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J. Sun



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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): J. Sun

      • 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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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)

      11:25 - 11:30  |  Author(s): J. Sun

      • Abstract
      • Presentation
      • Slides

      Background
      Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.

      Methods
      Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.

      Results
      Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.

      Conclusion
      Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.

      EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement***
      L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76%
      T790M 80 27 19 17 63%
      * identified by the cobas® EGFR tissue test
      ** identified by the cobas® EGFR blood test
      ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity

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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): J. Sun

      • 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): J. Sun

      • 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): J. Sun

      • 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): J. Sun

      • 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): J. Sun

      • 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: 1
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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): J. Sun

      • 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): J. Sun

      • 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): J. Sun

      • 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.