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W.S. Kim



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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-008 - The HSP 90 inhibitors suppress cell growth by suppression of ALK and TGF-beta1 signaling in crizotinib-resitant H2228 cells by Epithelial to mesenchymal transition (ID 2544)

      09:30 - 09:30  |  Author(s): W.S. Kim

      • Abstract

      Background
      Epithelial to mesenchymal transition (EMT) is related with reduced sensitivity to many chemotherapeutic drugs including EGFR tyrosine kinase inhibitors. We investigated whether EMT also could contribute to the resistance to crizotinib and there are other therapeutic options overcoming EMT-mediated resistance.

      Methods
      We established a crizotinib-resistant subline (H2228/CR), which was derived from the parental H2228 cell line by long-term exposure to increasing concentration of crizotinib. Characteristics related with EMT including morphology, EMT marker proteins and cellular mobility were analyzed. We examined whether the induction of EMT affect sensitivity to Hsp90 inhibitors.

      Results
      Compared with the H2228 cell, the growth of H2228/CR cells was independent on EML4-ALK, and they showed cross-resistance to TAE-684 (a 2[nd]-generation ALK inhibitor). Phenotypic change of a spindle-cell shape was found in H2228/CR, which was accompanied by a decrease of E-cadherin and an increase of vimentin and AXL. In addition, they showed the increased secretion and expression of TGF-β1. The capability of invasion and migration was dramatically increased in H2228/CR cells. TGF-b1 treatment for 72 h in parental H2228 cells induced reversible EMT leading to crizotinib-resistance while this was reversed through the removal of TGF-β1. Suppression of vimentin by siRNA treatment in H2228/CR cells restored the sensitivity to crizotinib. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitors similar to parental cells, H2228. HSP90 inhibition resulted in downregulation of TGF-β receptor II in addition to ALK.

      Conclusion
      EMT should be considered as one of possible acquired resistant mechanisms to crizotinib and HSP90 inhibitors can be a promising therapeutic option for EMT-mediated resistance.

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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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      P1.09-005 - The optimal timing of SRS add to EGFR-TKI treatment for brain metastasis from activating EGFR mutant NSCLC (ID 692)

      09:30 - 09:30  |  Author(s): W.S. Kim

      • Abstract

      Background
      Lung cancer is the most frequent cause of cancer-related death worldwide. Brain metastasis is an important issue because its incidence of 20-40% in non small cell lung cancer (NSCLC) patients and association of significant mortality and morbidity. There are several therapeutic modalities for CNS lesions such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and metastasectomy. It is well known that conventional chemotherapy is not effective for brain metastasis because of blood brain barrier (BBB). On the other hand, tyrosine kinase inhibitors (TKI) have showed efficacy in patients with brain metastasis from activating epithelial growth factor receptor (EGFR) mutant NSCLC. We assumed that SRS for brain metastasis could be delayed for the patients with activating EGFR mutation on taking gefitinib or erlotinib.

      Methods
      We retrospectively identified patients with brain metastasis from NSCLC harboring a sensitizing mutation of EGFR who were treated with SRS for the brain metastasis combined with TKI. EGFR mutations in exons 18, 19, 20 and 21 were analyzed by direct sequencing. SRS treatment was indicated for brain metastasis less than 6 lesions and not exceeding 4cm each of them. The patients in SRS first group were treated by SRS for brain metastasis, and then TKI was administrated. The other patients were treated with TKI before SRS and they were assigned to TKI first group. Progression free survival time was compared with each group.

      Results
      Forty-three patients were eligible (SRS first: 29, TKI first 14). Twenty-nine patients of them (67.4%) were women, median age was 56 (range 36-78). Most of them were adenocarinoma, except 1 squamous cell carcinoma and 1 NSCLC NOS. All patients have activating EGFR mutations, 2 patients had also T790M mutation known as TKI resistant mutation. TKI was used as 2[nd] line treatment for twenty five patients (58.1%). WBRT and brain metastasectomy were additionally employed for 9 and 6 patients. Although eight patients complained headache after SRS, it was self-limited. The median duration of TKI treatment were not different from each group (13.4 months in SRS first group, 14.7 months in TKI first group, p=0.986) As a result, the median progression free survival time was prolonged in SRS first group than in the TKI first group (12.6 months versus 2.3 months, p<0.001). And there was no significant adverse effect related with SRS in both groups.

      Conclusion
      It is better to consider SRS for brain metastasis as soon as possible, even if TKI is effective for patients with brain metastasis from activating EGFR mutant NSCLC. Also, the combined treatment of TKI with SRS was well tolerated by all patients in this study.

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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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      P3.10-027 - Selection of patients with adenocarcinoma of the lung for Gefinitib by FDG PET metabolic response (ID 1628)

      09:30 - 09:30  |  Author(s): W.S. Kim

      • Abstract

      Background
      Gefitinib is the standard therapy for non-small cell lung cancer patients harboring activating EGFR mutation. However, there are some limitations; 1) we need sufficient tumor tissue to analyze EGFR mutation test; 2) we have to wait result of the test, causing delay of treatment; and 3) we can evaluate the response 4 weeks later but some of the patients do not respond to EGFR TKIs even though they have an activating EGFR mutation. Therefore, we investigated the role of FDG PET as a method overcoming the limitations to evaluate the response to EGFR TKIs.

      Methods
      Key eligibility is as follows; advanced/metastatic adenocarcinoma of the lung; never smoker; no prior chemotherapy; ECOG PS of 0-1; and main lesion > 2cm. The patients performed two times of FDG PET; before starting gefitinib and after 7 days of gefitinib 250mg/d therapy. If % decrease of peak standardized uptake value (pSUV) of main lesion was 20% or more, gefitinib was continued till progression (Group A). After 6 weeks of the treatment, conventional response evaluation using chest CT was done. But, if % decrease of pSUV less than 20% or increase, treatment changed from gefitinib to pemetrexed/cisplatin (Group B). Primary endpoint was to see the response rate of gefitinib in the patients of Group A. EGFR mutation test using direct sequencing method was also performed but the result was not available or unknown to investigators before the report of second PET result.

      Results
      Between Apr 2012 and Apr 2013, 50 patients participated. After 7 day-treatment of gefitinib, 28 out of 50 patients showed decrease of pSUV of main lesion ≥ 20 % (47.4±15.8%) (Group A). Out of the 28 patients in Group A, 27 patients were evaluable; PR in 24 (85.7%), SD in 2 and PD in 1 (Table). EGFR mutation was identified later in 24 patients (85.7%) and 4 patients showed wild type EGFR with 2 PRs, 1 PD and 1 NE. Twenty-two patients showed decrease of pSUV < 20 % or increase (-0.3±15.3%). Interestingly, 19 patients (86.4%) had wild type EGRF while two had an activating EGFR mutation. One patient who showed mutated EGFR in Group B was given gefitinib continuously as physician’s decision. But the patient did progressed after all.

      Group A (gefitinib, n=28) Group B (pem/cis, n=22)
      Response EGFR mutation EGFR mutation
      Postive (n=24) Negative (n=4) Total (n=28) Postive (n=2) Negative (n=19) NE (n=1) Total (n=22)
      CR - - 0 - - - 0
      PR 22 2 24 (85.7%) 1 13 - 14 (63.6%)
      SD 2 - 2 (7.1%) - 4 - 4 (18.2%)
      PD - 1 1 (3.6%) - 1 - 1 (4.5%)
      NE - 1 1 (3.6%) 1 1 1 3 (13.6%)

      Conclusion
      The % decrease of pSUV of ≥ 20 % after 7 days of gefitinib treatment would be a good indicator to predict tumor response to EGFR TKI therapy in this clinical setting.