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S. Lu



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.13 - BEYOND: a randomized, double-blind, placebo-controlled, multicentre, phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) or placebo (Pl) in Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) (ID 2756)

      16:15 - 17:45  |  Author(s): S. Lu

      • Abstract
      • Slides

      Background
      Bevacizumab, a monoclonal antibody that inhibits angiogenesis via the vascular endothelial growth factor (VEGF) pathway, has proven efficacy in extending overall survival (OS) (Sandler et al, 2006) and progression-free survival (PFS) (Sandler et al, 2006; Reck et al, 2009) when added to platinum-doublet chemotherapy as first-line treatment for advanced non-squamous NSCLC. These pivotal studies included mainly Caucasian patients, however subgroup analyses in Asian patients also reported efficacy of the first-line Bv+CP regimen (Reck et al, 2009). The BEYOND study was initiated to confirm efficacy in a Chinese population.

      Methods
      Patients aged ≥18 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced non-squamous NSCLC and an ECOG performance status of 0–1 were randomised 1:1 to receive CP (paclitaxel 175mg/m[2] i.v. and carboplatin AUC6 i.v. on day 1 of each 3-week cycle for up to 6 cycles), plus either Pl or Bv 15mg/kg i.v. on day 1 of each cycle, until progression, unacceptable toxicity, withdrawal of patient consent or death. Patients had no prior treatment for advanced NSCLC. Patients were stratified by gender, smoking status and age. The primary endpoint was PFS in the intent-to-treat (ITT) population; secondary endpoints included objective response rate (ORR), OS, exploratory biomarkers and safety. Collection of blood samples for biomarker analyses was mandatory (at baseline, every two cycles during treatment, at progression, and 4–6 weeks post-progression); tissue samples were optional.

      Results
      276 patients were randomised into the study, 138 to each arm. Baseline characteristics were similar in both treatment groups. PFS was prolonged with Bv+CP versus Pl+CP: hazard ratio 0.40 (95% CI 0.29–0.54); median 9.2 versus 6.5 months; p<0.0001 (ITT population). ORR was also improved with the addition of Bv to CP: 54.4% versus 26.3% with Pl+CP. Disease control rate was 94.4% versus 88.7% with Bv+CP and Pl+CP, respectively. Median duration of response was 8.0 months with Bv+CP versus 5.3 months with Pl+CP. OS data are not yet mature. Safety data were similar to previous studies of Bv+CP in NSCLC; no new safety signals were observed. Treatment discontinuation due to adverse events was 18.4% (Bv+CP) and 15.0% (Pl+CP). Treatment-related deaths were low in both arms (Bv+CP: 2.2%; Pl+CP: 0.0%). Detailed safety data and biomarker analyses will be reported.

      Conclusion
      This study confirms that the addition of bevacizumab to first-line platinum-based chemotherapy appears to provide similar PFS benefits in Chinese patients with advanced non-squamous NSCLC compared with global populations. No new safety concerns were reported.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-016 - A single arm, multi-center, phase II study of intercalated erlotinib with gemcitabine/cisplatin as neoadjuvant treatment in stage IIIA non-small cell lung cancer (CTONG 1101, NCT01297101): preliminary result (ID 2041)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      The optimal treatment for stage IIIA non-small cell lung cancer (NSCLC) disease is not well established with only 15% of 5-year survival rate, probably due toalready micro-metastatic lesion at the diagnosis. Thus, neoadjuvant therapy might be a good choice for IIIA NSCLC patients. The treatment modality of EGFR (TKI) intercalated with chemotherapy has been demonstrated to significantly improve objective response rate (ORR), progression free survival(PFS) and overall survival (OS) in advanced NSCLC patients with or without activating EGFR mutations. The objective of this study is to assess the efficacy and safety profile of intercalated erlotinib with gemcitabine/cisplatin as neoadjuvant treatment in stage IIIA NSCLC.

      Methods
      This is a single arm, multi-center, clinical phase II trial. Patients with untreated stage IIIA bulky N2 NSCLC and ECOG PS 0/1 were enrolled to received up to 2 cycles of gemcitabine 1,000 mg/m[2] on days 1 and 8 and cisplatin 75 mg/m[2] on day 1 or carboplatin AUC=5 d1, followed by oral erlotinib (150 mg, once a day) on days 15 to 28 as neoadjuvant therapy. A repeat computed tomography (CT) scan evaluated the response after induction therapy and eligible patients would undergo surgical resection. The primary endpoint was ORR, and secondary endpoints included pCR, resection rate, DFS (disease free survival) and OS , safety, QoL and biomarker analyses. Subgroup analysis of ORR by EGFR mutation status was also performed

      Results
      Between March 2011 and December 2012, a total of 39 patients were enrolled in the study, in which 36 patients (92.3% ITT population) have completed 2-cycle neoadjuvant treatment. According to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 18 patients achieved partial response (PR) (ORR=46.2%) and 18 patients achieved stable disease (SD) (DCR=92.3%); 22(56.4%) patients underwent resection with 18 R0 (46.2%), 2 R1(5.1%),1 R2(2.6%),1 NE(2.6%). Fifteen patients have had EGFR mutation test, with 7 EGFR mutation and 8 EGFR wild type. ORR in patients with EGFR mutations and wild type was 85.7%(6/7) vs. 50%(4/8), respectively. Common toxicities included myelosuppression (38.5%), rash (28.2%), neutropenia (5.1%), alanine transaminase (ALT) elevation(5.1%), diarrhea(5.1%) , fatigue(2.6%) and alopecia(2.7%) . Five (12.8%) patients suffered from CTCAE ≥3. No CTCAE ≥4 complications were recorded perioperatively.

      Conclusion
      Two cycles of intercalated administered gemcitabine/cisplatin with erlotinib as an induction treatment is a feasible and efficacious approach for stage IIIA NSCLC, which provides evidence for the further investigation.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-021 - First-line erlotinib versus cisplatin/gemcitabine (GP) in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC): interim analyses from the phase 3, open-label, ENSURE study (ID 1849)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, has proven efficacy in second-/third-line advanced NSCLC, and provides superior first-line efficacy to chemotherapy for patients whose tumors harbor activating EGFR mutations. The phase 3, randomized, open-label ENSURE study evaluated erlotinib vs GP in patients from China, Malaysia and the Philippines with EGFR mutation-positive NSCLC.

      Methods
      Patients ≥18 years with histologically or cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and an ECOG PS of 0–2 were randomized 1:1 to receive either erlotinib (oral; 150mg qd until progression/unacceptable toxicity) or GP (G 1250mg/m[2] iv d1 & 8 q3w; P 75mg/m[2] iv d1 q3w for up to 4 cycles). Patients were stratified by EGFR mutation type, PS, gender, and country). Primary endpoint is progression-free survival (PFS) by investigator, with Independent Review Committee (IRC) assessment for sensitivity analysis; other endpoints include objective response rate (ORR), overall survival (OS), and safety. A pre-planned interim analysis was conducted after 73% of PFS events (cut-off 20 July 2012). An additional exploratory updated analysis (cut-off of 19 November 2012), included all planned PFS events.

      Results
      In total, 217 patients were randomized: 110 to erlotinib and 107 to GP. Baseline characteristics were similar in both groups. Efficacy data by treatment arm for the interim and updated analyses are presented (Table 1). PFS by investigator in EGFR exon 19 deletion and exon 21 L858R mutation subgroups is also presented (Table 1). Erlotinib was better tolerated than GP, with treatment-related serious adverse events (SAEs) occurring in 2.7% vs 10.6% of patients, respectively. The most common grade ≥3 AEs of any cause were neutropenia (25.0%), leukopenia (14.4%) and anemia (12.5%) in the GP arm, and rash in the erlotinib arm (6.4%). At the updated analysis (19 November 2012), erlotinib remained better tolerated than GP, with treatment-related SAEs occurring in 3.6% vs 11.5% of patients, respectively. Median duration of follow-up was 10.3 months and 11.7 months for the GP and erlotinib arms, respectively, at latest cut-off. OS data are not yet mature.

      Efficacy Outcome Interim analysis (cut-off 20 July 2012) Updated analysis (cut-off 19 November 2012)
      E GP E GP
      Investigator-assessed PFS Events, n 35 66 61 87
      Median, months 11.0 5.5 11.0 5.5
      HR (95% CI) 0.34 (0.22–0.51) 0.33 (0.23–0.47)
      log-rank p-value <0.0001 <0.0001
      IRC-assessed PFS Events, n 33 47 51 55
      Median, months 11.0 5.6 11.1 5.7
      HR (95% CI) 0.42 (0.27–0.66) 0.43 (0.29–0.64)
      log-rank p-value 0.0001 <0.0001
      ORR % 62.7 33.6 68.2 39.3
      p-value 0.0001 <0.0001
      Disease control rate (DCR) % 89.1 76.6 91.8 82.2
      p-value 0.015 0.0354
      EGFR exon 19 deletion subgroup PFS Median, months 11.1 4.2 11.1 4.3
      HR (95% CI) 0.20 (0.11–0.37) 0.20 (0.12–0.33)
      EGFR exon 21 L858R subgroup PFS Median, months 8.3 7.1 8.3 5.8
      HR (95% CI) 0.57 (0.31–1.05) 0.54 (0.32–0.90)
      p-value significance level: alpha=0.05

      Conclusion
      These analyses demonstrate that erlotinib provides statistically significant and clinically meaningful improvement in both investigator-assessed and IRC-assessed PFS compared with GP in Asian patients with EGFR mutation-positive NSCLC. Primary efficacy results were also supported by secondary endpoints including ORR and DCR.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-003 - Regulation of SIRT2 for Human Non-Small Cell Lung Cancer Therapy (ID 236)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      Seven Sirtuin family members (SIRT1-7), comprising a family of NAD+-dependent protein deacetylases and ADP-ribosyltransferases, are key proteins that regulate multiple physiological processes. SIRT2 was recently reported to play an important role in carcinogenesis. However, its role in non-small cell lung cancer (NSCLC) has not yet been investigated.

      Methods
      In this study, we analyzed the expression pattern of SIRT2 in NSCLC tissues from clinical patients and in cell lines

      Results
      We found that SIRT2 was significantly down-regulated at both the mRNA and protein levels in tumor than non-tumor tissues or cells, which were corroborated by the NSCLC tissue microarray results. Overexpression of SIRT2 in A549 and H1299 cells caused cell proliferation inhibition, cell apoptosis induction and cell cycle arrest. Further analysis showed that SIRT2 overexpression increased the ROS (reactive oxygen species) production and P27 levels. Moreover, up-regulation of SIRT2 by Resveratrol in NSCLC cells increased the sensitivity to cisplatin treatment. .

      Conclusion
      Taken together, our results implied that down-regulation of SIRT2 was associated with NSCLC, and regulation of SIRT2 might be an important target for NSCLC therapy

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-007 - Meta-Analysis of STAT3 and p-STAT3 Expression and Survival in Non-Small-Cell Lung Cancer (ID 786)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      The prognostic role of signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3(p-STAT3) in non-small-cell lung cancer (NSCLC) remains controversial. To clarify its impact on survival, we performed a meta-analysis to quantitatively assess STAT3 and p-STAT3 expression on prognosis of NSCLC.

      Methods
      Published studies were identified using a systematic and thorough literature search.To be eligible, a study had to investigate STAT3 or p-STAT3 expression rates of NSCLC patients in different characteristics and survival data of STAT3 or p-STAT3 expression.

      Results
      A total of 17 retrospective trials were chosen for meta-analysis, including 1793 patients.We showed that the estimated pooled HR (0.67, 95%CI: 0.57-0.77) of 9 trials (STAT3: HR 0.71, 95%CI 0.38-1.04; p-STAT3: HR 0.67 ,95%CI 0.56-0.77) for NSCLC was statistically significant (P<0.0001), suggesting that high STAT3 or p-STAT3 expression is a strong predictor of poor prognosis among patients with NSCLC.For the risk factors, pooled analysis of patients with STAT3 positivity, demonstrated a statistically significant OR (3.82, 95%CI: 2.37-6.16) between poorly differentiated carcinoma and well-moderately, OR( 5.68, 95%CI: 3.16-10.21)between patients in stage III-IV and patients in stage I-II, and OR (3.41, 95%CI: 2.12-5.49 ) between patients with lymph node metastasis and patients without lymph node metastasis. However, pooled analysis of patients with p-STAT3 positivity, only demonstrated a statistically significant OR (4.51, 95%CI: 1.57-12.96) between poorly differentiated carcinoma and well-moderately(P<0.05).

      Conclusion
      High STAT3 or p-STAT3 expression is a strong predictor of poor prognosis among patients with NSCLC. The conclusion should be confirmed by large prospective studies with long-term follow-up.

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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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      P3.10-044 - Overall Survival analysis results of TFINE Study (CTONG 0904): Different Dose Docetaxel plus Cisplatin as First-line Chemotherapy and Then Maintenance Therapy with Single Agent Docetaxel for Advanced non-Small Cell Lung Cancer (ID 2524)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      Docetaxel (75mg/m[2]) has been reported as first-line and maintenance treatment for Western population with advanced NSCLC. Different doses of docetaxel (60mg/m[2]) are currently delivered in Asian population. Pharmacogenomics alterations in taxanes disposition in different ethnic groups may explain this difference. TFINE study was to evaluate the efficacy, safety, and tolerability of Docetaxel in the maintenance setting, and to identify the preferable dose of docetaxel in Asian population. TFINE study demonstrated significant superiority in tolerability and similar efficacy for dose of 60mg/m2 of Docetaxel versus that of 75mg/m2 in first-line Chinese advanced NSCLC patients. And maintenance treatment with docetaxel significantly prolonged PFS compared with BSC. Here we report Overall Survival (OS) data from TFINE (ClinicalTrials.gov NCT01038661).

      Methods
      Previously untreated patients, aged between 18 and 75 years, histologically or cytologically confirmed advanced NSCLC with PS of 0-1 were included. Patients were initially randomized (R1, 1:1) to receive cisplatin (75mg/m2) plus docetaxel of 75 mg/m2 or 60mg/m2 for 4 cycles. Patients with disease control after the initial treatment were subsequently randomized (R2, 1:2) to best supportive care (BSC) or maintenance docetaxel of 60mg/m2 for up to 6 cycles. Genomic DNA was prospectively collected from all enrolled patients. The primary endpoint was PFS since R2, and the secondary endpoints included ORR, overall survival (OS), and toxicity. OS was defined as the time lasting from R2 to death of any cause. The subgroup analysis about OS included gender, historical category, smoking, ECOG PS. The maintenance treatments of every patient were recorded.

      Results
      This randomized study was undertaken in 15 centers in China. Between Dec 2009 and Aug 2011, a total of 382 patients were enrolled to R1 and 179 patients (46.8%) were enrolled to R2 (61 vs. 118). The median follow-up time for OS was 23.5 months (range 20.5, 28.1 months) for patients receiving BSC and 24.4 months (range 22.6, 25.3 months) for patients receiving maintenance docetaxel of 60mg/m2 for up to 6 cycles. Median OS of BSC group (13.7months, [95%CI:12.0, 15.7]) was not significantly different from that of docetaxel group(12.3months,[95%CI:11.2,14.1]) (p=0.77). No difference was found in the subgroup analysis. Post-discontinuation therapy was given at the discretion of the investigator. Numerically more patients in BSC group (n=35, 57.4%) received second-line treatments, including docetaxel, EGFR-TKI or pemetrexed, than those in maintenance group (n=56, 45.5%), although the difference is statistically insignificant (p=0.13). The failure observation of PFS gains translating into OS gains is partially related to post-progression therapy. Preliminary pharmacogenomics analysis demonstrated the CYP3A5*3C(6986 AG/GG) genotype associated with poor PFS and ABCB1:2677 GG genotype demonstrated less neutropenia in Chinese NSCLC patient treated with Docetaxel/DDP regiment, which did not correlated with OS.

      Conclusion
      Although there is no significant benefit in terms of OS with Docetaxel maintenance treatment, our finding for better tolerability suggest that Decetaxel maintenance treatment could be of some benefit to patients with advanced non-small cell lung cancer.

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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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      P3.12-002 - Prognostic significance of the lymph node involvement in stage II-N1 non-small cell lung cancer (ID 237)

      09:30 - 16:30  |  Author(s): S. Lu

      • Abstract

      Background
      The non-small-cell lung cancer (NSCLC) staging system published in the 7th edition of the Union for International Cancer Control (UICC) and American Joint Commission on Cancer (AJCC) cancer staging manuals in 2009 did not include any changes to current N descriptors for NSCLC. However the prognostic significance of the extent of lymph node (LN) involvement, including the lymph node zones involved (hilar/interlobar or peripheral), cancer-involved lymph node ratios (LNR), and the number of involved lymph nodes remain unknown. The aim of this report is to evaluate the extent of lymph node involvement and other prognostic factors in predicting outcome after definitive surgery among Chinese stage II-N1 NSCLC patients.

      Methods
      We retrospectively reviewed the clinicopathological characteristics of 206 stage II (T1a-T2bN1M0) NSCLC patients who had undergone complete surgical resection at Shanghai Chest Hospital, Jiao Tong University from June 1999 to June 2009. Overall survival (OS) and disease-free survival (DFS) were compared using Kaplan-Meier statistical analysis. Stratified and Cox regression analyses were used to evaluate the relationship between the lymph node involvement and survival.

      Results
      Peripheral zone lymph node involvement, cancer-involved lymph node ratio(LNR), smaller tumor size, and squamous cell carcinoma were shown to be statistically significant indicators of higher OS and DFS by univariate analyses. Visceral pleural involvement was also shown to share a statistically significant relationship with DFS by univariate analyses. Multivariate analyses showed only tumor size and zone of lymph node involvement were to be significant predictors of OS.

      Conclusion
      Zone of N1 lymph node, LNR and tumor size were both found to provide independent prognostic information in patients with stage II NSCLC. This information may be used to stratify patients into groups by risk for recurrence.