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X. Zhang



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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI16.13 - A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901) (ID 2762)

      16:45 - 18:15  |  Author(s): X. Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      For non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, preclinical data showed the superiority of exon 19 mutations to exon 21 mutations in both response to EGFR tyrosine kinase inhibitors (TKIs) and survival. Meanwhile, retrospective studies demonstrated that erlotinib was significantly superior to gefitinib in progression-free survival (PFS) for advanced NSCLC patients with EGFR mutations. However, no randomized controlled trials compared erlotinib to gefitinib in advanced NSCLC patients with EGFR exon 19 or 21 mutations.

      Methods:
      We conducted a randomized controlled trial (CTONG 0901;NCT01024413) comparing erlotinib to gefitinib in advanced NSCLC harboring EGFR exon 19 or 21 mutations from July 2009 to July 2014. Eligible patients were randomized to receive erlotinib (150 mg, qd) or gefitinib (250 mg, qd) at the ratio of 1:1 in any line settings. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), post-progression survival (PPS), and toxicities.

      Results:
      The last follow-up was on March 30, 2015. Totally, 256 patients (148 with exon 19 mutations and 108 with exon 21 mutations), of whom 165, 83 and 9 were in the first, second or further-line settings respectively, were randomized to receive erlotinib or gefitinib. Median PFS was 12.4 (95%CI: 10.6~14.1) months in erlotinib arm and 10.4 (95%CI: 8.8~11.9) months in gefitinib arm, HR=0.80 (0.61~1.05), p=0.100; ORR, median PPS and OS were 56.3% versus 52.3% (p=0.530), 6.9 (95%CI: 4.3~9.5) versus 6.9 (95%CI: 4.5~9.2) months (p=0.784), and 22.4 (95%CI: 17.9~27.0) versus 20.5 (95%CI: 17.1~23.8) months (HR=0.90 [0.67~1.22]; p=0.496) respectively. There were no significant differences in toxicities between the two arms, p>0.05. In the four subgroups (the first-line, second or further-line setting, exon 19 and 21 mutations), except for median PFS being 11.4 versus 7.9 months (HR=0.58 [0.37~0.90], p=0.015) in the second or further-line setting, no significant differencs were observed in median PFS and OS respectively between the two arms, p>0.05. Receiving erlotinib or gefitinib treatment, EGFR exon 19 mutant patients were superior to those with exon 21 mutations in terms of ORR (62.2% versus 43.5%, p=0.003), median PPS (9.1 [95%CI: 7.0~11.2] versus 4.6 [95%CI: 3.4~5.8] months, p=0.011 ) and OS (24.8 [95%CI: 20.9~28.8] versus 17.7 [95%CI: 15.1~20.3] months, HR=0.66 [0.48~0.89], p=0.006) respectively, even though there was no significantly difference in median PFS (11.4 [95%CI: 9.6~13.2] versus 11.1 [95%CI: 9.4~12.9] months, HR=0.80 [0.60~1.05], p=0.101). Multivariant Cox regression analysis showed that subsequent EGFR TKIs, combination of subsequent EGFR TKIs and local treatment, as well as subsequent chemotherapy were prognostic factors for OS, p<0.05.

      Conclusion:
      Erlotinib was not significantly superior to gefitinib in advanced NSCLC with either exon 19 or 21 mutations in response and survival, with similar toxicities. However, EGFR exon 19 mutant patients had remarkably increased ORR, PPS and OS than those with exon 21 mutations after taking erlotinib or gefitinib. Subsequent treatments after failure to EGFR TKIs were significantly prognostic factors for OS.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-051 - Biomarker Analyses from a Phase II Trial of Nab-Paclitaxel/Carboplatin vs Emcitabine/Carboplatin in Advanced Squamous Cell Lung Cancer (ID 2846)

      09:30 - 17:00  |  Author(s): X. Zhang

      • Abstract
      • Slides

      Background:
      The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase Ⅲ trial. However, our phase Ⅱ trial (NCT01236716; CTONG1002), which compared the efficacy and safety of first-line nab-PC with gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung, only showed a marginally improved ORR caused by first-line nab-PC. Meanwhile, the matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) and caveolin-1 are potential biomarkers for advanced NSCLC patients receiving nab-PC. Therefore, we retrospectively aimed to explore their predictive and prognostic value using immunohistochemistry (IHC).

      Methods:
      From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w ) or GC (G, 1,250 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w). There were 110 patients evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) respectively. However, there were 72 patients with sufficient tissue for IHC of both SPARC and caveolin-1 proteins. Different cut-off values of IHC scoring systems were used to explore predictive and prognostic role of both biomarkers.

      Results:
      The last follow-up was on January 16, 2015. Considering treatment, when the maximum rank method was used for cut-off values, median progression-free survival (PFS) was 7.5 (95%CI: 2.4~12.6) months in higher SPARC-expression arm and 4.3 (95%CI: 2.2~6.3) months in lower SPARC-expression arm for patients treated with GC, HR=0.43 (95%CI: 0.19~0.94), p = 0.030; Median overall survival (OS) was 20.0 (95%CI: 14.7~25.3) months in lower SPARC-expression arm and 10.1 (95%CI: 6.2~14.0) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.41 (95%CI: 1.08~5.40), p = 0.027. When average method was used for cut-off values, median OS was 18.2 (95%CI: 9.6~26.8) months in lower SPARC-expression arm and 8.4 (95%CI: 5.1~11.7) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.46 (95%CI: 1.07~5.65), p = 0.029. Regardless of treatment, when the maximum rank method was used for cut-off values, median OS was 14.5 (95%CI: 6.8~22.1) months in lower SPARC-expression arm and 8.4 (95%CI: 5.3~11.5) months in higher SPARC-expression arm, HR=0.47 (95%CI: 0.27~0.83), p = 0.007. When average method was used for cut-off values, median OS was 14.4 (95%CI: 9.2~19.5) months in lower SPARC-expression arm and 8.4 (95%CI: 5.4~11.4) months in higher SPARC-expression arm, HR=0.48 (95%CI: 0.27~0.87), p = 0.013. ORR was not correlated with expression of SPARC, p>0.05. However, there were no significant differences in ORR, PFS and OS between higher and lower caveolin-1 expression arms, p>0.05.

      Conclusion:
      SPARC expression could be a negative prognostic factor for OS of patients with advanced squamous cell carcinoma of the lung, but was not a predictive factor for ORR and PFS, except for patients treated with GC. However, caveolin-1 expression had neither predictive nor prognostic value.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-036 - Rare Discrepancies in a Driving Gene Alteration within Histologically Heterogeneous Primary Lung Cancers (ID 2229)

      09:30 - 17:00  |  Author(s): X. Zhang

      • Abstract
      • Slides

      Background:
      Most lung adenocarcinomas consist of a mixture of histological subtypes among which driving gene mutations occurred with different frequencies. However, little is known about intratumoral heterogeneity within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to clinical practice and personalized treatment.

      Methods:
      Morphologically different tumor areas within the same surgically resected primary tumors were extracted from tissue sections and the gene status in each growth pattern was analyzed. Driving genes, epidermal growth factor receptor (EGFR), KRAS, and rearrangements in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), were assessed by assays of different sensitivity.

      Results:
      Seventy-nine consecutive, surgically resected, adenocarcinomas or adeno-squamouse cell carcinomas harboring a driving gene mutation or rearrangement (EGFR, n = 65; KARS, n = 10; EML4-ALK, n = 4) were selected. For EGFR mutations in adenocarcinomas, ITH occurred in 13.3% (8/60) as determined by direct sequencing, but in only 1.7% (1/60) by ARMS(P= 0.016). A consistent intratumoral EGFR mutation status was found within 5 histologically heterogeneous adeno-squamous cell carcinomas, as shown with ARMS. ITH among KRAS mutations were detected in 20% (2/10) of regions examined by direct sequencing ,whereas a consistent status (10/10) was obtained with HRM. There were no discrepancies in EML4-ALK rearrangements according to FISH for four tumors.

      Conclusion:
      Rare ITHs deriving from EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas were found with methods of high sensitivity. Discrepancies might be due to the abundance of cells harboring driving gene and detection assays.

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