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Xuefei Li
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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): Xuefei Li
- 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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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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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): Xuefei Li
- 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.
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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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): Xuefei Li
- 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.
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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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): Xuefei Li
- 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.
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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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- 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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P1.01-111 - EGFR exon20 Insertion Patients Treated with First-Line Chemotherapy in Non-Small Cell Lung Cancer (ID 14323)
16:45 - 18:00 | Author(s): Xuefei Li
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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): Xuefei Li
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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): Xuefei Li
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53
