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Y. Ohe
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.02 - Association of Variations in HLA-Class II and Other Loci with Susceptibility to EGFR-Mutated Lung Adenocarcinoma (ID 4192)
11:10 - 11:20 | Author(s): Y. Ohe
- Abstract
- Presentation
Background:
Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention.
Methods:
We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls.
Results:
Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press).
Conclusion:
This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.06 - Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients (ID 5915)
15:15 - 15:25 | Author(s): Y. Ohe
- Abstract
- Presentation
Background:
Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice.
Methods:
This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns.
Results:
1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments.
Conclusion:
Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520)
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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: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-005 - A Retrospective Study of Sequential Chemoradiotherapy for LD-SCLC Patients in Whom Concurrent Therapy is Not Indicated (ID 4066)
14:30 - 14:30 | Author(s): Y. Ohe
- Abstract
Background:
The standard treatment for limited-disease small-cell lung cancer (LD-SCLC) is a combination of cisplatin-doublet chemotherapy and concurrent thoracic radiotherapy. However, sequential radiotherapy, rather than concurrent radiotherapy, is selected for some cases because of concerns regarding the irradiation field, patient age, comorbidities, or performance status. Nevertheless, the efficacy of sequential chemoradiotherapy in patients in whom concurrent chemoradiotherapy is contraindicated is not well known.
Methods:
We retrospectively analyzed 286 patients with LD-SCLC at the National Cancer Center Hospital and the NTT Medical Center in Japan between 2000 and 2014. We then compared the clinical characteristics and treatment outcomes of patients undergoing sequential radiotherapy with those undergoing concurrent radiotherapy.
Results:
One hundred and eighty-three patients received concurrent chemoradiotherapy and 30 received sequential chemoradiotherapy. The median age of the patients was 64 years (range, 18-81 years) for the concurrent group and 71.5 years (50-83 years) for the sequential group. The concurrent group contained 43 women (23%), while the sequential group contained 9 women (30%). The major reasons for the selection of sequential radiotherapy were patient age (13 patients), a large irradiation field (8 patients), and comorbidities (5 patients). In the sequential group, 23 (77%) received conventional radiotherapy, whereas 7 (23%) received accelerated hyperfractionated radiotherapy. The median overall survival period was 34.5 months for the concurrent group and 27.6 months for the sequential group (P = 0.39). The 2-, 3-, and 5-year survival rates were 71%, 50%, and 40% for the concurrent group and 56%, 56%, and 35% for the sequential group. Recurrence was seen in 149 patients (81%) in the concurrent group and 19 patients (63%) in the sequential group.
Conclusion:
We obtained treatment outcomes for patients who could not receive concurrent radiotherapy but could complete sequential radiotherapy that were comparable with the outcomes for those who received concurrent radiotherapy. For patients in whom concurrent chemoradiotherapy is not indicated, sequential chemoradiotherapy should be considered.
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P1.07-037 - Clinicopathological Significance of Cancer Stem-Like Cell Markers in High-Grade Neuroendocrine Carcinoma of the Lung (ID 4993)
14:30 - 14:30 | Author(s): Y. Ohe
- Abstract
Background:
Over the past decade, cancer stem cells or cancer stem-like cells (CSLCs) have been identified in various tumors. However, few studies have examined the significance of CSLC marker expression in high-grade neuroendocrine carcinoma (HGNEC). This study aimed to evaluate the clinicopathological significance of CSLC markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC).
Methods:
We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥ 10 represented positive expression.
Results:
There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS.
Conclusion:
The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.
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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-017 - Differences of Central Nerve System Metastasis during Gefitinib or Erlotinib Therapy in Patients with EGFR-Mutated Lung Adenocarcinoma (ID 4879)
14:30 - 14:30 | Author(s): Y. Ohe
- Abstract
Background:
A few reports have suggested a difference in the incidences of new metastasis to the central nerve system (CNS) during gefitinib and erlotinib therapy. However, a direct comparison of these two therapies has not yet been reported. We planned a retrospective study to investigate the incidences of CNS metastasis progression (new CNS metastasis or progression of existing CNS metastasis) during gefitinib and erlotinib therapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation.
Methods:
We retrospectively analyzed the incidences of CNS metastasis progression and the outcomes of NSCLC patients harboring EGFR mutation who received gefitinib or erlotinib as a first-line EGFR-TKI treatment at the National Cancer Center Hospital between 2008 and 2014.
Results:
A total of 175 patients were analyzed; 148 patients had received gefitinib, and 27 had received erlotinib. The median (range) ages were 64.5 (32-81) years and 62.0 (27-68) years, respectively; exon 19 deletion/L858R point mutations were present in 84/64 (56.7%/43.3%) and 17/10 (63.0%/37.0%) cases, respectively. The status of CNS metastasis before EGFR-TKI therapy was negative/positive in 105/43 (71.0%/29.0%) cases in the gefitinib group and 21/6 (77.8%/22.2%) cases in the erlotinib group, respectively. The incidence of CNS metastasis progression in the gefitinib group tended to be higher than that in the erlotinib group (29.0% vs. 11.1%; P = 0.051). In patients without CNS metastasis before EGFR-TKI therapy, the incidence of new CNS metastasis during EGFR-TKI treatment was significantly higher in the gefitinib group than in the erlotinib group (24.7% vs. 4.8%, P = 0.04). The progression-free survival (PFS) and overall survival (OS) periods of the patients who presented with CNS progression were shorter than those of the patients who presented without CNS progression (median PFS, 9.5 vs. 12.6 months, P = 0.034; median OS, 23.8 vs. 34.1 months, P = 0.002). Fifty-six patients underwent re-biopsy after the failure of EGFR-TKI therapy, but no difference in the incidences of EGFR T790M mutation was seen between patients with and those without CNS metastasis progression (40.0% for patients without CNS progression vs. 63.6% for patients with CNS metastasis progression, P = 0.19).
Conclusion:
The incidence of the progression of CNS metastasis during gefitinib therapy was higher than that during erlotinib therapy. In addition, the difference in this incidence was more remarkable among patients who had not developed CNS metastasis prior to the start of EGFR-TKI therapy.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-023 - A Phase III Study Comparing Gefitinib and Inserted Cisplatin plus Pemetrexed with Gefitinib for EGFR-Mutated Advanced Non-Squamous NSCLC (ID 4587)
14:30 - 14:30 | Author(s): Y. Ohe
- Abstract
Background:
Overcoming and prevention of acquired resistance to EGFR-TKIs in the treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC) is a critical issue. Although third-generation EGFR-TKIs, such as osimertinib, which are potent against EGFR carrying the T790M mutation, have been developed, they are insufficient to overcome other resistance mechanisms. We hypothesized that the insertion of platinum-doublet chemotherapy with EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong the patient survival. An early phase II study of inserted cisplatin and docetaxel with gefitinib showed promising outcomes, including a median progression-free survival of 19.5 months and median survival time of 48.0 months.
Methods:
Figure 1 This study (JCOG1404 / WJOG8214L: AGAIN study) is an intergroup, multicenter, randomized phase III study conducted by the Japan Clinical Oncology Group (JCOG) and the West Japan Oncology Group (WJOG). The objective of this study is to confirm the superiority, in terms of the overall survival, of the study treatment, described below, over gefitinib monotherapy. As the study treatment, gefitinib are administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin and pemetrexed are administered on days 71, 92, and 113. Thereafter, gefitinib is re-started on day 134 and continued until disease progression. The secondary endpoints are progression-free survival, response rate, adverse events, severe adverse events and proportion of EGFR T790M mutation positive in the tumor samples at disease progression. The key eligibility criteria are: patients with advanced or recurrent non-squamous NSCLC harboring EGFR activating mutations (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. This study was started in December 2015, and a total of 500 patients will be enrolled over a period of 3 years. This trial has been registered at UMIN-CTR[umin.ac.jp/ctr/] as UMIN000020242.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c - Poster Session with Presenters Present (ID 472)
- 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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P3.02c-097 - Nivolumab in Elderly or Poor Performance Status Patients with Advanced Non-Small Cell Lung Cancer (ID 4213)
14:30 - 14:30 | Author(s): Y. Ohe
- Abstract
Background:
Nivolumab showed durable antitumor activity and survival benefit in previously treated patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy and safety of nivolumab in elderly (≥75 year old) or poor performance status (PS; ≥2) patients with NSCLC, most of who have been excluded from clinical trials.
Methods:
This was a retrospective cohort study investigating the outcome of patients with advanced or post-operative recurrence NSCLC who received nivolumab from January to April 2016 in the National Cancer Center Hospital. Patient characteristics, the efficacy of nivolumab, survival, and adverse events were analyzed. Immunohistochemical (IHC) expression of programmed cell death ligand 1 (PD-L1) in pretreatment tissue (10 biopsy and 3 operation specimens) was assessed using the rabbit monoclonal PD-L1 antibody (clone 28-8; Abcam). Staining of ≥1% of tumor cells was considered as the cut-off value of positive PD-L1 expression.
Results:
A total of 20 patients, including 10 elderly patients with non-squamous NSCLC and 10 poor PS patients (7 with non-squamous and 3 with squamous NSCLC), received nivolumab. Objective responses were observed in 6 patients: 4 (40%) elderly and 2 (20%) poor PS patients. The median progression-free survival was 2.8 months and 1.7 months in the elderly and poor PS groups, respectively. Of 13 cases with quantifiable IHC results, 10 cases were positive for PD-L1. PD-L1 expression was not predictive of a response, which occurred in 4 of 10 (40%) patients with PD-L1-postive tumors, 1 of 3 (33%) patients with PD-L1-negative tumors, and 1 of 7 (14%) patients with an unknown PD-L1 status (p = 0.52). Treatment-related adverse events led to discontinuation of nivolumab in 6 patients (1 elderly and 5 poor PS patients). Figure 1
Conclusion:
Nivolumab had a clinically meaningful response for elderly or poor PS advanced NSCLC patients, but toxicity led to the discontinuation of nivolumab.
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SC15 - Clinical Trials: How to Set Priorities? (ID 339)
- Event: WCLC 2016
- Type: Science Session
- Track: Trial Design/Statistics
- Presentations: 1
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SC15.04 - The Japanese Perspective (ID 6661)
11:45 - 12:00 | Author(s): Y. Ohe
- Abstract
- Presentation
Abstract:
In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started. JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986. Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014.
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