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Z. Zhong



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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 - 09:30  |  Author(s): Z. Zhong

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-034 - Dual-function protein APE1 is a novel biomarker to predict tumor response in Chinese patients with stages IIIB to IV non-small-cell lung cancer. (ID 2569)

      09:30 - 09:30  |  Author(s): Z. Zhong

      • Abstract

      Background
      More than 70% of patients with lung cancer are diagnosed with advanced-stage, with short survival times. The discovery of epidermal growth factor receptor (EGFR) mutations is a major scientific breakthrough; tyrosine kinase inhibitor (TKI) treatment for patients with EGFR mutations reported a median overall survival of more than 2 years. Nevertheless, chemotherapy has steadfastly remained the most validated therapies in non-small-cell lung cancer (NSCLC) not only for vast majority of patients without EGFR mutations, but for those with EGFR-TKI resistance. There are many influence factors in platinum resistance, among them DNA repair genes have been extensively explored. Excision repair cross complementing 1 (ERCC1) and/or breast cancer susceptibility gene 1 (BRCA1) is generally associated with sensitivity to platinum, but the results were inconclusive and controversial. Apurinic/apyrimidinic endonuclease 1 (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with chemoresistance.

      Methods
      In total, 172 patients with advanced NSCLC who received platinum-based doublet chemotherapy, ages 34 to 84 years at diagnosis from 2007 to 2012 were enrolled into this study. We evaluated the impact of APE1, BRCA1, ERCC1 expression levels on response to platinum-based chemotherapy and median progression-free survival (mPFS) and/or median overall survival (mOS) outcomes, and protein expression levels were determined by immunohistochemistry (IHC).

      Results
      The mPFS was 8.8 months, mOS 12.8 months. A partial treatment response was found in 55 patients (31.98%). No significant association was found between BRCA1 protein expression and response rate, mPFS or mOS. Interestingly, patients whose tumors did not express APE1 had 50.00% response rate compared to 25.00% whose tumors expressed the protein (OR 0.34; 95% CI 0.17-0.69; P=0.002). Patients negative for APE1 had a significantly longer mPFS (10.3 vs. 8.0 months, P=0.016), but not mOS (17.1 vs. 10.9 months, P=0.263), than those positive for APE1. Patients negative for ERCC1 expression experienced better response to chemotherapy (OR 0.36; 95% CI 0.18-0.72; P=0.003), longer mPFS (9.8 vs. 6.8 months, P=0.001), and longer mOS (14.4 vs. 10.3 months, P=0.011). In particular, the expression of ERCC1 had a positive trend of correlation with APE1 expression (r[2]=0.23, P<0.01), and patients negative for both APE1 and ERCC1 had significantly higher response rate (OR 0.18; 95% CI 0.07-0.45; P<0.001), longer mPFS (12.0 vs. 6.8 months, P<0.001) and mOS (18.8 vs. 10.1 months, P=0.010), than those positive for both APE1 and ERCC1. Multivariate analysis adjusting for possible confounding factors showed that negative APE1 and/or ERCC1 expression was a significantly favorable factors for mPFS (HR 1.86, P=0.002 and HR 1.83, P=0.001; respectively) and mOS (HR 2.02, P=0.002 and HR 1.78, P=0.007; respectively).

      Conclusion
      The results suggest that dual-function protein APE1 may be a novel prognostic and predictive factor, and the combined detection of APE1 and ERCC1 expression might better individualize the efficacy of chemotherapy and improve survival in advanced NSCLC.