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O. Honjo



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    ORAL 10 - SCLC (ID 98)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      ORAL10.07 - Clinical and Molecular Profiling of Surgically Resected Small Cell Lung Cancer (ID 2235)

      10:45 - 12:15  |  Author(s): O. Honjo

      • Abstract
      • Presentation
      • Slides

      Background:
      NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).

      Methods:
      We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).

      Results:
      Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.

      Conclusion:
      These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-072 - A Phase II Study of Carboplatin/Pemetrexed/Bevacizumab Followed by Bevacizumab/Erlotinib Maintenance for NonSq-NSCLC with Wild-Type EGFR (ID 1677)

      09:30 - 17:00  |  Author(s): O. Honjo

      • Abstract
      • Slides

      Background:
      Maintenance therapy (MT) after platinum doublet chemotherapy has been shown to improve progression-free survival (PFS) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC), whereas optimal strategies for MT, such as continuation or switch maintenance, have yet to be determined. ATLAS trial adopted a combination maintenance strategy design in which both EGFR-positive and -negative NSCLC patients received platinum doublet chemotherapy at the choice of investigators plus bevacizumab (Bev) followed by Bev with either erlotinib (Erl) or a placebo as a maintenance therapy. The trial demonstrated that Erl plus Bev was favorable for PFS, but not for either OS or toxicity, when compared with placebo plus Bev. The aim of this phase II study was to clarify the effects and safety of a fixed induction regimen: carboplatin (Cb)/pemetrexed (PEM)/Bev followed by Bev plus Erl as a maintenance therapy in non-squamous (nonSq)-NSCLC patients with wild-type (WT) EGFR.

      Methods:
      All eligible patients (pts) had treatment-naive nonSq-NSCLC (stage IIIB, IV, or postoperative recurrent) with WT EGFR. Cb (AUC 5), PEM (500 mg/m[2]) and Bev (15mg/kg) were administered on Day 1 every three weeks for four-to-six cycles and maintenance therapy with Bev (15mg/kg) once every three weeks plus continuous Erl (150mg/body) was administered until occurrence of either disease progression or unacceptable toxicity. The primary endpoint was PFS at 6 months (mo). The secondary endpoints included OS, tumor response, toxicity, and quality of life (QOL).

      Results:
      From September 2011 to June 2014, 51 pts were enrolled. Fifty pts were evaluated for the efficacy and safety of the treatment. The median follow-up duration was 14.3 months (range: 1.1-30.7). The median age was 64 years (range: 36-74); male/female=27/23 (54/46%); ECOG PS 0/1=28/22 (56/44%); Stage IIIB/IV/recurrent=5/41/4 (10/82/8%); adenocarcinoma/NSCLC=48/2 (96/4%). The median cycles of the induction/maintenance therapy were 4 (range: 1-6)/4 (range: 1-20). Twenty-nine pts (58%) received the MT. Overall response rate was 48.0% (95% CI: 34.8-61.5%), and disease control rate was 86% (95% CI: 73.8-93.0%). Six-month PFS rate was 59.5% (95% CI: 45.0-72.6%). Median OS and PFS were 18.4 mo (95% CI: 11.9-24.9 mo) and 6.5 mo (95% CI: 5.8-7.2 mo), respectively. CTCAE Grade (Gr) 3/4 hematological toxicities were neutropenia (48%/3.4%), anemia (18%/3.4%) and thrombocytopenia (22%/0%). The most frequent Gr 3/4 non-hematological toxicities were anorexia (14%/3.4%), hypertension (10%/3.4%), malaise (6%/3.4%), nausea (6%/0%) and rash (0%/10%). There were two interstitial lung diseases (Gr1), one gastrointestinal perforation (Gr4), and one treatment-related death due to ventricular fibrillation. QOL results are still under analysis.

      Conclusion:
      Cb/PEM/Bev followed by maintenance Bev/Erl was effective and well tolerated in NS-NSCLC pts with WT EGFR.

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