC, EGFR mutation-positive (exon 19 deletion or 21 L858R mutation) and Bim polymorphism. Patients received gefitinib 250mg orally a day or gefitinib together with up to 4 cycles of pemetrexed/gemcitabine and platinum until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival (PFS); the second endpoint included objective response rate (ORR), overall survival (OS) and toxicity.
Result:
From June 2014 to September 2016, 65 patients were enrolled into this trial. 36 of them received gefitinib, and 29 received gefitinib plus pemetrexed/gemcitabine and platinum. Median PFS was significantly longer in EGFR-TKI plus chemotherapy-treated patients than in EGFR-TKI (7.2 [95% CI 5.35-9.05] vs 4.6 [4.01-5.19] months; p=0.008). The ORR was significantly lower in EGFR-TKI than in EGFR-TKI plus chemotherapy-treated patients (38.9% vs. 65.5% p=0.046). EGFR-TKI plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKI (8 neutropenia, 4 thrombocytopenia vs. no any event). Figure 1
Conclusion:
Compared with EGFR-TKI, EGFR-TKI plus chemotherapy conferred a significant higher ORR and longer PFS in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism. An open-label, multicenter, randomized, phase 2 study is ongoing to validate these results in our institute ( NCT03002844).
-
+
P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.02-011 - Clinical and Molecular Features of Lung Cancers with Increased FGFR1 mRNA and/or Gene Copy Number (ID 8825)
09:30 - 09:30 | Author(s): Fred R. Hirsch
- Abstract
Background:
Lung cancer cell line data suggest FGFR1 status defined by FGFR1 mRNA levels and FGFR1 gene copy number can predict sensitivity to FGFR tyrosine kinase inhibitors (TKIs).
Method:
A phase II biomarker preselected trial of ponatinib, an FGFR1, FGFR2, and FGFR4 targeted TKI was designed. Patients with metastatic EGFR- and ALK-negative lung cancers (both NSCLC and SCLC) were pre-screened for FGFR1 mRNA levels by in-situ hybridization (ISH) and FGFR1 gene copy number by silver in-situ hybridization (SISH). Positivity criteria for ISH were defined as a score of 3 (Dot clusters seen in 1 to <10% tumor cells; otherwise >10 dots/cell in ≥ 10% tumor cells), or 4 (Dot clusters seen in ≥ 10% of tumor cells). Positivity for SISH was defined as an average of ≥ 4 FGFR1 signal clusters/nucleus or FGFR1/CEN8 ratio ≥ 2.0. Clinical factors including sex, histology, age and sites of metastases at diagnosis of stage IV disease, smoking status, status of other known molecular drivers, and response to initial platinum-doublet therapy for stage IV disease were collected.
Result:
From 11/2013 to 05/2017, the study has pre-screened 163 patient samples for FGFR1 ISH and SISH. Thirty-eight (23.3%) had insufficient tissue; four had incomplete clinical or FGFR1 information. Clinical variables according to FGFR1 ISH/SISH status (n=121) are summarized in Table 1. Impact of alternate positivity cut-points, outcomes of patients treated with ponatinib and survival analysis according to ISH/SISH subgroups will be presented. Figure 1
Conclusion:
Although the numbers were small, the FGFR1 ISH+/SISH+ subgroup had a greater percentage small cell histology, liver metastases at diagnosis and male sex compared to other FGFR1 subgroups. FGFR1 ISH and/or SISH positivity can overlap with other known oncogenic drivers suggesting that the initial cut-points for FGFR1 positivity used may be too low to identify a true FGFR1 addicted state.
-
+
P2.02-070 - C-MET as a Biomarker in Patients with Surgically Resected Non-Small Cell Lung Cancer (ID 10323)
09:30 - 09:30 | Author(s): Fred R. Hirsch
- Abstract
Background:
c-MET protein overexpression has been proposed as potential prognostic as well as predictive biomarker for targeted therapy in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet and no clear cut-off value exists for immunohistochemistry (IHC) score.
Method:
We designed a retrospective cohort study, consisting of 725 patients with surgically removed non-small cell lung cancer. IHC was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue adjacent to the tumor, using a specific antibody against human c-MET (MET PharmDx). IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored.
Result:
c-MET H-score over 20 had a significant protective impact on OS in the multivariate analysis in the whole study population, both as continuous variable (p=0.014), as well as dichotomous variable with HR=0.79 (95%CI: 0.64-0.97, p-value = 0.022). The prognostic effect of c-MET H-score over 20 was stronger in patients who received adjuvant treatment with a HR=0.61 (95% CI: 0.40-0.93, p-value=0.022). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant even in the univariate analysis (HR=0.60, 95% CI: 0.43-0.83, p-value=0.002).
Conclusion:
c-MET H score > 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score > 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.
-
+
P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.03-019 - Sizing Capillary Electrophoresis with PCR to Detect Various EGFR Exon 19 Deletions in Non-Small Cell Lung Cancer (ID 8614)
09:30 - 09:30 | Author(s): Fred R. Hirsch
- Abstract
Background:
This study points out an issue of PCR-based methods to detect exon 19 deletions. PCR methods are used for clinical examination, because they are useful, rapid and cost-effective to detect EGFR mutations. Exon 19 deletions are most important among EGFR mutations to dictate EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small cell lung cancer (NSCLC), and have various species. The sensitive PCR methods select major exon 19 deletions, but cannot detect unusual variants. We investigated the clinical significance of minority exon 19 deletions.
Method:
A series of 73 NSCLC patients, which were treated with EGFR-TKI for recurrent disease after they had undergone surgery from 1992 to 2004. In all cases, Microdissenction and direct sequence were performed. Scorpion Amplification Refractory Mutation System (ARMS) and cobas version 2.0, as sensitive PCR methods, were performed in 47 patients along with sizing capillary electrophoresis for the exhaustive detection of exon 19 deletions.
Result:
EGFR mutations were detected from 35 patients (47.9%), which were one exon 18 mutation, 23 exon 19 deletions, and 11 exon 21 mutations in all 73 cases. The catalog of somatic mutation in cancer (COSMIC) database included 174 different exon 19 deletions in 4190 submitted cases at December 2014. E746_A750 deletion was most common deletion of exon 19, accounting for 70% of the total exon 19 deletions (2931/4190). Predicted frequency of exon 19 tested by Scorpion-ARMS was 81.6% (3419/4190), and that of cobas version 2.0 had 82.5% (3457/4190) in the detection of various exon 19 deletions. In clinical samples of this study, Scorpion-ARMS and cobas version 2.0 failed to detect four exon 19 deletions, in two squamous cell carcinomas (EGFR-TKI effects were stable disease and no assessable patient) and two papillary adenocarcinomas (EGFR-TKI effects were stable disease and no assessable patient). One of papillary adenocarcinoma had minority deletion ‘T751_I759 deletion and insertion S’, which had long stable disease for 43.4 months in EGFR-TKI therapy. Sizing capillary electrophoresis was able to detect this deletion.
Conclusion:
This study suggests sizing capillary electrophoresis is necessary for the exhaustive detection of exon 19 deletions, and may identify tumors responsive to EGFR-TKIs therapy, especially those with unusual deletions.
-
+
PL 03 - Immunology in Lung Cancer Update 2017 (ID 584)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:David P Carbone, Keunchil Park
- Coordinates: 10/18/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
-
+
PL 03.03 - Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples (ID 7836)
09:05 - 09:25 | Author(s): Fred R. Hirsch
- Abstract
- Presentation
Abstract:
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
