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Smadar Geva
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.06 - BRAF Mutant NSCLC: Correlation with PD-L1 Expression,TMB, MSI and Response to ICPi and Anti-BRAF Therapy (ID 10473)
11:00 - 12:30 | Author(s): Smadar Geva
- Abstract
- Presentation
Background:
The efficacy of immune check-point inhibitors (ICPi) in BRAF mutant non-small cell lung cancer (NSCLC) is largely unknown. The correlation with different parameters predicting efficacy of ICPi (e.g., PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) in these tumors needs further evaluation.
Method:
A retrospective analysis of 30 patients with BRAF mutant advanced NSCLC treated between Aug 2013 and May 2017 was performed. The patients were divided into 2 groups: BRAF V600 E (Group A, N=16), non-V600E BRAF (Group B, N=14). PD-L1 was assessed by immunohistochemistry using 22C3 Dako antibody clone on Dako or Ventana's platform in 16 patients. TMB and MSI were assessed in 9 and 11 patients, respectively. Median progression-free survival (mPFS) with ICPi and targeted agents as well as median overall survival (mOS) were assessed in each group by Kaplan-Meier method.
Result:
Baseline characteristics of the cohort: median age 66y (range 39-98); males 53%; current/past smokers/never smokers/NA 13%/44%/40%/3%; adenocarcinoma/other histology 80%/20%; ECOG PS 0/1/2/3/4/NA 27%/33%/10%/13%/0%/17%. The distribution of TMB, PD-L1 expression and MSI status between the 2 groups is presented in Table 1. Ten patients received ICPi (nivolumab-8, pembrolizumab-2), and thirteen patients received anti-BRAF therapy (dabrafenib+trametinib-6, dabrafenib-4, vemurafenib-3). mOS and mPFS with ICPi and anti-BRAF therapy are summarized in Table 1. Four patients with BRAF V600 E PD-L1 ≥ 50% tumors were included in the series; one patients responded to dabrafenib+trametinib combination (response ongoing, 7.1months+); in two patients ICPi were initiated, response assessment pending. One patient with a non-V600E BRAF mutant NSCLC responded to dabrafenib for 6.7 months.Figure 1
Conclusion:
BRAF mutant NSCLC tumors are associated with high level of PD-L1 expression, low/intermediate TMB and MSI stable status. ICPi may induce prolonged responses both in BRAF V600E and non-V600E BRAF mutant NSCLC. Some non-V600E BRAF mutant NSCLC may benefit from anti-BRAF targeted therapy.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-039 - Survival Impact of Next-Generation Sequencing in Lung Cancer (ID 10212)
09:30 - 16:00 | Presenting Author(s): Smadar Geva
- Abstract
Background:
Next-generation sequencing (NGS) enables a comprehensive genomic analysis of lung cancer patients. It has uncovered many novel genetic abnormalities and identified actionable genomic alterations in lung tumors that previously tested "negative" by conventional non-NGS tests. In this study, we evaluated the clinical impact of NGS, performed at different stages of the oncologic management, on overall survival of advanced lung cancer patients.
Method:
In this retrospective study, 178 consecutive non-small cell lung cancer (NSCLC) patients who performed hybrid capturing NGS were enrolled at the Thoracic Cancer Unit at Rabin Medical Center, Israel, between 2011-2017. Hybrid capture-based NGS was performed by Foundation Medicine and Gaurdant 360[TM] if tissue was not available.
Result:
178 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63±12.1 years. 83% had adenocarcinoma. NGS was performed upfront in 45.5% (81/178) and after 1[st] line failure in 54.5% (97/178). Treatment decision was taken toward targeted therapy subsequent to NGS analysis in 34% (61/178) of patients (29 and 32 respectively) with an objective response rate of 54%. Overall survival (OS) was evaluated for 51% (31/61) with a median of 12.2±14.1 months. For patients who performed upfront NGS, OS ranged between 1.8 to 32.5 months, with a median OS of 13.8 months. For patients who performed NGS on progression, OS ranged between 1.7 to 77.1, with a median OS of 12.7 months.
Conclusion:
Comprehensive tissue and liquid-based NGS have revealed targeted treatment options for one third of the patients. Overall Survival of patients treated with tailored therapy was positively impacted by earlier performed NGS.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-060 - The Clinical Utility of ctDNA Gene Analysis in Lung Cancer (ID 9948)
09:30 - 16:00 | Presenting Author(s): Smadar Geva
- Abstract
Background:
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. In this study, we evaluated the impact of ctDNA sequencing on outcomes and treatment strategy.
Method:
In this retrospective study, data was collected from files of advanced non-small cell lung cancer (NSCLC) patients at the Thoracic Cancer Unit, Rabin Medical Center, Israel, between 2014-2017. Plasma samples were analyzed by a commercial test (Guardant360[TM]), using massively parallel paired-end synthesis to sequence a targeted 68-73 gene panel.
Result:
116 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, 74% had adenocarcinoma. 41% performed ctDNA analysis before 1st line therapy (Group A) and 59% on progression (Group B), among them 41% after progression on EGFR TKIs (Group B1) and 59% on other treatments (Group B2). ctDNA analysis yielded actionable mutations (EGFR, ALK, RET, BRAF, MET, ERBB2 (HER2)) in 40.5%: 31% in group A, 47% in group B, 71% in group B1 and 30% in group B2. Treatment decision was taken toward targeted therapy subsequent to NGS in 26%.Genetic alterations frequencies among groups A, B, B1 and B2
Response assessment (RECIST) to targeted therapy showed complete response in 4%, partial response in 44%, stable disease in 37% and progressive disease in 15%. Response rate was 44% for group A, 50% for group B, 60% for group B1, 37.5% for group B2. Total objective response rate was 48% and disease control rate was 85%. Overall survival was evaluated for 40%, median was 14.4 months for patients who received targeted therapy vs 13.6 months for patients who received standard treatment.Group A 19 individual mutations Group B 52 individual mutations Group B1 34 individual mutations Group B2 18 individual mutations EGFR Sensitizing 52.5% (10/19) EGFR Sensitizing 42% (22/52) EGFR Sensitizing 59% (20/34) MET 55.6% (10/18) MET 16% (3/19) MET 27% (14/52) EGFR T790M 23% (8/34) ERBB2 16.7% (3/18) ERBB2 10.5% (2/19) EGFR T790M 15% (8/52) MET 12% (4/34) RET 16.7% (3/18) BRAF V600E 10.5% (2/19) ERBB2 8% (4/52) ERBB2 3% (1/34) EGFR Sensitizing 11.1% (2/18) RET 10.5% (2/19) RET 6% (3/52) ALK 3% (1/34) ALK 2% (1/52)
Conclusion:
Comprehensive ctDNA testing revealed treatment options for 40.5% of patients analyzed. The highest impact was seen in progressors on EGFR therapy. These positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the most efficacious therapy for each patient.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-096 - The Interaction Between Mast Cells and Lung Cancer Cells Through Extracellular Vesicles (ID 10200)
09:30 - 16:00 | Presenting Author(s): Smadar Geva
- Abstract
Background:
Exosomes are nano-sized extracellular vesicles that mediate cell-to-cell communication by transferring molecules. Mast cells are secretory cells that complete their differentiation and maturation in the micro-environment of tissues containing blood vessels, and were observed in the periphery of certain tumors. It has been hypothesized that tumor cells affect their environment by passing genetic codes such as miRNA through exosomes. In this study, we investigated the presence of exosomal content in the micro-environment of lung cancer cells as a communication mechanism that drives tumor development.
Method:
Human mast cells (HMC1) were exposed to Human lung cancer cells (H1299) in in vitro setting. Exosomes were isolated from mast cells alone, lung cancer cells alone and from a co-culture of mast cells and lung cancer cells. As a control, exosomes were produced from mast cells that were activated by membranes of lung cancer cells. Exosomes quantity and quality were analyzed including its miRNA composition. Samples were run on an HTG EdgeSeq Processor using the HTG EdgeSeq miRNA WT assay. Each assay contains 2102 probes for miRNA, including 13 housekeeper genes, 5 negative process controls, and 1 positive process control. The HTG EdgeSeq Parser was used to align the FASTQ files to the probe list to collate the data. CPM (counts per million) was normalized and differential expression was analyzed using DESeq2.
Result:
We exposed mast cells to membranes of lung cancer cells, in order to examine induction of mast cells. Out of 2066 miRNA analyzed only 3 were significantly upregulated: miR-31-5p, miR-100-5p and miR-125b-5p. Interestingly, the profile of the pathways activated by these 3 upregulated miRNAs shows the focal adhesion and adherens junctions as one of the top results. A comparison was made between miRNA expression of exosomes from mast cells vs. exosomes from lung cancer cells. Out of 2066 miRNA analyzed, a total of 112 miRNA were differentely expressed. 79 miRNAs were downregulated, for example hsa-miR-6802-5p downregulated in HMC1 in comparison with H1299, and moreover hsa-miR-4700-5p. 33 miRNAs were significantly upregulated, for example miR-146b-5p/miR-146a-5p. Top upregulated miRNAs were tested using KEGG pathway and predicted to lead to the activation of the pathways like viral carcinogenesis, pathways in cancer and cell cycle.
Conclusion:
Mast cells and cancer cells do have common and discriminating exosomal content. Interestingly, mast cells have been induced by the presence of lung cancer cells’ membranes, through a change in the canonical pathways of focal adhesion, by the upregulation of only 3 miRNAs.
