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S. Yano
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-008 - Phase I/II Study of Intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR: WJOG 4708L (ID 7556)
09:30 - 09:30 | Author(s): S. Yano
- Abstract
Background:
Erlotinib (ERL) is modestly active to non-small cell lung cancer (NSCLC) with wild type epidermal growth factor receptor (EGFR). We hypothesized that an intermittent delivery of erlotinib and docetaxel (DOC) would increase efficacy.
Method:
This was a multi-center, single-arm phase I/II study in patients with wild type EGFR NSCLC who failed one prior chemotherapy. The phase I was designed a standard 3+3 dose escalation design to determine feasibility, the maximum tolerated dose (MTD) and phase II recommend dose (RD) of ERL on days 2 to 16, in combination with a fixed dose of 60mg/m[2] DOC on day 1. The phase II primary endpoint was objective response rate (ORR) by independent review committee. This study required 41 patients with expected ORR of 30% and threshold ORR of 10% (one-sided α= 0.025; β=0.1). The target number was 45 patients assuming the loss of follow-up cases. All eligible patients had ECOG performance status of 0/1 and adequate organ functions.
Result:
Between Mar 2009 and Dec 2010, 12 patients were enrolled in the phase I, and between May 2011 and Feb 2015, 46 patients in the phase II. Five patients were excluded from per protocol set, because of deviation of entry criteria. Planned dose escalation was completed without reaching a MTD. The RD was determined as 150 mg/dose of ERL. In the phase II, the ORR was 17.1% (95%CI, 7.2-32.1). The median progression free survival and median overall survival were 3.48 months (95%CI, 3.06-4.50) and 11.27 months (95%CI, 8.61-16.56), respectively. Gender, smoking status, or concomitant drugs which influence the ERL metabolism had no significant differences in ORR, or disease control rate. All 46 patients were evaluable for toxicity. The grade 3 non-hematological toxicities included 9 (19.6%) febrile neutropenia, 7 (15.2%) appetite loss, 3 (6.5%) oral mucositis and 3 (6.5%) infections. The grade 4 hematological toxicities were 31 (67.4%) neutropenia. Two treatment related deaths were observed; interstitial lung disease, and pleural infection.
Conclusion:
Intermittent dosing of ERL plus DOC is clinically feasible, but has no statistically significant improvement of ORR, in patients with recurrent NSCLC with wild type EGFR.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-002 - Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations (ID 7917)
09:30 - 09:30 | Author(s): S. Yano
- Abstract
Background:
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatment for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. Therefore, novel therapeutic strategies for KRAS mutated cancer based on molecular mechanisms are needed to improve their prognosis. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle.
Method:
We used NSCLC cells with RAS mutation to evaluate the effect of a MEK inhibitor in combination with a HDAC inhibitor through the expression and localization of FOXO proteins in vitro and in vivo. Protein expression was examined by Western blotting.
Result:
Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell viability of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and increase in cell cycle inhibitors p21 and p27.
Conclusion:
These findings demonstrate that FOXOs might be one of the critical pathways in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-001 - The Impact of MET Inhibition on Small-Cell Lung Cancer Cells Exhibiting Aberrant Activation of the HGF/MET Pathway (ID 7898)
09:30 - 09:30 | Author(s): S. Yano
- Abstract
Background:
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as being extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF). Although aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion, the mechanisms in SCLC have not been elucidated clearly. The aim of the present study was to evaluate the effect of inhibiting the HGF/MET pathway on tumor progression in SCLC with multi-organ metastasis.
Method:
We used eight human SCLC cell lines to elucidate the effect of MET inhibition on tumor progression. MET inhibitors, crizotinib and golvatinib, were used in this study in vitro and in vivo.
Result:
We found that the HGF/MET signaling was aberrantly activated in chemo-resistant or chemo-relapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of these SCLC cells via the inhibition of ERK and AKT signals. We also revealed that treatment with either crizotinib or golvatinib in vivo suppressed the systemic metastasis of SBC-5 cell tumors in NK cell-depleted SCID mice, predominantly via cell cycle arrest.
Conclusion:
These findings reveal that the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells exhibiting aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells.
