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X. Li
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.03 - Preliminary Results of a Phase II Study about the Efficacy and Safety of Pyrotinib in Patients with HER2 Mutant Advanced NSCLC (ID 6069)
16:00 - 17:30 | Author(s): X. Li
- Abstract
- Presentation
Background:
There is still an unmet need for targeted drugs in non small cell lung cancer (NSCLC) patients with HER2 mutation. Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This phase II trial is designed to evaluate the safety and efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC.
Methods:
A single arm prospective phase II trial was undergone to evaluate the efficacy and safety of Pyrotinib in patients with HER2 mutant advanced NSCLC in a single center of Shanghai Pulmonary Hospital, Tongji University(NCT 02535507). Pyrotinib was administrated 320mg or 400mg orally once a day. Next generation sequencing or ARMS was used to identify the patients with HER2 mutation. The primary endpoint was objective response rate and the secondary endpoints were side effect, progression free survival and overall survival.
Results:
From Jul 15 2015 to Jul 21, 2016, 11 patients with her2 mutated advanced NSCLC were enrolled into this study. Among them, the median age was 58 years old, 6 were male, 4 were smoker, ECOG PS 0/1/2 were 5/6 and all of them were adenocarcinoma. None of them received pyrotinib as the first line therapy and the median previous anti-cancer regimen was 2. 9 patients had the details variants of HER2 mutation including 7 with exon 20 776YVMA, 1 with exon 20 770AYVM and 1 with 2326G>ATTT. All of them evaluated the response, including 54.5% with partial response(6/11), 27.3% with stable disease(3/11) and 18.2% with progressive disease(2/11). 1 patient got response to pyrotinib after progressed from afatinib. 5 patients were still on the study and the median PFS was 6.2 months. Side effects were mild including 4 with grade I/II diarrhea, 2 with grade II fatigue, 2 with grade I rash and 1 with dispnea.
Conclusion:
Pyrotinib showed promising results about the ORR and PFS together with mild toxicity in patients with HER2 mutant advanced NSCLC, further multicenter large scale phase II study is initiated to validate the results in this study.
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MTE21 - Next Generation Sequencing (Ticketed Session) (ID 314)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 07:30 - 08:30, Schubert 1
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MTE21.01 - Next Generation Sequencing (ID 6576)
07:30 - 08:30 | Author(s): X. Li
- Abstract
- Presentation
Abstract:
Non small cell lung cancer(NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations invariably develop resistance to EGFR tyrosine kinase inhibitors (TKIs). 20%-30% of NSCLC patients haboring sensitive mutations have no good initial clinical response to EGFR-TKIs, which is defined as having intrinsic resistance to EGFR-TKIs; while the rest of patients with activating mutations who are initially responsive to EGFR-TKIs eventually develop acquired resistance after 10–12 months of consistent clinical beneft, followed by disease progression. The drug resistance is a really tough and urgent clinical problem. Part of resistant mechanisms have been reported, including BIM deletion polymorphism, combined with other bypass signal pathway activation, epithelial-mesenchymal transition (EMT) for primary resistance; T790M, cMET amplification, SCLC transformation for acquired resistance. However, partial resistant mechanisms still unknown. In contrast to acquired resistance to EGFR-TKIs, intrinsic resistance is more complicated. Next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. We aimed to investigate the intrinsic resistant mechanisms to EGFR-TKIs by NGS, further to optimize treatment strategies and improve clinical outcome in EGFR activating mutant patients having intrinsic resistance to EGFR-TKIs. At present, the study is underway, and the results will be presented at the 2016 WCLC.
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.07 - Combining Anti-Angiogenesis and Immunotherapy Enhances Antitumor Effect by Promoting Immune Response in Lung Cancer (ID 4985)
11:00 - 12:30 | Author(s): X. Li
- Abstract
- Presentation
Background:
Increasing studies have shown that anti-angiogenic therapy targeting VEGF/VEGFR2 axis are furnishing demonstrable therapeutic effect on lung cancer，but the treatment benefit is transitory in clinic, generally followed by restoration of tumor growth and disease progression. Blockade of VEGF/VEGFR2 pathway can not only induce anti-vascular effect, but also remodel the immunosuppressive tumor microenvironment probably due to promoting suppressive cells infiltration and enhancing PD-L1 expression, resulting in impairing antitumor immunity. Therefore, the current study aimed to investigate whether combining anti-angiogenic and anti-PD-L1 treatments can induce synergistic antitumor effect by enhancing antitumor immune response in murine lung cancer.
Methods:
We evaluated the antitumor effects of anti-VEGFR2 agent (apatinib) as monotherapy or in combination with anti-PD-L1 monoclonal antibody in a murine lung cancer model using Lewis lung cancer cells (LLCs). The changes of immune components in tumor and spleen were dynamically tested in different treatment groups and time points by flow cytometry and immunohistochemistry.
Results:
The results showed that VEGF/VEGFR2 blockade could retard tumor growth and inhibit tumor neovascularization via eradicating Foxp3[+ ]regulatory T cells (Tregs) and myeloid derived suppressive cells (MDSCs) and reducing the density of microvessels in the first two weeks of treatment. On the third week of apatinib monotherapy, the number of Foxp3[+ ]Tregs and MDSCs had increased again. Although VEGF/VEGFR2 blockade induced more tumor infiltrating lymphocytes (TILs), especially CD8[+] T cells, infiltrating into the tumor mass than control group (P < 0.01), the expression of PD-1 and PD-L1was also significantly upregulated than that control group (P < 0.01). Compared to apatinib monotherapy, combining treatment demonstrated that anti-VEGFR2 plus anti-PD-L1 therapy could significantly inhibit tumor growth (P < 0.01) by persistently eliminating Foxp3[+ ]Tregs and MDSCs. Furthermore, combining anti-VEGFR2 and anti-PD-L1 therapy could not only dramatically increase TILs infiltration, especially CD8[+] T cells, but also significantly reduce the expression of PD-1 and PD-L1.
Conclusion:
Simultaneous blockade of VEGF/VEGFR2 and PD-1/PD-L1 pathways induced a synergistic anti-tumor effect in-vivo, possibly through eliminating immunosuppressive components including Tregs and MDSCs and enhance antitumor immune response.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-031 - Clinical Evaluation of Folate Receptor-Positive Circulating Tumor Cells Detection in Patients with Small Cell Lung Cancer (ID 5480)
14:30 - 15:45 | Author(s): X. Li
- Abstract
Background:
Small cell lung cancer (SCLC) is distinguished by extremely high numbers of circulating tumor cells (CTCs) in comparison to other malignancies, however, the role of CTCs in evaluating chemotherapy effect of SCLC is to be further clarified. The purpose of this study was to investigate the predictive and prognostic role of folate receptor–positive CTCs in unresectable SCLC.
Methods:
In this single-center prospective study, blood samples for folate receptor–positive CTCs analysis were obtained from 80 patients with chemotherapy-naive unresectable SCLC at baseline, after two cycles of chemotherapy, and on disease progression. All patients received chemotherapy with EC or EP regimen for at least two cycles. CTCs number at baseline, after chemotherapy and changes with chemotherapy were evaluated as predictive factors for chemotherapy effect, along with clinical characteristics.
Results:
Of all 80 patients, CTCs was detected at baseline as positive (CTCs>8.7 FU/3mL) in 67 patients, with the percentage of 83.8%, which was not associated with age, sex, smoking status or disease stage. In 72 evaluable patients, the disease control rate was 83.9% (52/62) and 50% (5/10) in CTCs positive and negative patients respectively (P=0.004). In CTCs positive patients, those harboring low levels of folate receptor (8.7
Conclusion:
CTCs number at baseline could be used as a useful prognostic biomarker for SCLC. Reduction in CTCs number with chemotherapy could predict better chemotherapy effect of SCLC.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-092 - Predictive and Prognostic Effect of Circulating Tumor Cells in Non-Small Cell Lung Cancer Treated with Targeted Therapy (ID 4815)
14:30 - 15:45 | Author(s): X. Li
- Abstract
Background:
We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values and the feasibility whether CTCs as a prognostic factor in advanced NSCLC with EGFR mutation/ALK translocation.
Methods:
This was a prospective, unopen-labeled, single-center trial. From July 25, 2014 to March 11,2016, 308 advanced NSCLC patients were enrolled to quantified CTC level by negative enrichment using immunomagnetic beads in combination with folate receptor-directed polymerase chain reaction(PCR) that allows secondary amplification of tiny amounts of CTCs in 3mL peripheral blood before the start of targeted therapy and after one month, every two months hereafter of treatment. Among whom, 272 NSCLC patients with EGFR mutation (exon 19Del mutation: n=135, L858R mutation: n=137) ,39 ALK translocation or undefined lung cancer patients. Sequential analyses were conducted to monitor CTC values during therapy and correlate radiological effects with treatment outcome.
Results:
There was no significant difference between CTC values and patients’ characristics including stage (P= 0.1015), EGFR mutation status(19 del:14.5 CTCs, L858R:12.6 CTCs, P=0.1868) , age (≤60 versus >60 years), gender, smoking status. Of 272 eligible and evaluable patients received EGFR-TKI, we found that patients harboring lower CTC levels (<20.5)were associated with longer PFS(432days, 95%CI:332.7-541.3) than those with higher CTC levels (≥20.5)(PFS: 308days, 95%CI:245.3-370.7;P=0.017). Patients with CTC <20.5 had a DCR of 77.11% compared with 58.49% in CTC >20.5 groups (P=0.008), patients with CTC <20.5 had a ORR of 51.20% compared with 33.96% in CTC >20.5 groups (P=0.029). Decreased CTC values correlated well with partial response after one month or three months’ treatment of EGFR-TKI (P=0.0082 and P=0.0023),but not with stable disease (P=0.1843 and P=0.8606).Multivariate analysis showed that CTC level was an independent prognostic factor for PFS (CTC level<20.5 vs ≥20.5,hazard ratio, 0.497; P=0.014).
Conclusion:
The change of CTCs correlated significantly with radiological response. This strategy may enable non-invasive, predictive and prognostic, specific biomarker in patients undergoing targeted therapies.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- 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 - 15:45 | Author(s): X. Li
- 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.
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P3.02b-104 - Rebiopsy for Patients with Non-Small-Cell Lung Cancer after Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Failure (ID 5808)
14:30 - 15:45 | Author(s): X. Li
- Abstract
Background:
All non-small cell lung cancer patients (NSCLC) with mutant epidermal growth factor receptor (EGFR) eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Rebiopsy and retesting plays more important role in clinical application for exploring resistant mechanisms and determining further therapy strategies. This retrospective study was be performed to determine the percentage of patients who underwent rebiopsy and retesting, and the rebiopsy and retesting effect on clinical strategies and patients prognosis.
Methods:
From October 2011 to March 2016, patients with advanced NSCLC who developed resistance to EGFR-TKIs were included into this study. EGFR mutation detection were performed by ARMS PCR in our institution.
Results:
A total of 539 patients were enrolled in this study with a median progression-free survival time (PFS) of 11.1 months according to RECIST criteria. In all, 297 (55.1%) patients underwent rebiopsy for 178 computed tomography (CT)-guided needle biopsies, 87 serous cavity effusion (including 80 pleural effusion, 3 ascitic fluid and 4 pericardial effusion), 21 superficial lymph node biopsy, 11 other procedures. 354 (65.7%) patients after EGFR-TKIs failure were performed EGFR mutation testing used by 288 rebiopsy and 66 plasma samples. 181 (51.5%) had T790M mutation. In 66 plasma samples, 29 (43.9%) hardored T790M mutation, 23 (34.8%) with mutation in accordance with before EGFR-TKIs treatment, 14 with wild-type EGFR. In all patients, 341 recieved further treatment in our hospital; 236 (69.2%) patients treated with chemotherapy, 43 (12.6%) recieved TKI combined local treatment, 42 (12.3%) changed second or third generation TKIs, 30 switched to other treament. But this part of data still underdone.
Conclusion:
Rebiopsy is feasible in patients after EGFR-TKIs failure. Rebiopsy could effect on further treatment strategies after especially third generarion EGFR-TKI in clinical application. While plasma is also an available surrogate of EGFR mutation testing for patients without suitable lesions for rebiopsy after disease progression.
