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S. Kim



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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.12 - AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC (ID 2289)

      11:30 - 11:35  |  Author(s): S. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.

      Methods
      AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.

      Results
      AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).

      Conclusion
      Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.

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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): 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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    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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      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

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

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-024 - Acute Exacerbation of Idiopathic Interstitial Pneumonia After Resection of Lung Cancer: Investigation of Pre Operative CT predictor (ID 1819)

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

      • Abstract

      Background
      To investigate the ‘preoperative CT predictor’ of postoperative acute exacerbation (AE) of lung cancer with underlying idiopathic interstitial pneumonia (IIP) compared to those without AE as control.

      Methods
      The 78 pulmonary resections for lung cancer with underlying IIP in a single tertiary center, 72 males (92.3%) and 6 females (7.7%), aged from 47 to 80 years old, with a median age of 66 years were retrospectively included. This study was approved by the Institutional Review Board and informed consent was waived. Underlying IIP was retrospectively assessed histological (n=46, 59.0%) and clinico-radiological (n=32, 41.0%) according to ATS/ ERS guidelines. We divided them in two groups, one acute exacerbation (AE group) and the other without acute exacerbation (non AE group) after operation of lung cancer. Records of patients who experienced postoperative acute exacerbation were extracted from the clinical data-base. Two independent expert chest radiologists analyzed CT findings in two times (four data sets) for one month interval. We analyzed age, gender, smoking history and pulmonary function test (PFT) differences between two groups. We analyzed HRCT findings as follows; extent of reticulation, honeycombing, ground-glass opacity, and emphysema in overall extent with area percentage. Fibrotic score (sum of reticulation and honeycombing) was also assessed. We performed the correlation between HRCT findings and presence of acute exacerbation. We used binary logistic regression analysis and student t-test with SPSS 21.0 version as statistics.

      Results
      Of the 78 lung cancer patients, six patients experienced postoperative acute exacerbation (7.7%). Smoking history and PFT between two groups were not significantly different except age and gender. Inter- and intra-reader correlation coefficient were 0.496~0.928 and 0.667~0.936/0.657~0.949, respectively, good to fair. Honeycombing (p=0.001; OR, 1.243; CI, 1.087~1.422) and fibrotic score (p=0.007; OR, 1.188; CI, 1.047~1.347) and abnormal area (p=0.042; OR, 1.059; CI, 1.002~1.119) were significantly high in AE group.

      Conclusion
      Physicians should consider the high extent of honeycombing, as well as high fibrotic score in CT, a potential risk factor for acute exacerbation after pulmonary resection for lung cancer.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-012 - Prognostic Value of Tumor Survivin Expression in Stage III Non-small Cell Lung Cancer Patients Treated with Platinum-based Chemoradiation Therapy Followed by Surgery (ID 2473)

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

      • Abstract

      Background
      The potential prognostic value of survivin is variably reported in various stage of lung cancer. This study evaluated the correlation between tumor survivin expression before and after chemoradiation therapy (CRT) and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with platinum-based chemoradiation therapy followed by surgery

      Methods
      Medical records from 53 patients whose tissues were suitable for study were reviewed. Tissues were stained by immunohistochemistry and were estimated the degree of stain with scoring for survivin. Clinicopathologic parameters and survivin expression score were evaluated for a prognostic relationship with overall survival (OS) and time to recurrence (TTR).

      Results
      Pathologic complete response, residual nodal involvement and radiologic response after CRT were not related with OS or TTR. Tumor survivin expression on pre-treatment tissues was presented in 47 patients (88.7%). Pre-treatment survivin score was not related with TTR and OS (p = 0.249 and p = 0.601, respectively). There was no correlation between pre-treatment and post-treatment survivin score (p = 0.309). Downregulation of survivin and post-treatment survivin score (0 – 1) after chemoradiation showed significant improvement in OS (p = 0.04 and p = 0.033, respectively). Age, downregulation of survivin score, and post-treatment survivin score (0 – 1) were significant prognostic factors for survival by multivariate analysis.

      Conclusion
      Downregulation of survivin score and post-treatment low survivin score in stage III NSCLC treated with platinum-based chemoradiation therapy followed by surgery has a value of prognostic factor regardless pre-treatment survivin score. Further studies to evaluate the relation of survivin expression and platinum-based chemoradiation therapy are warranted in NSCLC.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-010 - Phase I study of HM61713, a novel epidermal growth factor receptor (EGFR) mutant selective inhibitor, in non-small cell lung cancer (NSCLC) patients having an activating EGFR mutation but failed to prior EGFR tyrosine kinase inhibitor (TKI) therapy. (ID 1048)

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

      • Abstract

      Background
      NSCLC patients having an activating EGFR mutation initially responded well to EGFR TKI but most of them experienced progressive disease due to various resistance mechanisms including T790M (~50% of cases) mutation. HM61713 is an orally active, novel EGFR mutant selective inhibitor showing a strong anticancer activity in many lung cancer cell lines including T790M mutation harboring cell line. Therefore, HM61713 might provide the potential clinical benefit to those who have an activating EGFR mutation but have failed previous EGFR TKI treatment.

      Methods
      This is a phase I study using a standard 3+3 dose escalation scheme. NSCLC Patients with activating EGFR mutation and progressed after at least 2 prior chemotherapy regimens including EGFR TKI were eligible. The objective of this study is to determine the recommended phase II dose as well as to assess the preliminarily efficacy.

      Results
      To date, a total of 23 patients were treated with at doses of 75-250 mg/day. One patient at a dose of 200 mg/day experienced grade 3 drug induced idiosyncrasy and grade 4 elevation of amylase. The drug induced idiosyncrasy was skin rash of non-EGFR TKI type. The most common drug-related adverse events were desquamation, diarrhea, pruritus, and nausea; most were grade 1 or 2. The maximum tolerated dose (MTD) and recommended phase II dose were not determined yet. Plasma concentration of HM61713 reached the peak 2-4 hr after administration and declined with the half-life of 8-12 hr. Among 21 evaluable patients, 2 patients achieved partial response (PR) and one of them had confirmed T790M mutation while 12 patients had stable disease (SD) including 11 patients showed tumor shrinkage. Accrual to this study is ongoing and updated data will be presented at the meeting.

      Conclusion
      HM61713 showed good safety profile and promising anticancer activity in NSCLC patients with EGFR mutation who failed to prior EGFR TKI therapy. These results support the therapeutic potential of HM61713 for NSCLC patients with activating EGFR mutations after development of resistance to EGFR TKI therapy.

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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): 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.