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Caicun Zhou
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MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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MA02.01 - ROS1 Gene Rearrangements Are Associated with an Exaggerated Risk of Peri-Diagnosis Thromboembolic Events (ID 12442)
10:30 - 10:35 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Based on clinical observation, we hypothesized that ROS1 gene-rearranged non-small cell lung cancer (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. A multicenter, retrospective cohort study of TEE in advanced ROS1+, KRAS+, ALK+ and EGFR+ NSCLC was conducted.
a9ded1e5ce5d75814730bb4caaf49419 Method
Venous (DVT / PE) and arterial (MI/TIA/CVA) TEE within +/- 365 days of diagnosis of ROS1+, KRAS+, ALK+ or EGFR+ advanced NSCLC at 4 academic centers in USA and China from October 2002 to January 2018 were captured. The primary endpoint was the incidence of TEE in ROS1+ compared to KRAS+ NSCLC as a control group within +/- 90 days of diagnosis. Secondary endpoints compared TEE incidence between ROS1+ and ALK+, and ROS1+ and EGFR+. Fine-Gray Model was used to detect differences in TEE incidence while accounting for death as a competing risk.
4c3880bb027f159e801041b1021e88e8 Result
105 ROS1+, 101 ALK+, 112 EGFR+, and 114 KRAS+ NSCLC patients were enrolled. Incidence rate of TEE within +/- 90 days of diagnosis was 30.5% (32/105), 12.9% (13/101), 7.1% (8/112), and 12.3% (14/114) in the respective molecular cohorts. Compared to the ROS1+ cohort, the risk of TEE was significantly lower in the three other cohorts (KRAS+ HR 0.334, 95% CI: 0.18-0.62, p=0.001; ALK+ HR 0.357, 95% CI: 0.188-0.68, p=0.002; EGFR+ HR 0.193, 95% CI: 0.089-0.421, p<0.001) (Figure 1). First event TEEs were venous as opposed to arterial in 59.5% (22/37) ROS1+, 87.1% (27/31) ALK+, 80.6% (25/31) EGFR+, and 80% (16/20) KRAS+ cases. The median time (Interquartile Range) to TEE from the time of diagnosis for ROS1+/ALK+/EGFR+/ KRAS+ was 0 days (-6.75 to 7.0), 0 days (-20.0 to 35.0), 0.50 days (-43.7 to 21.3), and 13 days (0.49 to 32.0), respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
Among common molecular subtypes of NSCLC, ROS1+ oncogene is associated with a significantly higher risk of developing TEE within +/- 90 days of advanced NSCLC diagnosis.
6f8b794f3246b0c1e1780bb4d4d5dc53
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MA06 - PDL1, TMB and DNA Repair (ID 903)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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MA06.11 - Distinct Origins of Lymphatic and Brain Metastasis in Lung Cancer (ID 13333)
14:40 - 14:45 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Generally, distant metastases are seeded by lymph node metastases in most solid tumors. This concept provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. However, a recent study found that lymphatic and distant metastases could arise from independent subclones in the primary colorectal cancer. The current study aimed to investigate the origins of lymphatic and brain metastasis in lung cancer.
a9ded1e5ce5d75814730bb4caaf49419 Method
39 samples from twelve patients with primary lung cancer and brain metastases were identified. Three of them had the matched lymph node metastases. All tissues and matched peripheral blood samples were collected before any systemic treatment. Whole-exome (>150×) sequencing were conducted on these samples.
4c3880bb027f159e801041b1021e88e8 Result
Compared to the primary lesions, both brain and lymph node metastases had the significantly different patterns of somatic genome alterations. The mutational landscape of brain metastases was also distinctly different from matched lymph node metastases. Primary lesions, matched brain and lymph node metastases showed the similar mutation pattern in terms of transition and transversion, and all of samples displayed a higher percentage of C>T transition. Brain metastases had numerically higher tumor mutational burden (TMB) than primary lesions but it did not reach the statistical significance. Notably, we observed the totally distinct origins of lymphatic and brain metastasis in all three matched cases.
8eea62084ca7e541d918e823422bd82e Conclusion
The current evidence suggested that brain metastases and matched lymph node metastases had different mutational landscape in patients with lung cancer. Brain metastases had higher TMB than their primary lesions. Lymphatic and brain metastasis had distinct origins in lung cancer. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung cancer and brain metastases.
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MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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MA09.11 - Genomic Landscape and its Correlation with TMB, CD8 TILs and PD-L1 Expression in Chinese Lung Squamous Cell Carcinoma (ID 12370)
16:25 - 16:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
The current study aimed to comprehensively depict the genomic landscape of Chinese lung squamous cell carcinoma (LSCC) and investigate its correlation with tumor mutation burden (TMB), CD8 tumor infiltrating lymphocytes (TILs) density and PD-L1 expression.
a9ded1e5ce5d75814730bb4caaf49419 Method
Whole-exome sequencing (WES) were performed on tumor tissue collected from 189 patients with surgically resected LSCC. TMB was defined as total number of nonsynonymous single nucleotide and indel variants. High TMB was defined as greater than 75th percentile. CD8+ TILs and PD-L1 expression were assessed by immunohistochemistry. We determined the 5% of CD8+ TIL or PD-L1 expression as the cut-off point for high/low CD8+ TIL or PD-L1 positive/negative expression.
4c3880bb027f159e801041b1021e88e8 Result
We found recurrent mutations (>5%) in 8 genes, including TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN and FBXW7. FGFR1 and PIK3CA amplifications were found in 19% and 11% of samples. 24.9% of patients had high TMB. Except for expected differences by smoking status, baseline clinical variables were similar between those with high and low TMB. Interestingly, FGFR1, PIK3CA or SOX2 amplification was independently associated with higher TMB (P=0.020, P=0.017, P=0.029; respectively). Patients with copy number variations had significantly higher TMB than those without (P=0.009). Positive PD-L1 and CD8+ TILs expression were identified in 24.3% and 78.8% of all cases. Baseline features were comparable between those with positive and negative CD8+ TIL or PD-L1 expression. NFE2L2 mutation and PIK3CA amplification were independently associated with significantly higher PD-L1 expression (P=0.003, P=0.014; respectively). TP53 mutations were associated with higher CD8+ TILs expression (P=0.008), but FGFR1 amplification was correlated with lower CD8+ TILs expression (P=0.042). Of note, there is no association between TMB and PD-L1 expression (r=0.052, P=0.476), or CD8+ TILs expression (r=0.026, P=0.718). None of TMB, PD-L1 and CD8+ TIL expression could individually predict overall survival (OS). However, combination of TMB and PD-L1 could stratify total populations into two groups with distinct prognosis. Patients with negative PD-L1 expression and high TMB had the worst prognosis (P=0.008). Additionally, combination of TMB and CD8+ TIL expression could also divide total populations into two groups with different prognosis (worst prognosis in negative CD8+ TIL expression and high TMB, P=0.022).
8eea62084ca7e541d918e823422bd82e Conclusion
This was the first and most large-scale study to comprehensively portray genomic landscape of Chinese LSCC. The current study provides several meaningful and referential findings for the future design of clinical trials in LSCC, especially immunotherapy based on immune checkpoint inhibitors.
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.11 - Discrepancy of Tumor Neoantigen Burden Between Primary Lesions and Matched Metastases in Lung Cancer (ID 12289)
11:40 - 11:45 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Personalized vaccine based on tumor neoantigens showed the striking antitumor effect on several solid tumors, suggesting its significant and potential role in curing cancer. However, whether tumor neoantigens identified from primary lesions were similar to their matched metastases remain unknown. Here, we aimed to compare the tumor neoantigen burden (TNB) between primary lesions and matched metastases in lung cancer.
a9ded1e5ce5d75814730bb4caaf49419 Method
Primary lung cancers, matched metastatic sites and peripheral blood (10 mL, EDTA) were collected before any systemic therapy as part of the standard clinical care. Genomic DNA was extracted from all included samples. The matched peripheral blood leukocytes were used as the source for germline DNA control. DNA libraries were subjected to whole-exome capture and then sequenced on an Illumina HiSeq X-TEN platform. The criteria for tumor neoantigen identification were tumor specific mutations (missense, frameshift, inframe insertion or deletions), fold change > 10, high predicted affinity (IC50 < 500 nM) and predicted peptide of 9-10 amino acids in length.
4c3880bb027f159e801041b1021e88e8 Result
Totally, 14 cases with matched lung primary lesions and metastases were enrolled, including 10 patients with liver metastases and 4 with brain metastases. A wide range of TNB were identified in both primary lesions (median 157, range 21-1156) and metastases (median 135, range 35-1902). We observed a large discrepancy of TNB between primary lesions and matched metastases, with a median unique percentage of 82.20% (74.03%-95.24%) in primary lesions and 84.50% (77.45%-97.14%) in metastases. In patients with brain metastases, primary lesions had a percentage of 90.98% (79.57%-95.24%) unique tumor neoantigens, while metastases had 86.03% (77.45%-97.14%). For those with liver metastases, the median unique percentage of tumor neoantigens was 80.58% (74.03%-88.66%) in primary lesions and 83.35% (78.49%-91.14%) in metastases. Smoking history and histological types had no impact on the discrepancy of TNB (P > 0.05, P > 0.05; respectively). TNB of primary lesions was similar to matched metastases (P = 0.733). However, primary lesions of brain metastases had a significantly higher percentage of unique tumor neoantigen than that of liver metastases (P = 0.025).
8eea62084ca7e541d918e823422bd82e Conclusion
There is a large percentage of different tumor neoantigens between primary lesions and matched metastases in lung cancer. Whether this discrepancy could affect the efficacy of following personalized vaccine on primary lesions or matched metastases need further investigation.
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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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MA15.09 - Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR Mutant Advanced NSCLC Patients Treated with First-Line EGFR-TKIs (ID 13236)
14:30 - 14:35 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
We proposed a non-invasive, folate receptor (FR)-based circulating tumor cell (CTC) assay counts to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutant non-small cell lung cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients were enrolled and three milliliter (mL) of blood were obtained prior to initial treatment, after one month, and follow-up every two months hereafter. CTCs were isolated based on negative enrichment by immunomagnetic beads and detected by a ligand-targeted polymerase chain reaction (LT-PCR) method.
4c3880bb027f159e801041b1021e88e8 Result
232 patients with EGFR mutations treated with first-line EGFR-TKIs were included. The objective response rate (ORR) of patients with low baseline CTC level (<20.5 FU/3 mL) were significantly higher than those with high baseline CTC level (≥20.5 FU/3 mL) (55.8% vs 38.5%, P = 0.030). Moreover, patients with low baseline CTC level had a markedly longer progression-free survival (PFS) than those with high baseline CTC level (HR = 0.50, P < 0.001). This difference remained significant after multivariate analysis (P = 0.003). Dynamic change of CTC value was significantly associated with partial response (PR) (P = 0.042) and stable disease (SD)/progression disease (PD) (P = 0.032). Of note, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before CT scanning, median: 113 days; range: 45 to 169 days.
Table 1. Clinical and molecular characteristics of included patients.
CTC < 20.5 (n = 165)
%
CTC > 20.5 (n = 52)
%
P value
Age, years
Median
61
63
Range
27-85
40-83
Sex
Male
79
47.88
28
53.85
0.453
Female
86
52.12
24
46.15
Smoking status
Never-smoker
122
73.94
35
67.31
0.351
Current/ever Smoker
43
26.06
17
32.69
Pathological type
ADC
150
90.91
47
90.38
0.909
ADS
4
2.42
1
1.92
NOS
13
7.88
4
7.69
Clinical stage
Ⅲb
9
5.45
3
5.77
0.794
Ⅳ
156
94.55
49
94.23
Distant metastases
Brain
43
26.06
15
28.85
0.953
Bone
78
47.27
21
40.38
Liver
10
6.06
1
1.92
Other sites
109
66.06
34
65.38
No metastases
12
7.27
3
5.77
Mutation type
19DEL
76
46.06
24
46.15
0.012
L858R
79
47.88
19
36.54
Rare mutations
10
6.06
9
17.31
Response rate
Complete response
0
0.00
0
0.00
Partial response
92
55.76
20
38.46
Stable disease
48
29.09
21
40.38
Progressive disease
25
151.50
11
21.15
Disease control rate
140
84.85
41
78.85
0.310
Objective response rate
92
55.76
20
38.46
0.030
ADC, adenocarcinoma; ADS, adenosquamous carcinoma; CTC, circulating tumor cell.
8eea62084ca7e541d918e823422bd82e Conclusion
The current evidences suggest that FR-positive CTCs can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutant NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to CT scanning.
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MA15.10 - Loss of T790M Mutation is Associated with Early Progression to Osimertinib in Chinese Advanced NSCLC Patients Harboring EGFR T790M (ID 13645)
14:35 - 14:40 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Osimertinib has demonstrated striking superior efficacy in non-small cell lung cancer (NSCLC) patients detected acuqired T790M mutation as resistant mechanism to upfront early-generation EGFR-TKIs. However, not all the T790M positive tumors are homogeneously sensitive to osimertinib, and the duration of response often varies. Previous studies suggest that loss of T790M mutation upon progression is related to decreased therapeutic benefit from osimertinib. The aim of this study is to investigate the association of T790M-mutant status and clinical outcomes after osimertinib treatment in Chinese NSCLC patients harboring acquired EGFR T790M mutation.
a9ded1e5ce5d75814730bb4caaf49419 Method
We reviewed the electric medical records of all patients receiving osimertinib monotherapy after detected acquired T790M mutation in rebiopsy after resistant to prior EGFR-TKIs, and underwent re-rebiopsy again upon progression to osimertinib at our hospital. Detailed clinicopathologic characteristics and response data were collected for all patients.
4c3880bb027f159e801041b1021e88e8 Result
From January 2014 to December 2016, 230 patients were confirmed T790M mutation positive for acquired resistance to early-generation EGFR-TKIs (gefitinib, erlotinib, afatinib and icotinib). Among them, 90 patients received osimertinib monotherapy as subsequent treatment. Out of the patients, 84 (93.3%) were eligible for osimertinib-resistance analysis, and 31 (34.4%) patients underwent T790M detection in biopsy after disease progression to osimertinib. The most commonly used biopsy sample were tumor tissue, peripheral blood and hydrothorax. 16 patients remained T790M positive, while 15 patients lost T790M mutation in their re-rebiopsy samples. Loss of T790M upon progression was significantly associated with shorter duration of response to osimertinib (median time 5.93 vs 11.87 m, HR:0.325, 95%CI: 0.087 to 0.45, p=0.0005), while overall survival (OS) was not statistically different between T790M-loss and -remain groups. The objective response rates were also similar in two groups (85% and 100%, respectively). In multivariate analysis, T790M mutation loss remained significantly associated with early progression to osimertinib.
8eea62084ca7e541d918e823422bd82e Conclusion
Loss of T790M mutation was associated early progression to osimertinib in Chinese NSCLC patients harboring acquired T790M mutation. Dynamic detection during osimertinib treatment may be a potential strategy to timely reveal disease progression.
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.05 - Comprehensive Analysis of Treatment Response and Progression Pattern in Chinese Patients with Different ALK Fusion-Variants (ID 13883)
14:00 - 14:05 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
ALK inhibitors and chemotherapy are two major strategies in the treatment of patients with ALK-rearrangements in China. However, the respective treatment response varies and heterogeneous. This study aimed to comprehensively analyze the impact of ALK variants on different treatment response and explore progression pattern respectively.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively analyzed a cohort of 135 patients with determined ALK variants and medical record from January 2013 to July 2017 in Shanghai Pulmonary Hospital.
4c3880bb027f159e801041b1021e88e8 Result
8eea62084ca7e541d918e823422bd82e Conclusion
The most frequent ALK variant was variant 1 in 62 patients (46%), followed by variant 3a/b in 52 patients (38%) and variant 2 (12%). 69 (51.1%) of patients received chemotherapy, whereas 64 (47.4%) were treated with crizotinib and 2 (1.5%) with alectinib.The similar PFS was observed in patients ALK variant 1 and non-variant 1 regardless of first-line treatment strategy (crizotinib: 15.7 vs. 12.8 months, p=0.53; chemotherapy: 5.7 vs. 8.1 months, p=0.098). However, in the subgroup analysis, patients with ALK variant 1 and baseline brain metastasis had significantly shorter PFS in the first-line setting versus non-variant 1 (4.9 vs. 11.3 months, HR=2.96, p<0.01). Additionally, ORR was 21.6% and 50% in variant 1 and non-variant 1 patients with brain metastases, respectively. Moreover, in the analysis of progression pattern, 55 patients with ALK variant 1 and 57 patients with ALK non-variant 1 exhibited PD. As to ALK variant 1, the incidence of CNS relapse in patients treated with crizotinib was significantly higher than patients treated with chemotherapy (39.3% vs. 7.4%, p=0.005). In terms of ALK non-variant 1,the patients treated with chemotherapy had higher incidence of bone progression than patients treated with crizotinib (25% vs. 0%, p=0.021).
Our results firstly indicate the treatment-naïve patients with ALK variant 1 and baseline brain metastasis have inferior response to initial cancer treatment. Different ALK variants have distinct landscape of progression pattern when treated with crizotinib or chemotherapy.
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MA27 - Novel Drugs and PDX Models (ID 931)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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MA27.10 - EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies (ID 11863)
14:35 - 14:40 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immuneapproach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy.
a9ded1e5ce5d75814730bb4caaf49419 Method
We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry.
4c3880bb027f159e801041b1021e88e8 Result
Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment.
8eea62084ca7e541d918e823422bd82e Conclusion
Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.
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MS24 - Global Perspectives on Tobacco Control (ID 802)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 BD
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MS24.04 - Challenges of Tobacco Control in China (ID 11504)
11:15 - 11:30 | Presenting Author(s): Caicun Zhou
- Abstract
- Presentation
Abstract not provided
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OA07 - Oligometastasis: What Should Be the State-Of-The-Art? (ID 905)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Oligometastatic NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 107
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OA07.03 - Addition of Local Therapy to EGFR TKI Showed Survival Benefit in EGFR-Mutant NSCLC pts with Oligometastatic or Oligoprogressive Liver Metastases (ID 12263)
15:35 - 15:45 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Our previous study demonstrated that EGFR-mutant NSCLC patients (Pts) with liver metastases (LM) showed poor response to EGFR-TKIs than those without LM, suggesting that additional treatment is warranted. Recently, several clinical studies indicated that local therapy (e.g. surgery and radiotherapy) could significantly improve progression-free survival (PFS) in NSCLC Pts with oligometastatic or oligoprogressive disease. This study aimed to investigate whether addition of local therapy to EGFR-TKIs could provide a better survival benefit than TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.
a9ded1e5ce5d75814730bb4caaf49419 Method
Pts with EGFR-mutant NSCLC and LM were enrolled. Oligometastatic LM was defined as < 5 sites in liver without extrahepatic metastases at initial diagnosis. Oligoprogressive LM was defined as < 5 sites in liver without extrahepatic metastases during TKIs therapy. For oligoprogressive cohort, PFS1 was calculated from time of initiation of TKI therapy to first RECIST 1.1 defined progress disease (PD) or death. PFS2 was calculated from time of initiation of TKI therapy to off-TKI PD.
4c3880bb027f159e801041b1021e88e8 Result
Totally, 135 cases with EGFR-mutant NSCLC and LM were eligible (64 with oligometastatic LM and 71 with oligoprogressive LM). In oligometastatic cohort, 20 Pts received EGFR-TKIs (E) and 23 Pts received EGFR-TKIs plus local therapy (E+LT) as first-line treatment. The addition of local therapy showed a significantly longer PFS (12.9 vs. 7.9 m, P = 0.041) and OS (36.8 vs. 21.3 m, P = 0.034) than EGFR-TKIs alone. In oligoprogressive cohort, 24 Pts received continuation of EGFR-TKIs plus local therapy (cE+LT) and 25 Pts received switch therapy (ST). Median PFS1 was similar. Median PFS2 (13.9 vs. 9.2 m, P = 0.007) and OS (28.3 vs. 17.1 m, P = 0.011) was significantly longer in cE+LT group than in ST group. Multivariate analysis revealed that addition of local therapy was independently associated with prolonged PFS (HR = 0.435, P = 0.028) and OS (HR = 0.434, P = 0.071) in Pts with oligometastatic LM. Distant metastatic sites were the major pattern of failure in EGFR-TKI plus local therapy group while locoregional recurrence including primary lesions and LM was the major reason in TKI alone group.
8eea62084ca7e541d918e823422bd82e Conclusion
The current study suggested that EGFR-TKIs plus local therapy demonstrated the prolonged survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM. These findings suggest that local therapy should be further explored in large-scale, strictly designed clinical trials as a standard treatment option in this clinical scenario.
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OA07.05 - Local Ablative Therapy Improves Survival in Patients with Synchronous Oligometastatic NSCLC Harboring EGFR Mutation Treated with EGFR-TKIs (ID 11141)
16:00 - 16:10 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Non-small-cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide. Patients with oligometastatic disease can represent an indolent phenotype that could benefit from local ablative therapy(LAT). Howerver, whether first-line continual EGFR-TKIplus LAT could have potential benefit in EGFR-mutant NSCLC patients with oligometastatic disease remains undetermined.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with stage IV EGFR-mutant NSCLC and no more than five metastases at diagnosis in 2 months were enrolled. All patients were treated with first-line EGFR-TKIs. Consolidation LAT included radiotherapy or surgery. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.
4c3880bb027f159e801041b1021e88e8 Result
From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidation LAT to all oligometastatic sites (All-LAT group), 55 (37.9%) who received consolidation LAT to either primary tumor or oligometastatic sites (Part-LAT group), and 39 (26.9%) who did not receive any consolidation LAT (Non-LAT group). The median PFS in All-LAT, Part-LAT, and None-LAT group were 20.6 months, 15.6 months, and 13.9 months, respectively (P<0.001). The median OS in All-LAT, Part-LAT, and None-LAT group were 40.9 months, 34.1 months, and 30.8 months, respectively (P<0.001). The difference was significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between Part-LAT and Non-LAT group. The median OS was significantly improved with consolidation LAT for primary tumor (40.5 versus 31.5 months, P<0.001), brain metastases (38.2 versus 29.2 months, P=0.002), adrenal metastases (37.1 versus 29.2 months, P =0.032). Adverse events (Grade≥3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%).
8eea62084ca7e541d918e823422bd82e Conclusion
The current study demonstrated that consolidation LAT to all sites was a feasible option among patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidation LAT to partial sites or observation alone.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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.
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OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial (ID 12693)
11:35 - 11:45 | Presenting Author(s): Caicun Zhou
- Abstract
- Presentation
Background
Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.
a9ded1e5ce5d75814730bb4caaf49419 Method
Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.
4c3880bb027f159e801041b1021e88e8 Result
The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.
Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).
8eea62084ca7e541d918e823422bd82e Conclusion
Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-111 - EGFR exon20 Insertion Patients Treated with First-Line Chemotherapy in Non-Small Cell Lung Cancer (ID 14323)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
Epidermal growth factor receptor exon20 insertion(EGFR 20-ins) is a low frequency mutation among EGFR mutations, and chemotherapy is a major choice for these patients. The outcomes between different types of EGFR 20-ins and with EGFR sensitive mutation and wild type are not well studied.
a9ded1e5ce5d75814730bb4caaf49419 Method
From Oct 2011 to Feb 2018, EGFR 20-ins was detected using ARMS method. The mutation positive samples were subsequently confirmed by DNA sequencing. Clinicopathological features and outcomes between different kind of EGFR 20-ins patients as well as EGFR 20-ins patients with EGFR sensitive mutation and wild type patients were analyzed.
4c3880bb027f159e801041b1021e88e8 Result
Eighty-four 20-ins patients were detected in this study. Eight were not enough for DNA sequencing, 11 were wild type and 65 were mutation positive. The three major subtypes were: 28 c.2308_2309insCCAGCGTGG, 9 c.2311_2312insGCGTGGACA and 10 c.2319_2320insAACCCCCAC. Of the 45 patients who could access treatment effect in first-line chemotherapy, objective response rate(ORR) was 28.9%(13/45), disease control rate(DCR) was 86.7%(39/45) and median progression-free survival (mPFS) was 5.7 month. There were no significant differences in sex, age, smoking status, pathological types, ORR, DCR and PFS between c.2308_2309insCCAGCGTGG mutation and other 20-ins mutations. We compared the PFS of EGFR sensitive mutation, wild type and 20-ins patients, and found no significant difference(p=0.324).
8eea62084ca7e541d918e823422bd82e Conclusion
EGFR 20-ins is a distinct EGFR mutation. The clinicopathological features and clinical outcome were not significantly different between different EGFR 20-ins subtypes, as well as between EGFR 20-ins, EGFR sensitive mutation and wild type patients. Target drugs for this kind of patients are needed.
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P1.01-112 - Osimertinib vs Standard of Care (SoC) EGFR-TKI as First-Line Treatment in Chinese Patients With EGFRm Advanced NSCLC (ID 12211)
16:45 - 18:00 | Presenting Author(s): Caicun Zhou
- Abstract
Background
Osimertinib is an irreversible, central nervous system (CNS) active EGFR-TKI, selective for both EGFRm and T790M resistance mutations. FLAURA (NCT02296125) is a PhIII, double-blind, randomized study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI (erlotinib/gefitinib) in first-line patients with EGFRm advanced NSCLC. FLAURA results (556 patients, globally) are published. We present the China cohort results.
a9ded1e5ce5d75814730bb4caaf49419 Method
The cohort included self-identified Chinese patients, enrolled in China. Eligible patients: ≥18 years, Ex19del/L858R EGFRm advanced NSCLC, no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease. Neurologically stable patients with CNS metastases were allowed, if definitive treatment/corticosteroids were completed ≥2 weeks before enrolment. Patients were randomized 1:1 to osimertinib 80 mg once daily (qd) orally or SoC EGFR-TKI (gefitinib 250 mg qd orally selected by all Chinese sites), stratified by mutation status (Ex19del/L858R). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, per investigator. Data cutoff: 10/01/2018.
4c3880bb027f159e801041b1021e88e8 Result
Overall, 136 patients were randomized (osimertinib n=71; SoC n=65); 19 were also included in the global analysis. Baseline characteristics were balanced across arms (osimertinib/SoC): female 61/71%; smoking history 25/23%; WHO performance status 1 90/80%; Ex19del 51/51%, L858R 49/49%; CNS metastases 24/32%.
Efficacy endpoint Osimertinib
n=71SoC
n=65PFS events, total patients
(% maturity)40
(56%)51
(78%)PFS hazard ratio (HR)*
(95% CI)0.56 (0.37, 0.85); p=0.007 Median PFS, months
(95% CI)17.8
(13.6, 20.7)9.8
(8.3, 13.8)Objective response rate (ORR),
% (95% CI)83%
(72, 91)75%
(63, 85)Median duration of response (DoR), months
(95% CI)16.4
(12.3, NC)10.9
(8.3, 13.8)*A hazard ratio <1 favours osimertinib. PFS benefit was observed across all subgroups, irrespective of EGFR mutation status and including patients with/without CNS metastases at study entry. Median total treatment duration: osimertinib, 18.9 months; SoC, 13.6 months. No new safety signals were reported. Numerical increase in grade ≥3 AEs was reported in the osimertinib arm (49%) versus SoC arm (23%). Most grade ≥3 AEs in the osimertinib arm were investigator-reported laboratory and disease-related AEs; incidence of non-laboratory-related events was low. AEs leading to discontinuation: osimertinib, 13%; SoC, 6%. In the osimertinib arm, most AEs leading to discontinuation were fatal disease-related events.
8eea62084ca7e541d918e823422bd82e Conclusion
Osimertinib improved PFS vs SoC EGFR-TKI (HR: 0.56) as first-line treatment in Chinese patients with EGFRm advanced NSCLC, consistent with the global analysis.
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P1.01-98 - A Phase IIIb Trial of Afatinib in EGFRm+ NSCLC: Analyses of Outcomes in Patients with Brain Metastases or Dose Reductions (ID 12906)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
We previously reported interim results of a large (n=479) open-label, single-arm Phase IIIb study of afatinib in EGFR TKI-naïve patients with EGFRm+ NSCLC, in a setting similar to ‘real-world’ practice (Wu et al, WCLC, 2017). In this broad population of Asian patients, the tolerability profile of afatinib was predictable and manageable. Adverse events (AEs) were consistent with the LUX-Lung 3, 6 and 7 trials; 3.8% of patients discontinued due to drug-related AEs. Progression-free survival (PFS) and time to symptomatic progression (TTSP) was encouraging, in patients with both common and uncommon EGFR mutations. TTSP data suggested effective treatment beyond progression. Here, we assess the impact of baseline brain metastases and use of dose reductions on efficacy outcomes.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with locally advanced/metastatic EGFRm+ NSCLC were recruited in China, Hong Kong, India, Singapore and Taiwan. Afatinib 40mg/day was given until disease progression (investigator-assessed) or lack of tolerability. Treatment-related AEs could be managed by protocol-specified tolerability-guided dose adjustment.
4c3880bb027f159e801041b1021e88e8 Result
At data cut-off (13 Feb 2017), patient characteristics were as follows: median age, 59.0 years; female, 52.4%; EGFR mutations: Del19+/-L858R+/-uncommon, 86.0%; uncommon only, 14.0%; ECOG PS0, 19.8%; PS1, 78.1%. Prior chemotherapy lines: 0, 59.7%; 1, 30.1%; ≥2, 10.2%.
Overall, dose reductions from 40mg/day to 30mg/day occurred in 119 patients (25%). Incidences of the most frequently reported AEs before and after dose reduction were (any grade): diarrhea, 96/51%; rash/acne, 69/58%; stomatitis, 65/42%; (≥grade 3) diarrhea, 27/4%; rash/acne, 24/11%; stomatitis, 11/5%. A total of 96 patients had a dose reduction during the first six months; median PFS in this subgroup was 14.1 months (95% CI: 10.0–19.3) versus 11.33 (10.7–13.6) months in those who remained on the starting dose (n=383); HR=1.37 (1.01–1.85), p=0.041. Median TTSP was 17.7 (13.5–23.7) and 14.7 (12.7–17.0) months, respectively; HR=1.26 (0.92–1.72), p=0.15.
Among 92 patients (19.2%) with brain metastases at baseline, median PFS was 10.9 (8.3–14.3) months, versus 12.4 (10.8–13.9) months in those without metastases (n=387); HR=1.23 (0.91–1.65), p=0.18. Median TTSP was 14.8 (12.7–20.7) and 15.4 (12.9–18.0) months, respectively; HR=1.0 (0.71–1.40), p=1.0.
8eea62084ca7e541d918e823422bd82e Conclusion
These findings demonstrate that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs, while maintaining therapeutic efficacy. TTSP was similar between patients with and without brain metastasis. This is additional evidence for the efficacy of afatinib in patients with brain metastases.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-26 - First-Line Continual EGFR-TKI Plus LAT Demonstrated Survival Benefit in Egfr-Mutant Nsclc Patients with Oligoprogressive Disease (ID 11143)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
The effect of local ablative therapy (LAT) for oligoprogressive epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) remains undetermined. This study aimed to investigate the survival benefit of addition of LAT to EGFR-TKIs in EGFR-mutant NSCLC patients with oligoprogression during TKI therapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with stage IIIB/IV EGFR mutant NSCLC who had oligoprogressive disease during the first-line EGFR-TKI therapy from March 2011 to February 2016 were identified. The primary research point were progression-free survival1 (PFS1), defined as time of initiation of TKI therapy to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 defined progress disease (PD) or death and PFS2, defined as time of initiation of TKI therapy to off-TKI PD. The second research piont inclued overal survival (OS) and safety.
4c3880bb027f159e801041b1021e88e8 Result
A total of 206 patients were included. The median follow-up time was 42 months (20.0-69.6 months). The median PFS1, median PFS2 and median OS for the related cohort were 10.7 months (95% CI, 10.1-13.3 months), 18.3 months (95% CI, 17.4-19.2 months) and 37.4 months (95% CI, 35.9-38.9 months) respectively. Survival rates of 1 year, 2 years and 3 years were 94.1%, 78.9%, and 54.7%, respectively. Multivariate analysis revealed that female, EGFR exon 19 mutation, one metastatic lesion, partial or complete response to prior EGFR TKIs therapy were the independent prognostic factors. No unexpected toxicities were observed.
8eea62084ca7e541d918e823422bd82e Conclusion
The current study suggested that the addition of LAT to EGFR-TKI could provide satisfactory survival benefit for EGFR-mutant NSCLC patients with oligoprogression during first-line EGFR-TKI treatment.
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-13 - The Immune Checkpoint, HVEM Contribute to Immune Escape in Non Small Cell Lung Cancer of Lacking PDL1 Expression (ID 13116)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
A TMA of 527 resected NSCLC samples and 53 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems（AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.
4c3880bb027f159e801041b1021e88e8 Result
HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was18.6%(77/415) and 45.3%(24/53) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, P=0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, P=0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p=0.706) and PD-L1 expression (median 45 vs 48 months, p=0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.232, p=0.002, Figure 1A) in patients with NSCLC and also have a negative correlation in NSCLC cell lines(r=-0.055, p=0.764,Figure 1B).
8eea62084ca7e541d918e823422bd82e Conclusion
HVEM was found to be overexpressed in patients of NSCLC with advanced disease or lymph node metastasis and has a negative co-relationship with PD-L1 expression, while, it did not have a prognostic role in patients with NSCLC.
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P2.11 - Screening and Early Detection (Not CME Accredited Session) (ID 960)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.11-08 - Tumor Autoantibody Panel Can Improve the Accuracy of Early Diagnosis in Lung Cancer Presenting with GGNs /Solid Nodules (ID 14324)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
Autoantibody is an attractive diagnostic approach for early detection of malignant tumors. We performed this study to validate the performance of an autoantibodies (TAAs) panel (p53，PGP9.5，SOX2，GAGE7，GBU4-5，MAGE A1，CAGE) to aid early diagnosis of lung adenocarcinoma with ground-glass nodules (GGNs) and/or solid nodules in Chinese population and to find an effective simple blood test which can be used in further assessing the risk of lung cancer being present GGNs and/or nodules.
a9ded1e5ce5d75814730bb4caaf49419 Method
A prospective audit was conducted on 540 individuals known to have GGNs and/or lung nodules. These patients included 311 pulmonary malignant or borderline lung diseases, 229 lung benign GGNs and/or nodules. We detected TAAs quantitation by ELISA method.
4c3880bb027f159e801041b1021e88e8 Result
The sensitivity and specificity of autoantibody assay were 48.6% and 92.7% respectively. In lung invasive adenocarcinoma, the sensitivity of autoantibody assay was 51.9%. When the seven-autoantibody panel test was combined with CT imaging in patients with GGNs and/or nodules, the accuracy was increased to 90.42%.
8eea62084ca7e541d918e823422bd82e Conclusion
The greatest impact of using the new seven-autoantibody panel was the highly significant improvement in the sensitivity and specificity of the test in the clinical setting. Our study suggested that the seven-autoantibody panel can be combined with CT imaging to aid diagnosis of lung cancer with GGNs and/or solid nodules.
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P2.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 964)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.15-33 - Evaluation of Liquid Biopsies for Molecular Profiling in Patients (pts) with Advanced NSCLC: What Happens After Panel Testing by NGS? (ID 13011)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
Molecular profiling is limited by tumor heterogeneity and access to sufficient tissue for comprehensive analysis. Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for testing gene alterations and monitoring personalised treatment strategies. Because of its high expense, translation of the sensitive and accurate next generation sequencing (NGS) into routine cancer care has been slow.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively reviewed 60 advanced NSCLC pts who were performed gene test prior to treatment using tissue by ARMS. Blood collections (10ml K2-EDTA) were performed after disease progression and analysed by NGS using a 10-gene panel (EGFR, KRAS, BRAF, HER2, PIK3CA, ALK, ROS1, RET, MET and TP53). We evaluated the significance of the outcome of panel testing by NGS in guiding the subsequent treatment in clinical practice.
4c3880bb027f159e801041b1021e88e8 Result
Among 60 NSCLC pts, 39 were male, 28 were never-smokers, and 56 were adenocarcinoma. ctDNA profiling detected alterations in 50 pts (83%). TP53 (53%), EGFR (48%) and KRAS (15%) were the most common abnormalities detected. Additionally, MET (8%), ALK (3%), HER2 (3%) and PIK3CA (2%) mutations were detected, respectively. Sensitizing mutations were detected in 22 pts (37%) prior to treatment using tissue by the method of ARMS, including 20 EGFR mutations and 2 ALK fusions, and all pts received tyrosine kinase inhibitor (TKI) as first-line therapy. Among 20 EGFR mutant pts, T790M mutation was detected in 9 pts (45%), KRAS mutation was detected in 4 pts (20%), and TP53 mutation was detected in 12 pts (60%), while MET amplification was found in 1 pt (5%). 1 KRAS mutation and 1 TP53 mutation were detected in 2 ALK –TKI resistant pts, respectively. 28 pts (47%) reported as tissue negative had a positive liquid biopsy, including 4 MET 14 exon skipping mutations, 2 EGFR 19 DEL, 4 EGFR L858R and 1 EGFR L861Q, and 2 EGFR T790M mutations. The mutation abundance is all below 1%, except 2 EGFR 19 DEL and 4 L858R. Ten pts received TKIs; 2 got parcial responses, 5 stable diseases and 3 progressive disease.
8eea62084ca7e541d918e823422bd82e Conclusion
ctDNA can be used as a ‘liquid biopsy’ for molecular profiling of NSCLC pts, and NGS, as a highly sensitive method to detect mutations with low mutation abundance, can provide more chances to pts to receive precise treatment.
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P2.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 966)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.17-12 - Eliminating Radiation Resistance of Non-Small Cell Lung Cancer By DHA Trough Abrogating Immunity Escaping via Inhibiting PD-L1 Expression (ID 11169)
16:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
Lung cancer is a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T cell activation. Our previous research also demonstrate that radiation can induce a local inflammatory response and simultaneously induce programmed death ligand 1 (PD-L1) expression that attenuate the sensitivity of radiation response in NSCLC. Current data have implicated that the molecular mechanisms by which DHA functions as radiosensitizer are varied, such as inducing apoptosis, extracellular signal-regulated protein kinases 1/2 (Erk1/2) activity, nuclear factor-kappa-B (NF-ƘB), and so on. However, there is no research about the immunity system alterations after the treatment of DHA plus radiation.In the present study, we demonstrate that combined DHA and radiotherapy synergistically enhances the anti-tumor effect by inhibiting the expression of PD-L1, eradicating the local accumulation of tumor-infiltrating regulatory T cells (iTregs) and myeloid-derived suppressor cells (MDSCs) and stimulating CD8+ T cell infiltration in the tumor microenvironment. Furthermore, DHA may also through inhibiting TGF-β, p-AKT and p-STAT3 pathways, epithelial-mesenchymal transition (EMT) process, facilitating apoptosis, and regulating TRIM21 to induce the synergistic anti-tumor effect.
a9ded1e5ce5d75814730bb4caaf49419 Method
Radiation resistance cell lines (A549/X) was induced from A549 by conventionally fractionated radiation. The relationship between PD-L1 expression and the radiation resistance and the immune cell was investigated by immunohistochemistry (IHC) and western blot in vitro and vivo. Apoptosis was evaluated by flow cytometry. The signaling pathway proteins, epithelial-mesenchymal transition (EMT)-related protein were analyzed by western blot.
4c3880bb027f159e801041b1021e88e8 Result
PD-L1 was up-regulated after radiation in vivo and vitro. Concomitant with radiation-mediated tumor regression, combined DHA and radiotherapy synergistically enhances the anti-tumor effect by inhibiting the expression of PD-L1. DHA plus radiotherapy also reduced the local accumulation of tumor-infiltrating regulatory T cells (iTregs) and myeloid-derived suppressor cells (MDSCs) and stimulated CD8+ T cell infiltration in the tumor microenvironment. Furthermore, DHA may also through inhibiting TGF-β, p-AKT and p-STAT3 pathways, epithelial-mesenchymal transition (EMT) process, facilitating apoptosis, and regulating TRIM21 to induce the synergistic anti-tumor effect.
8eea62084ca7e541d918e823422bd82e Conclusion
Our study demonstrated a synergistic anti-tumor effect of DHA in combination with radiation trough abrogating immunity escaping via inhibiting PD-L1 expression, which establish a basis for the rational design of combination therapy of DHA plus radiotherapy in NSCLC.
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P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.04-21 - Antibiotics Attenuate the Clinical Benefit of Anti-PD-(L)1 Immunotherapies in Chinese Patients with Advanced Non-Small Cell Lung Cancer (ID 13555)
12:00 - 13:30 | Author(s): Caicun Zhou
- Abstract
Background
Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 have shifted the treatment paradigm of advanced non-small cell lung cancer (NSCLC), but responses are often heterogeneous and temporary. Several landmark publications have confirmed the dominant role of gut microbiome in modulating tumor responses to ICIs, suggesting the predictive value of antibiotics (ATB) in patients treated with anti-PD-(L)1 antibody. However, more evidence is needed to comprehensively reveal the association between ATB usage and ICIs therapeutic response in NSCLC, especially in Chinese populations.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively reviewed the medical records of patients with advanced/metastatic NSCLC received anti-PD-(L)1 based therapies at our hospital. Detailed clinicopathologic characteristics, response data and ATB usage were collected for all patients. The patients receiving ATB within one month around the first administration of ICIs (defined as ATB-treated) were compared to those without (ATB-untreated).
4c3880bb027f159e801041b1021e88e8 Result
109 cases receiving anti-PD-(L)1 based therapies and underwent response evaluation were identified. 65 (59.3%) of them received monotherapy and 44 received combination therapies including anti-PD-(L)1 plus anti-angiogenesis/chemotherapy. 35 (32.1%) patients had been prescribed ATB 60 days before or during the course of ICIs treatment, and 20 (18.3%) were categorized as ATB-treated group. The most commonly administered ATB were β-lactam inhibitors, fluoroquinolones and macrolides. No major statistical differences in baseline clinicopathologic features were observed between ATB-treated and -untreated groups. The objective response rates (ORR) to ICIs in two groups were 65% and 82%, respectively. ATB treatment was significantly associated with shorter progression-free survival (PFS) (median 3.73 vs 9.3 m, p<0.001), and also tended to be associated with primary disease progression (35% vs 18%, p=0.087). The overall survival (OS) (median 31.9 vs 37.6 m, p=0.74) was similar in two groups, but ATB appeared to be related to decreased duration of survival from ICI treatment start to death (median 6.07 vs 26.9 m, p=0.002). In multivariable analysis, ATB treatment was markedly associated with poorer ORR and survival to ICIs after adjusting for prior line treatment setting, ICI regimens, numbers of ICI-related toxicity and clinical characteristics.
8eea62084ca7e541d918e823422bd82e Conclusion
ATB usage was a predictor for decreased clinical benefit from anti-PD-(L)1immunotherapies in Chinese NSCLC patients. More comprehensive understanding of the interaction between gut microbiome and ATB is still in urgent need. Furthermore, modulating ATB-related gut microbiome dysbiosis may enhance response to anti-PD-(L)1 immunotherapies.
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