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N. Yamamoto



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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-010 - Impact of the presence of EGFR mutation on the definitive chemoradiotherapy in patients with locally advanced non-small cell lung cancer: pattern of relapses and survival analyses in 198 patients (ID 1227)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      The epidermal growth factor receptor (EGFR) mutational status is an important biomarker in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the frequency and clinical significance of EGFR mutation in patients with potentially curable locally advanced NSCLC (LA-NSCLC) who are eligible for definitive chemoradiotherapy (CRT).

      Methods
      Between Jan 2001 and Dec 2010, we conducted analysis for the presence of EGFR mutations, in consecutive non-squamous NSCLC (mainly in adenocarcinoma) patients who were eligible for CRT. The response rate (RR), progression-free survival (PFS), 2-year progression-free rate, first recurrent sites, and overall survival were investigated according to the EGFR mutational status.

      Results
      A total of 528 patients received CRT at the National Cancer Center Hospital during the study period, of which 274 were diagnosed as having non-squamous NSCLC (mainly adenocarcinoma). Sufficient specimens for mutational analyses could be obtained from 198 patients, and EGFR mutations were found at a frequency of 17% in these patients. In addition to the well-known characteristics of NSCLC patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller (T1/2) primary lesions was also higher in the patients carrying mutated EGFR than in those carrying wild-type EGFR. Patients carrying mutated EGFR showed similar RR (79% vs. 76%), median PFS (11.8 m vs. 10.6 m) and 2-year progression-free survival rate (22% vs. 30%) as compared to those carrying wild-type EGFR. Local recurrence as first relapse occurred less frequently in patients carrying mutated EGFR than in those carrying wild-type EGFR (4% vs. 21%). A majority of the patients with mutated EGFR showing disease progression received EGFR-TKIs (55%), and these patients showed a longer post-progression survival and a higher 5 year survival rate (50% vs. 34%) than the patients with wild-type EGFR.

      Conclusion
      Among the LA-NSCLC patients eligible for definitive CRT who were included in this analysis, 17% harbored EGFR-activating mutations in the carcinoma specimens. Although definitive CRT was similarly effective in both patients with mutated EGFR and wild-type EGFR, substantially lower frequency of local relapse was noted in the patients carrying mutated EGFR. Among the LA-NSCLC patients harboring EGFR mutations who developed disease progression, those treated with EGFR-TKIs showed a longer post-progression survival and overall survival as compared to those who did not receive EGFR-TKIs.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-029 - An analysis of the drug-drug interaction between docetaxel and gefitinib in patients with advanced non-small cell lung cancer (ID 1564)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      Both Docetaxel (DTX) and Gefitinib (Gef) have been established as a standard therapy for the treatment of non-small cell lung cancer (NSCLC). Since these active two agents have different mechanisms of action as well as toxicity profiles, the combined use of DTX and Gef could be highly effective for the advanced NSCLC. However, as they are both metabolized by cytchrome P450 (mainly CYP3A4) enzyme, there are concerns about drug-drug interactions. The aim of this study is to assess the influence by the combined use of Gef on DTX's pharmacokinetics (PKs) and toxicity in patients with advanced NSCLC.

      Methods
      DTX was intravenously administered over 1-hr every 3 weeks on day 1. Gef (250-mg) was co-administrated orally once daily from day 2. The dose of DTX was escalated from 45 mg/m[2] (level 1, n = 6) to 60 mg/m[2] (level 2, n = 6). The total of 20-point PK samplings were performed on day 1 (DTX alone) and day 22 (DTX + Gef) to measure plasma concentrations of DTX using high- performance liquid chromatography (HPLC). DTX PK profile was estimated by non-compartment analysis. Analysis of variance was performed on AUC~0-24h~ to estimate adjusted mean differences between day 1 and 22. DTX clearance (CL), geometric mean (GM) of AUC, adjusted GM ratio (GMR, i.e., the ratio of DTX AUC on day 22 to that in day 1) and 90% CI of the GMR were also calculated.

      Results
      Twelve patients with advanced NSCLC were enrolled. Two out of 12 patients at dose level 1 withheld the second cycle of treatment (i.e., on day 22) due to progressive disease, and DTX PKs data were available for the rest of 10 patients treated on day 1 and 22. The toxicity profiles of DTX and Gef in this study were generally acceptable, and frequency and severity of hematological toxicity possibly related to DTX were similar to those with historical data in Japanese NSCLC patients. The ≥ grade 3 neutropenia was observed in 66% of patients. GMs of AUC~0-24 ~on day 1 and 22 were 1128 and 1184 ng・h /ml at dose level 1 (n=4), while those were 1827 and 1630 ng・h /ml at dose level 2 (n=6). GMs of DTX CL in all patients on day 1 and 22 were 60 and 63 L/h and GMRs at dose level 1 and 2 were 1.05 (90%CI: 0.96-1.14) and 0.89 (90%CI: 0.82-0.97), respectively.

      Conclusion
      The above results demonstrate that DTX PKs is not affected by the combined use of Gef in patients with advanced NSCLC. These two active agents can be safely co-administered.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-016 - Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small-cell lung cancer harboring an epidermal growth factor receptor activating mutation (ID 1107)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      Gefitinib yields a longer progression-free survival (PFS) period than platinum-doublet chemotherapy as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum-doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib monotherapy.

      Methods
      We performed a phase II study of the following first-line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1-56. After a two-week rest, three cycles of cisplatin (80 mg/m[2]) and docetaxel (60 mg/m[2]) were administered on days 71, 92, and 113. Gefitinib was re-started on day 134 and was continued until progression. The primary endpoint was the two-year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2-year PFS.

      Results
      Thirty-three Japanese patients were enrolled. Twenty-five patients could recieve the second gefitinib, 12 achieved a PFS period of over 2 years, and 7 continued to receive the protocol treatment without experiencing progression. The 1-, 2-, and 3-year estimated PFS rates were 67.0%, 40.2%, and 36.9%, respectively, and the median PFS time was 19.5 months. The 1-, 2-, and 3-year estimated survival rates were 90.6%, 71.9%, and 64.8%, respectively, and the median survival time had not been reached at the time of analysis. Treatment-related deaths and unexpected severe toxicities were not seen.

      Conclusion
      Our results indicated that first-line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising in patients with advanced NSCLC with EGFR mutation. A phase III study of this treatment compared with gefitinib monotherapy is warranted.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P2.11-012 - Phase Ia/Ib study of the anti-MET antibody onartuzumab (MetMAb) in patients with solid tumors or MET-positive lung cancer (ID 1164)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      MET, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), play a key role in cancer progression and prognosis. Aberrant activation of the HGF/MET pathway can enhance invasion, proliferation, and survival of cancer cells, providing a rationale for developing therapeutics that block MET activation. Onartuzumab was engineered as a unique recombinant humanized one-armed anti-MET monoclonal antibody that inhibits HGF-induced MET signaling without agonistic activity.

      Methods
      This 2-stage study was the first in Japanese patients to evaluate efficacy, safety, and pharmacokinetics (PK) of onartuzumab or onartuzumab in combination with erlotinib. In Stage 1—a 3+3 dose-escalation stage—patients with advanced solid tumors, refractory to the standard of care or for which there is no standard of care, received onartuzumab at doses of 4, 15, or 30 mg/kg IV once every 3 weeks until disease progression. In Stage 2—a combination stage—onartuzumab at a dose of 15 mg/kg IV once every 3 weeks was given in combination with erlotinib 150 mg/day to patients with advanced MET-positive non–small-cell lung cancer who had received at least 1 prior platinum-containing regimen (as regards EGFR-TKI, only 1 regimen was permitted); this regimen was continued until disease progression. Exploratory biomarker analyses were also conducted.

      Results
      In Stage 1, 9 patients (male/female: 6/3) were enrolled. Median age was 68 years. There were no dose-limiting toxicities (DLTs) and the maximum tolerated dose was not reached at 30 mg/kg. Hypoalbuminemia (33.3%) and constipation (33.3%) were the most frequent adverse events (AEs). Hypoalbuminemia was the only AE occurring at grade 3 severity, indicating that onartuzumab was well tolerated up to 30 mg/kg. In Stage 2, 6 patients were enrolled (male/female: 1/5; adeno/squamous: 5/1; EGFR wild type/mutant: 3/3; median age 69 years). There were no DLTs. The most frequent AE was diarrhea (83.3%). Grade 1/2 AEs occurred in all patients. There was one grade 3 case of each of deep vein thrombosis, pulmonary embolism, rash, hypoxia, dermatitis acneform, diarrhea, and neutropenia. No grade 4/5 AE was observed. PK analysis from patients in Stages 1 and 2 indicated dose proportionality of C~max~ and AUC. No drug–drug interaction between onartuzumab and erlotinib was observed. In Stage 2, progression-free survival was beyond 6 months in 2 patients (7.2 and 12.2 months); 1 patient achieved a partial response. Median circulating HGF concentration after onartuzumab was elevated to approximately three times the baseline level.

      Conclusion
      Onartuzumab alone or with erlotinib was well tolerated in Japanese patients. The PK profile of onartuzumab was not affected by co-administration with erlotinib.

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      P2.11-040 - Phase 1 study of ipilimumab in combination with paclitaxel/carboplatin in patients with non-small cell lung cancer (ID 2775)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      Ipilimumab is a fully human IgG1 monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) and augments antitumor T-cell responses. In a global phase 2 study in subjects with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), ipilimumab administrated in a phased schedule in combination with paclitaxel/carboplatin, improved immune-related progression-free survival with an acceptable safety profile. A pronounced benefit was observed in squamous NSCLC. We conducted the phase 1 study of ipilimumab in combination with paclitaxel/carboplatin in Japanese patients with NSCLC.

      Methods
      Target population was Japanese subjects with stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC. Patients received ipilimumab 3 mg/kg or 10 mg/kg (starting at Cycle 3) in addition to paclitaxel 175 mg/m2 and carboplatin AUC=6 every 3 weeks for up to 6 cycles. Dose limiting toxicity (DLT) was evaluated during the first two cycles of ipilimumab administration (Cycle 3 and Cycle 4). The recommended dose (RD) was defined as the highest dose at which no more than 2 out of 6 ipilimumab-treated patients experienced a DLT.

      Results
      A total 15 patients were enrolled and 12 patients received ipilimumab (female/male=1/11, range of age =53-70, stage IIIB/IV/recurrent=0/9/3, squamous/non-squamous= 1/ 11, ipilimumab 3 mg/kg / 10 mg/kg=6/6). DLTs were observed in 2 out of 6 ipilimumab-treated patients in ipilimumab 3 mg/kg arm (febrile neutropenia, amylase increased / 1patient, thrombocytopenia / 1patient) and 1 out of 6 ipilimumab -treated patients in ipilimumab 10 mg/kg arm (entercolitis, total-bilirubin increased, lipase increased). Of 10 patients evaluable for tumor response based on RECIST criteria, partial response and stable disease were achieved in 6 and 4 patients, respectively.

      Conclusion
      For Japanese patients with NSCLC, the RD of ipilimumab in combination with chemotherapy was identified as 10 mg/kg and it demonstrated acceptable safety profile and potential efficacy. Two global Phase 3 studies are ongoing in subjects evaluating ipilimumab 10 mg/kg in combination with chemotherapy in advanced squamous NSCLC (with carboplatin/paclitaxel) and extensive stage SCLC (with etoposide/platinum).

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-007 - Clinical feasibility study of a novel sorting system for detecting EGFR mutations from captured circulating tumor cells in patients with lung cancer (ID 1046)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      Circulating tumor cells (CTCs) are cells that originate from a primary solid tumor and are found transiting the circulatory system. CTCs are expected to provide useful clinical information on biology of their primary, as ”liquid biopsy.” We have developed a novel cell-sorting system equipped with a disposable microfluidic chip (On-chip Sort, On-Chip Biotechnologies, Tokyo, JAPAN). At American Association for Cancer Reseach meeting 2013, we previously reported about its CTCs enumeration capability when performed in a clinical setting. Currently, On-chip Sort enables recovery of more CTCs than conventional cell sorting systems for further characterization.

      Methods
      In a preclinical study, PC-9 and H1975 human lung cancer cells harboring EGFR mutations (E746_A750del and L858R, T790M, respectively) were spiked into the blood from healthy donors. After samples were negatively enriched using anti-CD45-coated magnetic beads, the spiked cancer cells in the samples were captured by On-chip Sort. The captured tumor cells were subjected to mutation detection by ARMS/Scorpion PCR assay. A clinical feasibility study was then conducted in lung cancer patients harboring EGFR mutations.

      Results
      On-chip Sort performed recovery of the spiked PC-9 and H1975 cancer cells (5 cells in 4 ml of blood) in a preclinical experiment. Successively, we were able to detect the EGFR mutations from the captured cells. In a clinical feasibility study, 4 blood samples from lung cancer patients harboring EGFR mutation were collected and were evaluated. All the samples were successful in capturing CTCs by On-chip Sort. ARMS/Scorpion PCR assay detected the EGFR deletion mutation from two of the samples (50%).

      Conclusion
      The preclinical study and the results of the clinical feasibility study suggested the possibility of the On-chip Sort assay to detect EGFR mutations from peripheral blood of patients with lung cancer. Further investigation is going to be conducted to evaluate the correlation of EGFR mutations in captured CTCs and primary lesions.

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    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.13-002 - Stereotactic radiosurgery for brain metastases after prophylactic cranial irradiation in limited disease small-cell lung cancer (ID 1137)

      09:30 - 09:30  |  Author(s): N. Yamamoto

      • Abstract

      Background
      Brain metastases are very common in patients with small-cell lung cancer (SCLC). Prophylactic cranial irradiation (PCI) has been shown to reduce the incidence of brain metastases and to improve overall survival in patients with limited-disease SCLC (LD-SCLC). However, brain metastases are often observed after PCI, and the optimal treatment for these brain metastases is still unclear. The present study investigated the recurrence of brain metastases after PCI in patients with LD-SCLC and the therapeutic efficacy of stereotactic radiosurgery for these metastases.

      Methods
      Between December 2000 and December 2012, 228 patients with LD-SCLC were treated and 98 of these patients with a complete response (CR) or a near CR to chemoradiotherapy underwent PCI at the National Cancer Center Hospital. We retrospectively reviewed the medical records and imaging data for these 98 patients.

      Results
      Twenty-four (24%) of the 98 patients developed brain metastases after PCI. The characteristics of the 24 patients were as follows: median age, 62 years (49-72 years), male/female, 21/3; performance status 0/1/2, 2/16/6. Twelve (50%) of the 24 patients had cranial recurrences only. Twelve patients had single brain metastases, and 12 patients had multiple lesions. Nine patients had neurological symptoms due to brain metastases. The median period after PCI until the appearance of the metastases was 9.9 months (1.1-34.9 months). Fifteen (63%) of the 24 patients underwent stereotactic radiosurgery (gamma knife radiosurgery [GKRS]), and one patient received whole brain radiotherapy. Six patients were treated with chemotherapy plus best supportive care (BSC), and two patients underwent BSC alone. The 15 patients who received GKRS had brain metastases with/without extracranial lesions (7 with, 8 without); three were symptomatic, and 12 were asymptomatic. The median number of brain metastases at the time of the first GKRS was one (range, 1-4). The local control rate of the lesions treated with GKRS was 86.7% (complete response in 3 patients, partial response in 7 patients, and stable disease in 3 patients). Five patients underwent further GKRS because of newly developing brain metastases (median: 4 times, range: 2-7 times). The median intracranial control time of the 15 patients was 6.8 months. The median survival time of the 15 patients was 29.3 months after the initial diagnosis, 13.7 months after the development of brain metastases, and 12.7 months after the treatment of GKRS. The median survival time of the patients without extracranial lesions was 20.2 months after the development of brain metastases and tended to be longer than that of the patients with extracranial lesions (12.6 months). Severe adverse events arising from GKRS were not observed in this series.

      Conclusion
      Stereotactic radiosurgery may be an effective option as a salvage therapy for brain metastases after PCI in patients with LD-SCLC.