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A. Passaro
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-044 - Baseline Peripheral Blood Cell Subsets Associated with Survival Outcomes in Advanced NSCLC Treated with Nivolumab in Second-Line Setting (ID 4103)
14:30 - 14:30 | Author(s): A. Passaro
- Abstract
Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of Squamous (Sq) and non-Squamous (non-Sq) metastatic NSCLC in second-line setting, showing a survival benefit in randomized phase III trials. The aim of this study is to investigate the potential role of baseline peripheral blood cells in relation to clinical outcomes following nivolumab treatment.
Methods:
From November 2015 to to June 2016, we evaluated 45 patients with Sq (n = 10) and non-Sq (n = 35) NSCLC, previously treated with first-line platinum-based chemotherapy, that received nivolumab 3 mg/kg IV on day 1 of each 2 week treatment cycle. Clinical characteristics (T-Stage, lymph nodes involvement, M-Stage) were assessed. Total numbers of leukocytes, myeloid-derived suppressor cells (MDSCs), including both monocytic (Mo-MDSC) and granulocytic (Gr-MDSC) type, regulatory T cells (T-regs), and serum lactate dehydrogenase (LDH) were assessed. Endpoints were correlation with objective response (OR), progression-free survival (PFS, categorized as ≤ 3 or > 3 months) and overall survival (OS). Tumor response was assessed using RECIST criteria, version 1.1, at week 9 and every 6 weeks thereafter until disease progression. Statistical methods were based on univariate analyses (Wilcoxon rank test).
Results:
The median PFS of the overall study population was 3 months. Data about Gr-MDSCs (identified by flow cytometry as Lin-CD15+CD14-CD11b+HLA-DR[low/-]), Mo-MDSCs (Lin-CD14-CD11b+HLA-DR[low/-]) and absolute eosinophil counts (AEC) were available in 37/45 patients (82%) of treated patients. Baseline absolute numbers of Gr-MDSCs, Mo-MDSCs and AEC were greater in patients with good prognosis (PFS > 3 months) and better outcomes. In particular among patients with shorter PFS, the median numbers of Gr-MDSCs, Mo-MDSCs and AEC were significantly lower than those detected in patients with longer PFS (4 vs 13 cell/µl, p=0.01; 4 vs 21 cell/µl, p=0.06; 55 vs 155 cell/µl; p=0.02, respectively). No correlation was observed between T-regs, LDH, absolute neutrophil, monocyte, lymphocyte counts and clinical outcomes.
Conclusion:
A baseline blood signature characterized by low levels of Gr-MDSCs, Mo-MDSCs and AEC is associated with poor outcome (median PFS ≤ of 3 months) in 67.6% of patients treated with nivolumab. In contrast, patients (32.4%) with high levels of these three biomarkers showed a median PFS significant longer than 3 months. Overall survival analysis is ongoing.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)
14:30 - 14:30 | Author(s): A. Passaro
- Abstract
Background:
EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.
Methods:
We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.
Results:
Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.
Conclusion:
Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.
