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B.C. Cho



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.08 - The frequency and impact of ROS1-rearrangement on clinical outcomes in never-smokers with lung adenocarcinoma (ID 1253)

      16:15 - 17:45  |  Author(s): B.C. Cho

      • Abstract
      • Presentation
      • Slides

      Background
      To determine the frequency and predictive impact of ROS1-rearrangements on treatment outcomes in never-smoker patients with lung adenocarcinoma.

      Methods
      We concurrently analyzed ROS1- and ALK- rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never-smokers with lung adenocarcinoma. ROS1- and ALK- rearrangements were identified by fluorescent in situ hybridization.

      Results
      Of 208 tumors screened, seven (3.4%) were ROS1-rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase polymerase chain reaction. The frequency of ROS1-rearrangement was 5.7% (6/105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1-rearrangement had a higher objective response rate (ORR; 60.0 vs. 8.5%; P=0.01) and a longer median progression-free survival (PFS; not reached vs. 3.3 months; P=0.008) to pemetrexed than those without ROS1/ALK-rearrangement. The PFS to EGFR-TKIs in patients harboring ROS1-rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 vs. 7.8 months; P=0.01).

      Conclusion
      The frequency of ROS1-rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1-rearrangement is a druggable target in East-Asian never-smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1-rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

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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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      P1.10-025 - Randomized phase II trial of Safety of Biweekly Docetaxel/Cisplatin vs Gemcitabine/Cisplatin as first-line therapy for advanced non-small cell lung cancer patients who are elderly or poor performance status (ID 1484)

      09:30 - 16:30  |  Author(s): B.C. Cho

      • Abstract

      Background
      Cisplatin with docetaxel (DP) or gemcitabine (GP) is one of standard regimen for advanced non-small cell lung cancer(NSCLC). DP is regarded more toxic compared with GP. There is an increasing interest in a biweekly split administration of DP to reduce its toxicity. Hypothesis here was 1st-line biweekly DP is as safe as GP in elderly or poor performance status (PS) patients (pts).

      Methods
      Chemotherapy naïve pts with NSCLC (IIIB/IV) who were elderly(>65) or poor PS (ECOG 2) were randomized to biweekly DP or GP by balancing for ECOG (0-1 vs 2), stage (IIIB vs IV) and age (<65 vs >65). DP with docetaxel (35mg/m2)/cisplatin(30mg/m2) iv or GP with gemcitabine (1000mg/m2) /cisplatin(30mg/m2) iv was given on days 1,8 every 3 weeks . Chemotherapy lasted upto 6 cycles or until progression. Primary endpoint was safety (proportion of grade 3/4 toxicities). Planned sample size was 49 pts in each.

      Results
      From Nov 2009 to Jan 2013, a total of 97 pts were randomized (DP 50/GP 47). Adenoca was 58% in DP and 51% in GP while that of squamous cell ca 34% in DP and 40% in GP. Stage IIIB/IV was 33%/66% in DP and 42%/59% in GP. In DP a total 228 adverse events (AEs) were reported and 27 were grade 3/4 toxicities while 211 AEs and 21 grade 3/4 toxicities in GP. Neutropenia was the most frequent grade 3/4 toxicity in both (DP 8.9%; GP 15.9%). In DP grade 3/4 leukopenia (8.9%), hyponatremia(6.7%), anemia(4.4%) and anorexia (4.4%) were observed while anemia (9.1%) and hyponatremia (6.8%) in GP. In total AEs, anemia was the most common in both (DP 66.7% ; GP 63.6%). Then, in the following order, hyponatremia (53.3%), anorexia (53.3%) and fatigue(40%) were common in DP while anorexia, (56.8%), fatigue(36.4%) and neutropenia(45.5%) were common in GP. Death during treatment was occurred in 1 pt in each. Both regimen showed similar grade 3/4 toxicities with similar profiles. Survivals seemed to be favorable in GP compared with DP with no statistical significance. Progression-free survivals were 3.72 (DP) and 5.56 (GP) months (p=0.341). Overall survivals were 14.93 (DP) and 20.82 (GP) months (p=0.209).

      Conclusion
      This study showed DP is similar with GP in terms of toxicity and efficacy in treatment of elderly or poor performance patients.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-001 - Transglutaminase 2 can be predictive of epidermal growth factor receptor tyrosine kinase inhibitor efficacy and cytotoxic chemotherapy success in non-small cell lung cancer (ID 96)

      09:30 - 16:30  |  Author(s): B.C. Cho

      • Abstract

      Background
      Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and the constitutive activation of NF-κB, a pro-inflammatory transcription factor. We investigated the association of the EGFR-TKI or cytotoxic chemotherapy clinical efficacy with transglutaminase 2 and NF-ĸB expression in non-small cell lung cancer (NSCLC).

      Methods
      TG2 and NF-ĸB expression was immunohistochemically studied in 120 patients with NSCLC who received an operation. Kaplan-Meier survival analysis and Cox regression analysis were used to estimate the effect of TG2 and NF-ĸB expression on chemotherapy clinical efficacy.

      Results
      Median age of patients was 64 years (41–82). There were 102 (85%) cases of adenocarcinoma and 18 patients (15%) had other histologies. Eight patients received adjuvant chemotherapy, 29 received platinum-based doublet chemotherapy and another 29 patients received EGFR-TKI. Smoking status was as follows: 25 current, 16 former and 79 never. There were 55 patients with an EGFR mutation. TG2 median value was 50 (0 to 300) and NF-kB median value was 20 (0 to 240). Response to platinum-based doublet was as follows: Overall response rate (ORR) was 13.8% and disease control rate (DCR) was 69% (Complete response (CR) 0%, partial response (PR) 13.8%, stable disease (SD) 55.2% and progressive disease (PD) 24.1%). Responses to EGFR-TKI was as follows: ORR was 24.1% and DCR was 58.6% (CR 3.4%, PR 20.7%, SD 34.5% and PD 34.5%). Among the 88 patients who received adjuvant chemotherapy, disease-free survival (DFS) did not differ between the low and high TG2 groups. Among patients (n=29) who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was significantly longer in the low TG2 group when compared with the high TG2 group (34.0 versus 15.0 months, p = 0.003). Among those who received EGFR-TKI (n=29) (first line 7, second line 18, third line 3, fourth line 1), PFS was significantly longer in the low TG2 group when compared with high TG 2 group (11.0 versus 2.0 months, p = 0.013). In patients with EGFR wild-type mutations treated with EGFR-TKI, progression free survival was longer in patients with low TG2 expression (9.0 vs 2.0 months, p=0.013).

      Conclusion
      This study suggests that TG2 expression can be predictive of success of cytotoxic chemotherapy and EGFR-TKI for patients with non-small cell lung cancer, particularly in patients with EGFR wild-type mutations.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-007 - Preliminary safety results of MONET-A: A Prospective, Asian Phase 3, Randomized, Placebo-controlled, Double-blind Trial of the Investigational agent Motesanib in Combination with Paclitaxel and Carboplatin for Asian patients of Advanced Non-squamous Non-small Cell Lung Cancer (ID 889)

      09:30 - 16:30  |  Author(s): B.C. Cho

      • Abstract

      Background
      Inhibition of the vascular endothelial growth factor receptor (VEGFR) pathway appears to be an effective treatment strategy for frontline non-small cell lung cancer (NSCLC), but small molecule VEGFR kinase inhibitors have failed to show survival benefit. Motesanib is an orally administrated small molecule antagonist of VEGFR 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-kit). In a subgroup analysis of Asian patients (n = 227) from the global phase 3 study (MONET-1), treatment of motesanib in combination with paclitaxel and carboplatin demonstrated significant improvements in overall survival (HR, 0.65; 95% CI, 0.46-0.91), progression free survival (HR, 0.59; 95% CI, 0.44-0.79), and overall response rate compared to placebo. To prospectively evaluate efficacy and safety of motesanib in Asian patients with NSCLC, this phase 3 study has initiated.

      Methods
      Stage IV/recurrent non-squamous NSCLC patients without prior chemotherapy receive oral motesanib (125 mg) or placebo once daily in combination with paclitaxel (200 mg/m[2]) and carboplatin (AUC = 6) every 3 weeks up to 6 cycles and continue motesanib or placebo until disease progression, consent withdrawal, or unmanageable adverse event. ECOG performance status 0 or 1 are eligible for this study regardless of epidermal growth factor receptor (EGFR) mutation status. Patients with untreated or symptomatic central nervous system metastases are excluded. Approximately 400 patients will be randomized in a double-blind 1:1 ratio to motesanib or placebo. Stratification factors include EGFR mutation status, weight loss of ≥ 5% in the previous 6 months, and region. This MONET-A trial will be assessed twice by the Independent Data Monitoring Committee (IDMC), at the time 50 and 150 patients complete their first cycle for unblinded safety data.

      Results
      This study initiated in July 2012 and is being conducted in Japan, Korea, Taiwan, and Hong Kong. The enrollment is ongoing. First evaluation by IDMC was performed using the data as of 26 December 2012. A total of 64 patients were enrolled and 63 patients (63 Japanese; median age, 64.5 years) received study treatment. All the blinded patients who received study treatment experienced adverse events (AEs); Grade 3 to 5 AEs were reported in 38 patients (60.3%). Common AEs included alopecia (63.5%), peripheral sensory neuropathy (57.1%), and decreased appetite (50.8%). 7 patients had 8 serious AEs (SAEs). SAEs considered to be related to blinded study drug were cholecystitis in 2 patients, gastric ulcer haemorrhage, nausea, and upper gastrointestinal haemorrhage in 1 patient. A treatment-related fatal AE (interstitial lung disease) was reported in one patient (blinded). AEs leading to permanent discontinuation of unblindedunblinded study drug (motesanib or placeco) were cholecystitis (Grade 2), liver injury (Grade 3), purpura (Grade 2), rash (Grade 3), eye haemorrhage (Grade 2), upper gastrointestinal haemorrhage (Grade 3), and gamma-glutamyltransferase increased (Grade 4).

      Conclusion
      The first IDMC recommended continuation of the study after the review of unblinded data of 63 patients. Updated safety data will be presented after the second IDMC (JapicCTI-121887).

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-012 - Clinical and prognostic implication of ALK and ROS1 rearrangement in never smoker with surgically resected lung adenocarcinoma (ID 2232)

      09:30 - 16:30  |  Author(s): B.C. Cho

      • Abstract

      Background
      Rearrangements of oncogenic kinase proteins, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), were discovered as key oncogenic molecular drivers of lung adenocarcinoma recently. The aim of this study is to evaluate the prevalence and survival outcomes of ALK and ROS fusion in never smoker patients with surgically resected lung adenocarcinoma.

      Methods
      We analyzed consecutive stage IB to IIIA never smoker lung adenocarcinoma patients who underwent curative surgery in our institution. All resected tumors underwent comprehensive molecular profiling including EGFR mutation, KRAS mutation test, and fluorescence in situ hybridization (FISH) assay for ALK rearrangement. ROS1 rearrangement was evaluated by FISH assay in all triple-negative tumors (negative for EGFR, KRAS, and ALK).

      Results
      Of 162 never-smoker patients with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) patients had ALK and ROS1 rearrangement, respectively. Proportion of ALK or ROS fusion-positive (fusion-positive) patients was 26.0% (15 out of 73) among patients who are negative for EGFR and KRAS mutation. Fusion-positive patients tend to have a shorter disease free survival (DFS) than fusion negative patients, but without statistical significance (p= 0.124). However, multivariate analysis showed significantly poorer DFS of fusion-positive patients than fusion-negative patients with adjustment for T stage and lymph node metastasis (Hazard ratio 2.26; 95% Confidence interval, 1.19-4.30; p = 0.013). The 3-year DFS rate was 47.0% in fusion-negative patients and 32.7% in fusion–positive patients. Fusion-positive patients also showed poorer DFS in stage IB to IIB subgroup. (n=123, p= 0.046) Overall survival of patients was not different according to ALK or ROS fusion status. (p= 0.535) More extrathoracic metastasis was noted in fusion-positive patients than fusion-negative patients at the first time of recurrence. (46.2% vs. 35.8%, p= 0.539) The median progression free survival on EGFR tyrosine kinase inhibitor treatment after recurrence was 0.9 months in fusion-positive patients, which was significantly shorter than 10.2 months in EGFR mutation positive and 6.4 months in wild type patients..

      Conclusion
      This study shows significantly poorer DFS of ALK or ROS fusion positive patients in Asian never smoker lung adenocarcinoma patients. Development of ALK or ROS targeted adjuvant therapies in this subset of patients is needed to improve their poor survival after curative surgery.