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Zhen Wang



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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-104 - Survivals in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer Treated with First-Line Crizotinib (ID 1735)

      09:45 - 18:00  |  Author(s): Zhen Wang

      • Abstract
      • Slides

      Background

      The c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) can be treated effectively with crizotinib, a tyrosine kinase inhibitor (TKI) of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). However, few studies have investigated on survivals in ROS1-rearranged advanced NSCLC patients treated with first-line crizotinib.

      Method

      We retrospectively analyzed clinicopathological and survival data of ROS1-rearranged patients with advanced NSCLC treated with crizotinib between August 2013 and January 2019 at the Guangdong Provincial People's Hospital. ROS1 rearrangements were detected by Reverse Transcription-Ploymerase Chain Reaction(RT/PCR),Fluorescence in situhybridization (FISH), or Next-generation Sequencing (NGS) . Overall survival (OS) and progression-free survival (PFS) were compared between first-line crizotinib, chemotherapy followed by crizotinib and first-line chemotherapy without any subsequent targeted therapy.

      Result

      Among totally 40 patients with ROS1-rearranged advanced NSCLC, 29 were treated with crizotinib (16 with first-line; 13 with second- or further-line), and 11 were not treated with crizotinib at data cutoff (April 4, 2019). Median OS was significantly prolonged in patients with first-line crizotinib (N=16) than those with first-line chemotherapy followed by subsequent crizotinib (N=9), not reached vs. 27.1 months, P=0.042. However, there was no significant difference in median PFS between the two groups, 16.3 vs. 5.7 months, P=0.054. Meanwhile, first-line crizotinib (N=16) was significantly superior to first-line chemotherapy without any subsequent targeted therapy (N=8) in both median OS (not reached vs. 9.1 months, P=0.024) and PFS (16.3 vs. 4.8 months, P=0.017).

      Conclusion

      First-line crizotinib prolongs survivals than chemotherapy for patients with ROS1-rearranged advanced NSCLC.

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      P1.01-82 - The Different Frequencies and Genetic Profiles of Histologic Transformation After Different EGFR-TKIs in EGFR-Mutant Adenocarcinomas (ID 418)

      09:45 - 18:00  |  Author(s): Zhen Wang

      • Abstract
      • Slides

      Background

      Histologic transformation is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(TKIs) in EGFR-mutant non-small cell lung cancers(NSCLCs). Those adenocarcinomas with histologic transformation usually underwent poor prognosis. However, few studies have focused on the different occurrence rates and genetic profiles between EGFR-mutant adenocarcinomas treated with different generations of EGFR-TKIs.

      Method

      Pathology was confirmed in 345 EGFR-mutant patients at baseline and recurrence. Among these patients,235 patients were treated with gefitinib or erlotinib,54 with afatinib and 56 with osimertinib. But only 11 patients with sufficient tumor specimens could be evaluated for the genetic profiles by next-generation sequencing (NGS). Demographics, disease features, and outcomes of these patients were analyzed.

      Result

      The frequency of these EGFR-mutant adenocarcinomas with histologic transformation after the treatment of different generation TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.2% (17/235),while the others were 5.6%(3/54, afatinib group)and 17.9%(10/56, osimertinib group). The median progression free survival (PFS)to EGFR-TKIs of those patients were 12.2 months(gefitinib/erlotinib group), 5.3 months (afatinib group)and 7.7 months(osimertinib group) respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma treated with afatinib was founded to have acquired MET amplification and transformed to small-cell lung cancer meanwhile. Moreover, the PFS of one patient to afatinib was just 3 months and her genetic profile at baseline was characterized by Rb1, TP53, and PIK3CA mutations. There were 3 patients treated with osimertinib underwent histologic transformation from adenocarcinomas to squamous carcinoma. One patient after progressive disease of osimertinib did not have enough tissue to detect NGS,and her blood NGS result just showed EGFR L858R and T790M mutation. The tissue NGS result of the second patient showed EGFR p.Glu746-Ala750 deletion, EGFR T790M and C797S mutations, CDK4/ CCND1/ EGFR/ KRAS amplifications. The second patient received the chemotherapy of pemetrexed+ carboplatin + bevacizumab and the best response was partial response. The third patient take palbociclib and osimertinib meanwhile and his symptoms improved with the tissue NGS of EGFR T790M mutation and CDK4/ MDM2/ EGFR amplifications. They were characterized by EGFR amplification and CDK4 amplification. The others transform from adenocarcinomas to small cell cancers or neuroendocrine tumors were seem to harbor with TP53, Rb1 and PIK3CA mutations.

      Conclusion

      It seems more common in some subtypes that the EGFR-mutant adenocarcinomas treated with osimertinib undergo histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers/neuroendocrine tumors in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.

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      P1.01-85 - Treatment for Advanced NSCLC with EGFR Mutations and De Novo MET Amplification/Overexpression (ID 2190)

      09:45 - 18:00  |  Author(s): Zhen Wang

      • Abstract
      • Slides

      Background

      Combination of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs) are effective in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation and acquired MET-amplification. However, there are few reports about treatments of patients with EGFR mutation and de novo MET amplification/ overexpression.

      Method

      We retrospectively screened 88 consecutive advanced NSCLC patients harboring EGFR mutation and de novo MET amplification/overexpression at Guangdong Provincial People's Hospital of China from January, 2014 to December, 2018. Among them, a total of 41 patients receiving first-line targeted therapy were included and stratified into EGFR-driven, MET-driven and EGFR/MET co-driven groups illustrated respectively in Table 1.

      Table 1. Classification of advanced NSCLC with EGFR mutation and MET overexpression/amplification.
      Group EGFR mutation MET overexpression/amplification Response to first-line TKI
      EGFR-driven Exon 19 deletion or exon 21 L858R mutation (tested by next generation sequencing (NGS) or amplification refractory mutation system (ARMS) or polymerase chain reaction (PCR)).

      Overexpression: strong intensity staining was in more than 50% of tumor cells (tested by immunohistochemistry (IHC)).

      Amplification: CNG≥5, or MET/centromeric portion of chormosome 7 ratio≥2.2, with an additional criterion of focal amplification was in more than 10% of tumor cells (tested by fluorescence in situ hybridization (FISH)).

      PFS>3 months, best response is complete response (CR)/partial response (PR)/stable disease (SD); not receiving MET-TKIs in later-line treatment, or had MET-TKIs but PFS≤3 months.
      MET-driven PFS≤3 months, receive MET-TKIs monotherapy or MET-TKIs plus EGFR-TKIs in later-line treatment and PFS>3months, or PFS≤3 months,but with acquired mechanism to MET.
      EGFR/MET co-driven Response to EGFR-TKIs at least one time, receiving EGFR-TKIs plus MET-TKIs in later-line treatment and PFS>3 months, or PFS≤3 months, but with acquired mechanism to MET.

      Result

      Among enrolled patients, 40 of them received first-line first-generation EGFR-TKIs while 1 treated with MET-TKI. Twenty-eight received targeted therapy in the later-line treatments after resistance. Thirty-one (75.6%), 5 (12.2%) and 5 (12.2%) patients were classified into EGFR-driven, MET-driven and EGFR/MET co-driven groups. Median progression-free survival (PFS) was 12.1, 1.0 and 5.3 months respectively in the first-line setting. Objective response rates were 58.1%, 0.0% and 20.0% (P=0.028) respectively. Among 28 patients receiving subsequent targeted therapies, 58.1% (18/31), 100.0% (5/5) and 100.0% (5/5) were EGFR-driven, MET-driven and EGFR/MET co-driven respectively. Median PFS was 7.0, 6.5 and 10.3 months for the EGFR-driven group receiving subsequent EGFR-TKIs, the MET-driven group receiving MET-TKIs with or without EGFR-TKIs, and the EGFR/MET co-driven group treating with EGFR-TKIs plus MET-TKIs respectively (P=0.399). Also, no significant difference was observed in overall survival for these 28 patients (33.8 vs. 11.8 vs. 27.9 months, P=0.098).

      Conclusion

      Subsequent individualized targeted therapy or co-targeted therapies might favor clinical outcomes for both MET-driven and EGFR/MET co-driven patients with advanced NSCLC after resistance to first-line EGFR-TKIs.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-39 - Acquired ALK Rearrangement in EGFR-Mutant Lung Adenocarcinoma Treated with EGFR TKIs (ID 1784)

      09:45 - 18:00  |  Author(s): Zhen Wang

      • Abstract
      • Slides

      Background

      Few studies have been reported on acquired anaplastic lymphoma kinase (ALK) rearrangement in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients with EGFR tyrosine kinase inhibitors (TKIs).

      Method

      EGFR-mutant lung adenocarcinoma patients were screened after resistance to EGFR TKIs from September 2017 to December 2018 at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments.

      Result

      Totally 320 patients were tested by NGS after resistance to EGFR TKIs ( 175, 42 and 103 with first-, second- and third-generation EGFR-TKIs respectively). Frequency of acquired ALK rearrangement was 1.14% (2/175), 2.38% (1/42) and 1.94% (2/103) in patients treated with first-, second- and third-generation EGFR TKIs respectively. The fusion partners of ALK were EML4 in 2 patients, CLIP4 (1), NPM1 (1) and PIBF1 (1). Non-EML4-ALK fusion accounted for 60%. One with acquired EML4-ALK achieved minor response with osimertinib plus crizotinib. One with acquired NPM1-ALK achieved partial response with erlotinib plus crizotinib. Unfortunately, one with acquired CLIP4-ALK fusion and BRAF V600E mutation did not respond to ensartinib single agent. One with acquired PIBF1-ALK had no clinical benefit with osimertinib plus alectinib. Finally, one with acquired EML4-ALK died shortly without any treatment due to poor performance status.

      Conclusion

      The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-35 - Acquired MET-Aberrance Is a Mechanism of Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer     (Now Available) (ID 1739)

      10:15 - 18:15  |  Author(s): Zhen Wang

      • Abstract
      • Slides

      Background

      Anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI) is standard of care in ALK-positive advanced non-small-cell lung cancer (NSCLC). Unfortunately ALK-positive NSCLC patients treated with ALK TKIs inevitably develop resistance mediated by complex mechanisms including ALK mutations, ALK amplification, or activation of alternative signaling pathways. However, there are few reports about Mesenchymal-epithelial transition factor (MET) signal in NSCLC.

      Method

      Totally 136 ALK-positive advanced NSCLC patients were screened for ALK rearrangement detected by tumor tissue or plasma Next-generation sequencing(NGS) at the Guangdong Lung Cancer Institute from January 2016 to December 2018 .MET-aberrance was defined as c-Met overexpression performed by immunohistochemical(IHC) staining method with SP44 antibody and MET amplification assessed by tumor tissue or plasma Next-generation sequencing (NGS) or fluorescent in situ hybridization(FISH).

      Result

      Totally 5.89% (8/136) of patients were identified with MET-aberrance in 136 ALK-rearranged cases. Among the 8 patients,there were 6 with de novo MET-aberrance and 2 with acquired MET-aberrance.The median progression-free survival (PFS) in ALK-rearranged patients with de novo MET-aberrance was 9.6 months (95% CI 0.0 to 19.2months).The other 2 patients gained MET-aberrance after the treatment with alectinib. Both of them received lorlatinib, but the PFS only lasted for 2months. One achieved partial remission with crizotinib , which was originally developed as an inhibitor of the MET gene.

      Conclusion

      Acquired MET-aberrance maybe a mechanism of acquired resistance to the second-generation ALK-TKIs for ALK-rearranged advanced NSCLC patients.

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