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M. Ahn

Moderator of

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    O21 - SCLC II (ID 119)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 8
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      O21.01 - A multicenter phase III randomized double-blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small cell lung cancer (SCLC) (ID 1568)

      16:15 - 16:25  |  Author(s): M.J. Seckl, C. Ottensmeier, M. Cullen, P. Schmid, L. James, C. Wadsworth, H. Farrant, D. Muthukumar, J. Thompson, S. Harden, G. Middleton, K. Fife, B. Crosse, P. Taylor, I. Khan

      • Abstract
      • Presentation
      • Slides

      Background

      Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in SCLC patients to determine if overall survival (OS) was affected by the addition of pravastatin to standard treatment.

      Methods
      Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice but recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity.

      Results
      Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed >4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Unblinded results showing the effect of pravastatin on OS, PFS, local PFS and toxicity will be presented.

      Conclusion
      This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients.

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      O21.02 - Phase III trial comparing irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in Korean patients with extensive disease (ED) small cell lung cancer (SCLC) (ID 2937)

      16:25 - 16:35  |  Author(s): D. Kim, H. Kim, J. Kim, K. Park, H.K. Kim, J.S. Jang, B. Kim, J. Kang, K.H. Lee, S. Kim, H.M. Ryoo, J. Kim, K.H. Lee, J.H. Kwon, J. Choi, D.S. Hong, S.W. Shin, S. Hahn, D.S. Heo

      • Abstract
      • Presentation
      • Slides

      Background
      IP showed superior survival outcomes compared with EP in Japanese patients. However, IP failed to show the superiority in subsequent studies in Western population. We conducted a multi-center randomized controlled trial to determine whether IP regimen is superior to EP regimen in Korean patients (ClinicalTrials.gov Identifier: NCT00349492)

      Methods
      Patients were randomly assigned (simple randomization, stratified by ECOG performance status and center) to IP (irinotecan 65 mg/m2 IV on D1&8 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) or EP (etoposide 100 mg/m2 IV on D1-3 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) for maximum 6 cycles, until disease progression, or until unacceptable toxicity occurred. The primary objective was to compare overall survival (OS).

      Results
      A total of 362 patients were randomized to IP (N=173) and EP (N=189) arms. Median OS was 10.9 and 10.3 months (m) for IP and EP, respectively (hazard ratio for death in the IP group, 0.879; 95% one-sided confidence interval, 0 to 1.054; P=0.1207). Objective response rate was higher with IP than with EP (62.4%, 48.2%, P=0.0064), however, there was no significant difference in median progression free survival between IP and EP (6.5 and 5.8 m, P=0.1158). In the pre-planned subgroup analyses, IP was associated with longer OS than with EP in male (11.3 vs 10.1 m, P=0.0361), <65 years old (12.7 vs 11.3 m, P=0.0240), ECOG performance status 0/1 (12.4 vs 10.9 m, P=0.0407) patients group. Grade 3/4 anemia, nausea and diarrhea were more frequent in patients treated with IP. There was no difference in the frequency of grade 3/4 neutropenia, thrombocytopenia, neutropenic fever, infection between both arms.

      Conclusion
      IP failed to show superiority in overall survival compared to EP in Korean patients with ED SCLC. However, prolongation of OS was observed with IP in pre-defined subgroup of patients with male gender, young age, or good performance status.

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      O21.03 - N-0923, A randomized double-blind phase II study of the Seneca Valley Virus (NTX-010) vs placebo for patients with extensive stage SCLC (ES-SCLC) who were stable or responding after at least 4 cycles of platinum-based chemotherapy: Alliance (NCCTG) Study (ID 899)

      16:35 - 16:45  |  Author(s): A. Adjei

      • Abstract
      • Presentation
      • Slides

      Background
      Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC.

      Methods
      Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x10[11]vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here.

      Results
      Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively.

      Conclusion
      Conclusion: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS

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      O21.04 - DISCUSSANT (ID 3964)

      16:45 - 17:00  |  Author(s): N. Murray

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O21.05 - A multicenter, double-blind, placebo-controlled, randomized phase 2 study of ganitumab or rilotumumab with platinum-based chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) (ID 725)

      17:00 - 17:10  |  Author(s): B. Glisson, A. Kazarnowicz, K. Nackaerts, S. Orlov, R. Ramlau, B. Besse, M. Cobo Dols, H. Menon, L. Paz-Ares Rodriguez, Y. Zhang, M. Zhu, Y. Jiang, E. Loh, J. Gansert, S. Dubey

      • Abstract
      • Presentation
      • Slides

      Background
      The type 1 insulin-like growth factor receptor (IGF1R) and MET, the receptor for hepatocyte growth factor (HGF)/scatter factor, appear to play key roles in SCLC. Ganitumab and rilotumumab are investigational, fully human monoclonal antibodies targeting IGF1R and HGF, respectively. A phase 1b/2 study evaluated ganitumab or rilotumumab combined with etoposide plus carboplatin (CE) or cisplatin (PE) in extensive-stage SCLC. The phase 1b results were previously reported (Lorigan et al. Ann Oncol 2010;21[supplement 8]: abstract 444P). Here, the phase 2 results are reported.

      Methods
      Key eligibility criteria: ≥18 years, confirmed SCLC, ECOG performance status ≤1, no prior chemotherapy. Patients were randomized 1:1:1 to receive blinded investigational product (IP) either ganitumab (18 mg/kg IV, day 1) or rilotumumab (15 mg/kg IV, day 1) or placebo, with etoposide (100 mg/m[2] IV, days 1-3) plus, at investigator’s discretion, either carboplatin (AUC=5 mg/mL*minute IV, day 1) or cisplatin (75 mg/m[2] IV, day 1) every three weeks for 4-6 cycles followed by IP monotherapy. Patients were stratified by gender and chemotherapy (CE; PE). Primary endpoint: overall survival (OS). Key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), pharmacokinetics.

      Results
      185 patients (ganitumab/rilotumumab/placebo: 62/62/61) were enrolled between 2 February 2010 and 12 January 2011. Male: 77%/76%/77%. Median age: 60/61/61 years. More patients received carboplatin (41/40/40) than cisplatin (21/22/21). Most common reason for discontinuation of IP was disease progression (69%/61%/74%). Among 179 patients (59/61/59) who received IP, the most frequent any grade AEs (occurring in ≥30% of patients in any arm) were neutropenia (69%/59%/71%), anemia (39%/34%/36%), nausea (41%/30%/22%), alopecia (41%/23%/27%), thrombocytopenia (22%/30%/12%), and vomiting (19%/10%/31%). Grade ≥3 AEs and serious AEs were reported in 69%/72%/80% and 39%/38%/36% of patients, respectively. There were three IP-related grade 5 AEs: cardiac arrest (rilotumumab, n=1), febrile neutropenia (rilotumumab, n=1), gastric ulcer hemorrhage (placebo, n=1). No neutralizing antibodies were observed for either ganitumab or rilotumumab. Efficacy is shown in the table. Ganitumab and rilotumumab combined with chemotherapy showed comparable exposures as those under monotherapy and did not affect the pharmacokinetics of chemotherapy.

      Ganitumab (n=62) Rilotumumab (n=62) Placebo (n=61)
      OS
      Median (95% CI) months 10.7 (8.1–14.1) 12.2 (8.8–14.6) 10.8 (9.4–11.9)
      Adjusted HR[a] (95% CI) 1.01 (0.67–1.52) 0.91 (0.60–1.39)
      PFS
      Median (95% CI) months 5.5 (4.4–5.7) 5.4 (4.4–5.7) 5.4 (4.6–5.8)
      Adjusted HR[a] (95% CI) 1.03 (0.70–1.52) 1.03 (0.69–1.52)
      Objective Response
      Complete response, n (%) 0 (0) 2 (3) 1 (2)
      Partial response, n (%) 39 (63) 40 (65) 35 (57)
      Stable disease, n (%) 13 (21) 12 (19) 16 (26)
      [a]Adjusted for baseline lactate dehydrogenase levels and stratification factors. CI=confidence interval; HR=hazard ratio.

      Conclusion
      In this study of chemonaïve patients with extensive-stage SCLC, the combination of ganitumab or rilotumumab with CE or PE was tolerable; no unexpected toxicities were observed. There were no meaningful improvements in OS, PFS, or ORR with either combination. Survival analyses in biomarker and pharmacokinetic subgroups are ongoing.

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      O21.06 - MLN8237 (alisertib), a selective Aurora A Kinase (AAK) inhibitor, in patients with relapsed/refractory small cell lung cancer (SCLC): Phase 2 results (ID 2815)

      17:10 - 17:20  |  Author(s): L. Havel, C. Dees, C. Lockhart, J. Bennouna, P. Serwatowski, S. Liu, H. Niu, S. Badola, C. Schusterbauer, C. Dansky Ullmann, B. Zhang, E. Benaim

      • Abstract
      • Presentation
      • Slides

      Background
      AAK, a key mitotic regulator, plays an important role in carcinogenesis. AAK is frequently overexpressed/amplified in a variety of human cancers. Inhibition of AAK has been associated with tumor inhibition in SCLC patients; thus, AAK is an attractive target in SCLC treatment. The investigational, oral, selective AAK inhibitor MLN8237 is under evaluation in patients with advanced hematologic and non-hematologic malignancies. A phase 1/2 study (NCT01045421) evaluated MLN8237 in patients with solid tumors; phase 2 data for the SCLC cohort are presented.

      Methods
      Patients aged ≥18 years with relapsed/refractory SCLC, ECOG PS 0–1, and ≤2 prior cytotoxic chemotherapy regimens were eligible (symptomatic and untreated brain metastases were excluded); sensitive and resistant/refractory was defined as recurrence > or ≤90 days of frontline therapy respectively. MLN8237 50 mg was administered twice-daily for 7 days (21-day cycles). Using a Simon’s optimal 2-stage design, ≥2 objective responses were required in the first 20 response-evaluable patients to proceed to the expansion stage. Primary objective: overall response rate (ORR) by RECIST v1.1. Secondary objectives: safety, duration of response (DOR), and progression-free survival (PFS). Exploratory studies included whole-exome sequencing in banked tumor specimens to identify genetic markers/mutated pathways associated with differential response.

      Results
      As of April 2013, 60 patients were enrolled; median age, 62 years (range 43–76); median number of cycles 2 (range 1–15). 48 patients (80%) were response-evaluable (chemo-sensitive, n=36; chemo-refractory, n=12). Prior lines of therapy and efficacy data are shown in the table. ORR was 21%, median PFS 2.11 months. Most common grade ≥3 drug-related AE included neutropenia (53%) and febrile neutropenia (8%); all AEs were reversible.14 patients discontinued due to AEs (treatment-related in 3 patients: hyponatremia, thrombocytopenia, acute generalised exanthematous pustulosis; each, n=1). 13 on-study deaths were reported; none were considered drug-related (most frequent cause was disease progression [n=6]). Whole-exome sequencing of selected tumor samples was completed. Preliminary results will be presented.

      Conclusion
      MLN8237 has a generally manageable toxicity profile; data from this study suggests it has single agent antitumor activity in SCLC patients with sensitive or resistant-refractory relapse, supporting further evaluation of MLN8237 in different combination strategies in this tumor type.

      All Chemo-sensitive Chemo-refractory
      Prior lines of therapy
      First line, n (%) N=48 n=36 n=12
      Platinum/etoposide 45 (94) 33 (92) 12 (100)
      Other 3 (6) 3 (8) –
      Second line, n (%) N=23 n=19 n=4
      Rechallenge 13 (57) 12 (63) 1 (25)
      Topotecan 3 (13) 2 (11) 1 (25)
      Other 7 (30) 5 (26) 2 (50)
      Efficacy data
      N=48 n=36 n=12
      Median cycles (range) 2.5 (1–15) 3.5 (1–15) 2 (2–6)
      Best response, n (%)
      ORR (PR) 10 (21) 7 (19) 3 (25)
      SD 16 (33) 13 (36) 3 (25)
      PD 22 (46) 16 (44) 6 (50)
      Median DOR (months) 4.1* –** –**
      Median PFS (months) 2.11 2.58 1.74
      * Numbers of events: 7; **Not enough events to give meaningful estimates.

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      O21.07 - A new prognostic model for relapsed/refractory extensive stage small cell lung cancer (ES-SCLC) derived from prospective SWOG trials: implications for study design (ID 966)

      17:20 - 17:30  |  Author(s): P. Lara, J. Moon, M. Redman, K. Kelly, J. Allen, B. Gitlitz, P. Mack, D. Gandara

      • Abstract
      • Presentation
      • Slides

      Background
      ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo have traditionally been categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). Plat-sensitivity status has previously been strongly associated with response and survival in the 2[nd]/3[rd] line treatment setting. However, in a recent pooled analysis of SWOG trials in 2[nd]/3[rd] line SCLC pts, plat-sensitivity status was found to no longer be a significant independent variable for survival (Lara, ASCO 2013). We subsequently developed a new SCLC prognostic model for overall survival (OS) for potential clinical trial and bedside application.

      Methods
      Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for OS were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. To investigate a predictive model for OS, recursive partitioning was performed using the likelihood tree model of LeBlanc and Crowley. The minimum node size was set at 20.

      Results
      Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; Performance Status (PS) 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors showed that plat-sensitivity status was not significantly associated with OS. Elevated LDH was significantly associated with PFS while LDH, PS, weight loss, and male sex were independently associated with OS. Clinically relevant prognostic risk groups (High, Intermediate, and Low) were identified by recursive partitioning analysis, as shown below (MST= median survival time). High Risk (MST = 2 months: Elevated LDH And > 5% Weight Loss Or PS >0) Intermediate Risk (MST = 5 months: Elevated LDH but not High Risk Or Male) Low Risk (MST=8 months: Normal LDH And Female)

      Conclusion
      In this large database analysis, clinically relevant prognostic risk groups were identified, categorized as low, intermediate, and high risk, with differential survival outcomes observed for each group. Validation of these risk groups in an independent SCLC dataset is warranted. If validated, these risk groups will have important implications for individualized patient counseling in clinic and stratification of patients in prospective trials in the second and third line setting.

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      O21.08 - DISCUSSANT (ID 3965)

      17:30 - 17:45  |  Author(s): K. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO07.02 - Clinical experience with crizotinib in patients with advanced <em>ALK</em>-rearranged non-small cell lung cancer and brain metastases in PROFILE 1005 and PROFILE 1007 (ID 2932)

      16:20 - 16:25  |  Author(s): M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is an oral tyrosine kinase inhibitor targeting ALK and is approved multinationally for the treatment of advanced ALK-rearranged non-small cell lung cancer (NSCLC) due to its efficacy in controlling systemic tumor burden. The clinical effects of crizotinib in patients with brain metastases have not been previously studied in detail. To evaluate the clinical outcomes of patients with brain metastases on crizotinib, we conducted a retrospective analysis of pooled data from PROFILE 1005 (NCT00932451; a large ongoing global open-label, single-arm phase II study of crizotinib in patients with ALK-rearranged NSCLC who have received one or more treatment regimen for advanced/metastatic disease) and PROFILE 1007 (NCT00932893; an ongoing global randomized phase III study that compared crizotinib with standard second-line chemotherapy [docetaxel or pemetrexed] for advanced ALK-rearranged NSCLC; Shaw et al, N Engl J Med 2013). Subgroup analysis in PROFILE1007 showed that progression-free survival was longer with crizotinib than with chemotherapy for both patients with brain metastases (HR 0.67) and patients without brain metastases (HR 0.43) at baseline.

      Methods
      Patients with previously treated (but ALK-inhibitor-naïve) advanced ALK-rearranged NSCLC enrolled in either PROFILE 1005 or PROFILE 1007 (and randomized to crizotinib) were included in this analysis. Patients with asymptomatic brain metastases were eligible for both studies. The starting dose of crizotinib was 250 mg twice daily. Tumor assessments were evaluated by investigators based on RECIST. Baseline brain imaging (with either computed tomography or magnetic resonance imaging) was required in both studies, and if brain metastases were detected, subsequent brain imaging was required at 6-week intervals. Otherwise, imaging to assess brain metastases on treatment was performed as clinically indicated. Brain metastases were monitored as non-target or target lesions.

      Results
      A total of 275 patients, 31% of 888 patients included in this retrospective analysis, had asymptomatic brain metastases at baseline. Of the 888 patients included, 109 patients (12%) had no prior radiotherapy and 166 patients (19%) had prior radiotherapy for their brain metastases. Among the 109 patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR; % complete responses + partial responses + stable disease) at 12 weeks was 63%, with a systemic objective response rate (ORR) of 53%, and the intracranial DCR at 12 weeks was 56%, with an intracranial ORR of 7%. Among the 166 patients with previously treated brain metastases, the systemic DCR at 12 weeks was 65%, with a systemic ORR of 46%, and the intracranial DCR at 12 weeks was 62% weeks, with an intracranial ORR of 7%. Additional data, including outcomes for patients without brain metastases at baseline, will be presented.

      Conclusion
      In this large retrospective analysis, crizotinib was associated with an initial intracranial DCR of approximately 60% at 12 weeks in patients who were ALK-inhibitor-naïve and had untreated or previously treated brain metastases identified prior to initiation of therapy. Prospective studies may help to determine if crizotinib can delay the natural occurrence or progression of brain metastases in advanced ALK-positive NSCLC.

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      MO07.14 - DISCUSSANT (ID 3954)

      17:30 - 17:40  |  Author(s): M. Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.01 - Integrative and comparative genomic analysis of East-Asian lung squamous cell carcinomas (ID 2667)

      16:15 - 16:20  |  Author(s): M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background
      Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SqCC, we probed somatic genome alterations of lung SqCC cases from Korean patients.

      Methods
      We performed whole-exome sequencing of DNA from 104 lung SqCC samples from Korean patients and matched normal DNA. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

      Results
      This cancer cohort is characterized by a very high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of cigarette-smoke exposure. Seven genes demonstrated statistical enrichment for mutation (TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA). Comparative analysis between Korean and North American lung SqCC demonstrated similar spectrum of alterations in these two populations, in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SqCC.

      Conclusion
      These findings provide new steps towards the identification of genomic target candidates for precision medicine in lung SqCC, a disease with a significant unmet medical need.

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.13 - Volume based growth tumor kinetics as a predictive biomarker in patients with EGFR-mutant lung adenocarcinoma receiving EGFR tyrosine kinase inhibitor (ID 1229)

      11:40 - 11:45  |  Author(s): M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background
      To determine whether volumetric assessment has potential as a predictive biomarker and to assess relationship between longitudinal tumor data during treatment and prognosis in lung adenocarcinoma patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitor (TKIs).

      Methods
      We retrospectively assessed patients with EGFR-mutant stage IV lung adenocarcinoma, who underwent EGFR TKIs as second-line therapy and this treatment was repeated every three weeks until disease progression. All 106 patients with at least one measurable lung lesions were quantitatively analyzed in terms of tumor size and volume based on the whole tumor volume, on baseline contrast-enhanced CT scans and on follow-up CT scans of every two treatment cycle. A quantify for tumor response was evaluated with growth tumor kinetics, followed by determining correlation with early tumor parameters including change of size, volume, and response rate. Cox-proportional hazard model and Log-rank test were also applied to predict the overall survival. Figure 1

      Results
      Percent of volume change after two cycles of TKI treatment had a strong correlation with progression rate based on growth tumor kinetics (P < 0.001). Responders based on percent of volume change after two cycles of TKI treatment had a higher overall survival rate than non-responders (P = 0.001). The velocity of progression was also a good potential parameter to predict overall survival (P < 0.001). Figure 1

      Conclusion
      Early radiologic parameters of the tumor helped predict treatment response and overall survival in EGFR mutant lung adenocarcinoma patients treated with TKIs. Longitudinal tumor data also showed potential as a predictive factor.

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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O18.02 - Impacts of environmental tobacco smoke on EGFR mutations and ALK rearrangements in never smokers with non-small cell lung cancer: Analyses on a prospective multinational ETS registry (ID 1255)

      10:40 - 10:50  |  Author(s): M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and ALK are important driver mutations in never smokers. While we reported the significant association of increased environmental tobacco smoke (ETS) with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), it has not been fully understood in other ethnicities and also the correlation of ETS with ALK has not been reported yet. In this study, we evaluated the association of ETS with the prevalence of EGFR mutations and ALK translocations in various ethnicities including East-Asia (Japan, Korea, China, and Singapore) and the USA.

      Methods
      ETS exposure on never smokers with non-small cell lung cancer (NSCLC) was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood/ adulthood and at home/ workplace, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3).

      Results
      From March 2008 to December 2012, 498 never smokers with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/ female, 114/ 384; age <65/ >=65, 286/ 212; histology of adenocarcinoma/ BAC/ squamous cell carcinoma/ adenosquamous cell carcinoma/ other NSCLC, 459/ 12/ 13/ 5/ 9; frequency (%) of CETS < median CETS (40 years) in Japanese/ Korean/ Chinese/ Caucasian, 32.8/ 44.1/ 71.7/ 83.3. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319).

      Conclusion
      Increased ETS exposure was closely associated with EGFR mutations in never smokers with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never smokers with NSCLC was not significant.

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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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      P1.10-037 - A retrospective comparison of adjuvant chemotherapeutic regimen for non-small cell lung cancer (NSCLC): Paclitaxel plus platinum versus Vinorelbine plus Cisplatin (ID 2176)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      Adjuvant vinorelbine/cisplatin (VC) has been demonstrated to increase overall survival in patients with AJCC 6th stage II/IIIA non-small cell lung cancer (NSCLC). Although adjuvant paclitaxel/carboplatin failed to demonstrate its efficacy in a study which enrolled only patients with AJCC 6th stage IB NSCLC, the exploratory analysis showed that patients with large tumor (≥ 4cm) got survival benefits from this regimen. We need to compare the clinical outcomes of these two regimens as adjuvant chemotherapy for NSCLC, since the previous prospective trials used different eligible stage criteria and AJCC stage system was recently updated.

      Methods
      We retrospectively analyzed patients with surgically completely resected NSCLC between December 2004 and December 2011. They received adjuvant chemotherapy using either paclitaxel/platinum (PP) or VC. Clinicopathological parameters, survivals including disease free survival (DFS) and overall survival (OS) and toxicity between two groups were compared. All tumor stages were updated based on the AJCC 7th edition.

      Results
      Of the 467 patients with surgically resected NSCLC, 236 received PP (paclitaxel/cisplatin, n=29; paclitaxel/carboplatin, n=206) and 231 patients got VC (n= 231). Two groups were well balanced with regard to demographics, histology, stage and type of surgery. Efficacy was comparable between two regimens: DFS (PP vs. VC: 65 vs. 55 months; p=0.42) and OS (73 vs 58 months; P=0.37). Regarding the adverse events, sensory neuropathy (41% vs. 11%), alopecia (19% vs. 4%), and myalgia (32% vs. 5%) are more frequent in the PP group, while anemia (71% vs. 87%), neutropenia (22% vs. 71%), fatigue (11% vs. 18%), anorexia (19% vs. 41%), and vomiting (9% vs. 19%) are more frequent in the VC group.

      Conclusion
      Although the adverse event profiles were different, the efficacy data in terms of DFS and OS were comparable between the two adjuvant regimens. Therefore, both regimens are appropriate as the adjuvant chemotherapy for NSCLC, and the selection can be done personally according to the expected profiles of adverse events.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-030 - Is there any predictor for clinical outcome in EGFR mutant<br /> NSCLC patients treated with EGFR TKIs ? (ID 2202)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have demonstrated dramatic response rate and prolonged progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutation. However, PFS and overall survival (OS) among those patients who were treated with EGFR TKIs are variable. In this study, we evaluated predictors of clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs.

      Methods
      From January 2008 to December 2010, a total of 148 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated with either erlotinib or gefitinib as a first-line (n=10) and a second-line or more treatment (n=138) were retrospectively reviewed. The first analysis with a total 148 patients and subgroup analysis with patients who had received EGFR TKIs as second-line treatment (n=105) were undertaken to identify any difference in the clinical and molecular features among those patients who were treated with EGFR TKIs.

      Results
      Median follow-up duration was 21.9 months (range, 1.1-62.5) and median number of cycles was 7 (range, 1-44). The median PFS and OS for a total 148 patients were 10.6 months (95% CI, 9.0-12.2) and 21.8 months (95% CI, 18.5-25.1), respectively. The survival outcomes were similar between first-line and second-line or more line of treatment of EGFR TKIs (p=0.512 for PFS, p=0.699 for OS). A high number of metastasis sites (3-6 versus 1-2) was associated with shorter PFS and OS (median PFS 9.9 vs. 11.9 months, p=0.019; median OS 16.4 vs. 22.2 months, p=0.021, respectively) in univariate analysis, but not in multivariate analysis. According to the clinical and molecular markers by multivariate analysis, there were no significant differences in PFS. When PFS was dichotomized by median 11 months for 105 patients treated with EGFR TKIs as second-line therapy, no significant differences in any clinical or molecular features were found between longer PFS and shorter PFS groups.

      Conclusion
      Despite the heterogeneity in PFS among EGFR mutant patients treated with EGFR TKIs, no significant differences of clinical features were noted, suggesting more understanding of the variability of underlying biology should be needed.

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    P2.12 - Poster Session 2 - NSCLC Early Stage (ID 205)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.12-018 - Brain metastases as a first site of recurrence in surgically resected non-small-cell lung cancer (ID 2755)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      With improved survival after multimodality treatment in surgically resected non-small-cell lung cancer (NSCLC), the incidence of brain metastases as a first site of recurrence has increased. We analyzed the characteristics and prognostic factors in patients with postoperative brain metastases as a first site of relapse in surgically resected NSCLC, focusing on difference between patients with brain only metastases (B) and patients with brain and extracranial systemic metastases (BS) simultaneously.

      Methods
      We retrospectively analyzed patients with surgically resected NSCLC at Samsung Medical Center (SMC) between 2004 and 2010. Clinicopathological parameters and prognostic factors between two groups (brain only metastases vs brain and extracranial sites) were reviewed. Interval to brain metastases as a first site of relapse after surgery and overall survival after brain recurrence was calculated.

      Results
      Of the 3134 patients with surgically resected NSCLC, 106 (3.4%) patients developed postoperative brain metastases as a first site of recurrence. Among them, 73 patients (2.3%) relapsed in B and 33 patients (1.1%) were in BS simultaneously. Median time to brain metastases as a first site of relapse after surgery was 11 months (range 0-54 months). Most common histologic subtype was adenocarcinoma (n=65, 61.3%) and large number of patients had IIIa disease (n=56, 52.8%). Single brain metastases were observed in 42 patients (39.4%) and local treatments were performed in 102 patients (96.2%). The baseline characteristics between two groups (B vs BS) were not significantly different. Among 73 (brain only), 8 patients (11%) received systemic treatment as well as local treatment and 16 patients (21.9%) developed extracranial systemic metastases after brain relapse. The median interval time to extracranial systemic metastases after brain relapse was 10 months (range 0-27 months). The overall survival following B and BS was 30 months and 13 months, respectively (P=0.004). Significantly favorable prognostic factor for survival in patients with brain only metastases included single brain metastases whereas adenocarcinoma was associated with good prognosis in patients with BS.

      Conclusion
      Our results suggested that brain metastasis is common site of metastasis after surgery and patients who develop brain only metastases after curative resection of NSCLC show favorable prognosis with local treatment.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P3.06-004 - T790M Mutation in Patients with Acquired Resistance to EGFR Tyrosine Kinase Inhibitors: Is It Associated with Clinically Distinct Features? (ID 352)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      The T790M mutation is considered to be the major mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its clinical implication in patients with non-small cell lung cancer (NSCLC) is yet determined.

      Methods
      NSCLC patients with acquired resistance to initial EGFR TKIs such as gefitinib or erlotinib were identified, and post-progression tumor specimens were prospectively collected for T790M mutation analysis. Clinical features including the pattern of disease progression (intrathoracic only versus extrathoracic), treatment outcomes for initial or subsequent TKIs, post-progression survival, and overall survival were compared between patients with and without T790M.

      Results
      Out of 70 cases, 36 (51%) were identified to have the T790M mutation in the rebiopsy specimen. There was no difference in the pattern of disease progression, progression-free survival for initial TKIs (12.8 and 11.3 months), post-progression survival (14.7 and 14.1 months), or overall survival (43.5 and 36.8 months) in patients with and without T790M. In total, 34 patients received afatinib after post-progression biopsy as a subsequent treatment. Among them, six (18%) achieved objective response. The median progression-free survival for afatinib was 3.7 months for the entire group, and 3.2 and 4.6 months for the groups with (n = 21) and without (n = 13) T790M, respectively (p = 0.33). Figure 1Figure 2

      Conclusion
      Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from new treatment strategies.

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      P3.06-008 - Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer (ID 1089)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      Clinical implications of KRAS mutations in advanced non-small cell lung cancer remain unclear.

      Methods
      Kras mutation status was identified by direct sequencing test in 844 specimens that were diagnosed of NSCLC at Samsung Medical Center from 2006 to 2011. This study included stage IV NSCLC patients who were treated with systemic chemotherapy. We retrospectively evaluated the prognostic and predictive value of KRAS mutations in patients with advanced NSCLC.

      Results
      Among 484 patients with available results for both KRAS and EGFR mutations, 39 (8%) had KRAS and 182 (38%) EGFR mutations, with two cases having both mutations. The median overall survivals for patients with KRAS mutations, EGFR mutations, or both wild types were 7.7, 38.0, and 15.0 months, respectively (P < 0.001). The KRAS mutation was an independent poor prognostic factor in the multivariate analysis (hazard ratio=2.6, 95% CI: 1.8–3.7). Response rates and progression-free survival (PFS) for the pemetrexed-based regimen in the KRAS mutation group were 14% and 2.1 months, inferior to those (28% and 3.9 months) in the KRAS wild type group.

      Conclusion
      KRAS mutation tended to be associated with inferior treatment outcomes after gemcitabine-based chemotherapy, while there was no difference regarding taxane-based regimen. Although the clinical outcomes to EGFR tyrosine kinase inhibitors (TKIs) seemed to be better in patients with KRAS wild type than those with KRAS mutations, there was no statistical difference in response rates and PFS according to KRAS mutation status when EGFR mutation status was considered. Two patients with both KRAS and EGFR mutations showed partial response to EGFR TKIs. Although G12D mutation appeared more frequently in never smokers, there was no difference in clinical outcomes according to KRAS genotypes. These results suggested KRAS mutations have an independent prognostic value but a limited predictive role for EGFR TKIs or cytotoxic chemotherapy in advanced NSCLC.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 2
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      P3.09-013 - Outcomes and predictors for recurrence and survival after neoadjuvant concurrent chemoradiation followed by operation in patients with clinical stage III-N2 non-small-cell lung cancer (ID 2053)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      This study assessed the impact of imaging, surgical, histopathologic and patient-related factors on the risks of local and distant recurrence and overall survival for patients with stage III-N2 non small cell lung carcinoma (NSCLC) undergoing definitive resection after neoadjuvant concurrent chemoradiation (neoCCRT).

      Methods
      We retrospectively examined 129 consecutive patients with stage III-N2 NSCLC received neoCCRT followed by curative surgery between 2008 and 2011. We reviewed clinical data and operation method. We also analyzed histopathologic factors such as subtype, pathologic invasive tumor characteristics, differentiation, residual tumor size, or the number of residual LNs as well as imaging characteristics on chest CT and PET/CT. Disease free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and predictive factors for recurrence and survival were identified by univariate and multivariate Cox-proportional analyses.

      Results
      112 (87%) patients were pathologically staged for N2-positive status (82 patients by mediastinoscopic biopsy and 30 patients by EBUS). The 5-year recurrence rate was 28.3 %, and the 5-year survival rate was 43.4 %. Five-year OS for patients with recurrence compared with those without was 29.5 versus 59.1 % (P = 0.028). Based on the multivariate Cox-proportional analysis and log-rank test, history of adjuvant therapy was the only significant prognostic predictor for prolonged OS (HR 0.134, 95 % CI 0.039–0.455, P = 0.001). As for recurrence, less size decrease on CT (HR 1.030, 95 % CI 1.005–1.056, P = 0.017), higher T stage (HR 2.450, 95 % CI 1.322–4.540, P = 0.004), larger residual tumor size on the pathologic specimen (HR 1.124, 95 % CI 1.010–1.252, P = 0.016), and presence of lymphovascular invasion (HR 4.180, 95 % CI 1.093–15.984, P = 0.037) were the significant predictors in both the multivariate Cox-proportional analysis and the log-rank test. Figure 1

      Conclusion
      Recurrence remains high in resected stage III-N2 NSCLC patients after neoCCRT and nodal downstaging, and patients who received adjuvant therapy had longer overall survival rate than patients who did not. Size decrease on CT, T stage, residual tumor size on the pathologic specimen, and presence of lymphovascular invasion would be predictive for higher recurrence and may necessitate more aggressive adjuvant treatment.

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      P3.09-015 - The role of adjuvant treatment in N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiation followed by surgery: A retrospective single center experience. (ID 2673)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      The optimal management of locally advanced N2 positive non-small cell lung cancer (NSCLC) is still controversial. Some studies have shown promising results of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection in terms of survival benefit without increasing morbidity and mortality. However, the role of adjuvant treatment after completion of neoadjuvant CCRT followed by surgery in N2 positive NSCLC patients has not defined yet.

      Methods
      From March 2006 to December 2011, 249 N2 positive NSCLC patients received neoadjuvant CCRT (weekly docetaxel/cisplatin with 45Gy/25Fx of thoracic radiotherapy) followed by curative surgery. Patients who died with post-operative complications within a month after surgery (n=5) were excluded to minimize selection bias.

      Results
      Among 244 patients, 80 patients (32.8%) receieved adjuvant radiotherapy alone, 26 patients (10.7%) received adjuvant chemotherapy alone, 57 patients (23.4%) received both of adjuvant radiotherapy/chemotherapy, and 80 patients (32.8%) did not receive adjuvant treatment. Survival was compared according to adjuvant treatment (any kind of adjuvant treatment [n=164, 67.2%] vs. no adjuvant treatment [n=80, 32.8%]). There was no significant differences between two groups in age over 60 years, ECOG performance, initial T stage, initial multistation N2 disease, completion of neoadjuvant CCRT, R0 resection, and pathologic down staging of N2 disease. In the univariate analysis, median overall survival (OS) and progression-free survival (PFS) were 54.1 months vs. 37.9 months (P=0.016) and 23.4 months vs. 17.7 months (P=0.239) in adjuvant treatment group and no adjuvant treatment group, respectively. In subgroup analysis, adjuvant treatment group showed significantly better OS than no adjuvant treatment group in patients who achieved N2 down staging by neoadjuvant CCRT (n=146, 59.8%) (78.1 months vs. 44.7 months, P=0.027) but not in patients who did not achieve pathologic N2 down staging (n=98, 40.2%) (32.3 months vs. 21.6 months, P=0.125).

      Conclusion
      This results suggest that adjuvant treatment may contribute survival benefit even after completion of neoadjuvant CCRT following curative surgery in N2 positive NSCLC. The role of adjuvant treatment should be seeked further in carefully selected patients who benefit most, such as CCRT sensitive patients who achieved pathologic N2 down staging.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-035 - An Open Label Compassionate Use Programme of BIBW 2992/afatinib in Advanced Non-Small Cell Lung Cancer Patients Pre-treated with Erlotinib or Gefitinib in Korea (ID 3028)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      Afatinib is a potent and selective, irreversible ErbB family blocker. Previous phase 3 trial demonstrated that afatinib prolonged progression-free survival compared with placebo in patients with advanced lung adenocarcinoma who progressed after 12 weeks of treatment with reversible EGFR tyrosine-kinase inhibitors (TKIs). The purpose of this Open Label Compassionate Use Programme is to provide afatinib to patients with advanced NSCLC with previous treatment failure on erlotinib or gefinitib and for whom no other approved treatment is available.

      Methods
      who have failed at least one line of platinum-based cytotoxic chemotherapy and following at least 6 months on erlotinib or gefinitib were eligible. Thestarting dose of afatinib was 50mg daily.

      Results
      Between Aug 2011 and Dec 2012, 107 patients were treated with afatinib. Most patients were females (60.7%) and never-smokers (69.2%) with a median age of 57 years. Of the 95 patients who had prior EGFR mutation results, 82 (86.3%) were positive. With afatinib treatment 25 (23.4%) of 107 patients had a partial response. Median progression-free survival was 4.6 months (95% CI 4.1-5.1). The most common adverse events were diarrhea (97 [90.7%] patients; 22 [20.6%] were grade 3) and rash or acne (72 [67.3%] patients; 11 [10.3%] were grade 3). No drug-related death was found. Sixty-four (59.8%) patients needed a dose reduction because of an adverse event.

      Conclusion
      Our results suggested that afatinib could be a feasible option to patients with advanced lung adenocarcinoma who have progressed after clinical benefit on previous EGFR TKIs.

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      P3.11-036 - Comparison of Clinical Outcome between Gefitinib and Erlotinib treatment in patients with non-small cell lung cancer harboring an epidermal growth factor receptor exon 19 or exon 21 mutations (ID 2599)

      09:30 - 09:30  |  Author(s): M. Ahn

      • Abstract

      Background
      Gefitinib and Erlotinib are oral small-molecule kinase inhibitors that inhibit signaling via EGFR and both agents showed dramatic response rate and prolonged PFS in patients harboring activating EGFR mutation. We investigated the clinical outcomes between gefitinib- and erlotinib-treated patients with recurrent or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations.

      Methods
      A total 375 patients with recurrent or metastatic stage IIIB/IV NSCLC who had either an exon 19 deletion or L858R mutation on exon 21 and received gefitinib(n=228) or erlotinib(n=147) therapy between August 2007 and December 2011 were retrospectively reviewed. By using a matched-pair case-control study design, 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, ECOG performance status, and types of EGFR mutation.

      Results
      The median age of all patients was 58 years(range, 30-84) and more than half of patients were never smokers(63.6%). Most patients had adenocarcinoma (98.3%) and good ECOG performance status (0, 1) (90.9%). The median number of cycles in TKI treatment was 12.7 in gefitinib group and 10.8 in erlotinib group. Of 242 patients, 64(26.4%) received an EGFR TKI as first line therapy. The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 85.5% versus 79.8 % (p=.375) and 94.0% versus 89.1%, respectively (p=.242). There was no statistically significant difference noted with regard to OS (median, 22.1 vs 25.2; p=.546) and PFS (median, 12.5 vs 9.9; p=.114) between the gefitinib-treated and erlotinib-treated groups. For a subgroup which patients were treated with TKI as first line therapy, the overall response rates were higher than those of patients who had progressed on prior chemotherapy (90.3% vs 79.9%; p=.063). However, there was no significant differences in PFS (median, 13.1 vs 10.1; p=.082) between subjects with first line TKI therapy and more than second line treatment. Regarding safety and dose adjustment of EGFR TKIs, patients with erlotinib more frequently had G3/4 toxicity than ones with gefitinib and required dose reduction(18.1% vs 1.65%).

      Conclusion
      Both gefitinib and erlotinib showed similar effective activity in selected population of NSCLC that harbored an EGFR mutation and further studies are needed to evaluate the efficacy of EGFR TKI as first line treatment.