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A. Ono
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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): A. Ono
- 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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P3.05 - Early Stage NSCLC (ID 721)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.05-006 - Integrated Genomic Analysis to Assess the Molecular Signature of Japanese Patients with Non-Small Cell Lung Cancer (ID 8950)
09:30 - 09:30 | Author(s): A. Ono
- Abstract
Background:
Increasing molecular evidences have led to the development of molecular-targeted cancer therapies for non-small cell lung cancer (NSCLC). Especially, clinical implementation of EGFR- and ALK-targeted therapies has improved clinical outcomes in lung adenocarcinoma (LUAD). However, not all patients with LUAD benefit from these therapies. Moreover, molecular-targeted therapies for lung squamous cell carcinoma (LUSC) have not progressed much, because definitive drug targets have not been identified. To further expand the range of molecular-targeted therapeutics for NSCLC, this study explored novel therapeutic targets by integrated genomic characterization.
Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 372 patients with NSCLC (LUAD, 296; LUSC, 76) were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by a targeted RNA-sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected with OncodriveFML and Cancer Genome Interpreter.
Result:
Patient characteristics (LUAD; LUSC) were as follows: median age (70; 73), men (52%; 87%), smokers (59%; 99%), ratio of stage I/II/III/IV (70/16/13/1%; 57/32/12/0%). The median tumor mutational burden (TMB) in LUAD and LUSC was 1.59 mutations (mt)/Mb (0.06–65.6) and 5.63 mt/Mb (0.32–26.2), respectively. Eleven and two patients showed a hypermutator phenotype (TMB ≥ 20 mt/Mb) in LUAD and LUSC, respectively. In LUAD, hypermutator had significantly more truncating somatic mutations in DNA repair genes than others (73% vs. 5%, p < 0.0001). Oncogenic fusions of EML4-ALK, KIF5B-RET and EZR-ROS1, and FGFR3-TACC3 were observed in 2.7%, 0.3%, and 0.3% of LUAD, and 2.6% of LUSC, respectively. Promising oncogenic mutations were detected in EGFR, KRAS, SMARCA4, RBM10, BAP1 and PBRM1 in LUAD; in KEAP1, PIK3CA, NFE2L2, KMT2D, NF1, ATM, RASA1 and PTEN in LUSC; and in TP53 and CDKN2A in both tumor types. Promising amplified genes include FRS2, MDM2, CDK4, MET, AURKA, CCNE1 and ERBB2 in LUAD; in SOX2 and CDK6 in LUSC; and in EGFR and TERT in both tumor types.
Conclusion:
Theses promising oncogenic genetic alterations of the patients with NSCLC revealed in this study could contribute to the development of novel molecular-targeted therapies.
