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C. Tsai



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.04 - A Randomized Phase 3 Study Comparing First-line Pemetrexed plus Cisplatin Followed by Gefitinib as Maintenance with Gefitinib Monotherapy in East Asian Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (nSqNSCLC) (ID 1943)

      16:15 - 17:45  |  Author(s): C. Tsai

      • Abstract
      • Presentation
      • Slides

      Background
      The IPASS study reported that in a clinically selected lung cancer patient population (East Asian, light ex-/nonsmokers with adenocarcinoma) gefitinib (G) provided superior progression-free survival (PFS) than chemotherapy with carboplatin/paclitaxel; however, the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumors whereas patients with wild-type (WT) tumors had inferior outcomes. Pemetrexed, in combination with cisplatin, (PC) has demonstrated improved efficacy in first-line treatment of nSqNSCLC and is a preferred chemotherapy choice. The primary objective was to compare PC induction therapy followed by G as maintenance therapy to G monotherapy, in terms of PFS, as first-line treatment in a similar “IPASS” patient population.

      Methods
      Patients with unknown EGFR mutation status (N=236) were randomized 1:1 to PCG treatment for 6 cycles or G. Patients on Arm A without progressive disease after 6 cycles received G maintenance therapy. Stage IIIB/IV nSQ NSCLC, light ex-smokers or never-smokers, and ECOG PS 0-1 patients with no prior systemic therapy were eligible. Primary endpoint analysis was conducted using a Wilcoxon test after 169 PFS events. This assessment provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples from consenting patients were analyzed for EGFR mutation status.

      Results
      Baseline characteristics were balanced across treatment arms. One-hundred-forty-one patients provided tissue for EGFR mutation analysis (59.7%). Mutation status was determined for 74 samples (52.5%);50/74 samples (67.6%) had mutations (mutation type: EX19_DEL, n=25; L858R, n=23; other, n=2). The primary analysis of PFS showed no significant difference between treatment arms (Wilcoxon p=0.217). The unadjusted HR was 0.85 (95% CI: 0.63, 1.13). During most of the study period, the KM curve for PC remained above the G curve. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (p=0.008), showing treatment effect significantly differed by EGFR mutation status. The HR for PFS favored PC in both EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients [EGFR-mutated patients HR=0.83 ([95% CI: 0.42, 1.62], p=0.585); EGFR-WT HR 0.18 ([95% CI: 0.06, 0.51], p=0.001)]. HRs for ITT and EGFR-mutated patients should be interpreted with caution as they were not constant. Arm A had more patients with ≥1 possibly drug-related CTCAE grade 3/4 TEAEs but similar rates of all-grade TEAEs during induction. Selected grade 3/4 or all-grade TEAEs which occurred significantly more included anemia, neutropenia, emesis, and neuropathy in Arm A and AST/ALT elevations, diarrhea, pruritus, and skin rash in Arm B. The toxicity profile was similar in both arms during the G maintenance period.

      Conclusion
      In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, results are consistent with the existing consensus that patients with WT EGFR do not benefit with front-line EGFR TKI treatment. Overall, the results show that identification of the EGFR mutational status is key in the management of advanced NSCLC. Even in the presence of clinically favorable predictors of EGFR mutation positivity (>60% in our population), “empirical” choice of EGFR TKIs as front-line therapy may be detrimental to NSCLC patients without EGFR mutations.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.05 - Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three trials of afatinib in EGFR mutation-positive lung cancer (ID 1114)

      10:30 - 12:00  |  Author(s): C. Tsai

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

      Methods
      This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

      Results
      Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

      Mutation ORR, % (n=) Median duration of response, months (95% confidence interval) DCR (ORR + stable disease), % (n) Median PFS, months (95% confidence interval) Median survival, months (95% confidence interval)
      De novo T790M alone or in combination with other mutations (n=14) 14.3 (2) Individual response durations: 4.1, 12.4 64.2 (9) 2.9 (1.2−8.3) 14.9 (8.1−24.9)
      Exon 20 insertions (n=23) 8.7 (2) Individual response durations: 4.2, 10.1 65.2 (15) 2.7 (1.8−4.2) 9.4 (4.1−21.0)
      Other (n=38) 71.1 (27) 11.1 (4.1, 15.2) 84.2 (32) 10.7 (5.6−14.7) 18.6 (16.4−not estimable)

      Conclusion
      Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

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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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      P1.11-001 - Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) related interstitial lung disease in Taiwanese patients with non-small cell lung cancer (ID 261)

      09:30 - 16:30  |  Author(s): C. Tsai

      • Abstract

      Background
      In the recent years, it has been shown that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), gefitinib or erlotinib, can provide significant benefit to patients with advanced non-small cell lung cancer (NSCLC). A major concern during EGFR-TKI treatment is the development of interstitial lung disease (ILD). The incidence and clinical characteristics of ILD associated with EGFR-TKIs in Taiwanese patients are less well defined.

      Methods
      Patients with advanced NSCLC in the Taipei Veterans General Hospital were screened and patients who had received EGFR-TKIs were enrolled in this study. The clinical information including medical records and chest images were reviewed. The diagnosis of EGFR-TKI related ILD was confirmed by two pulmonologists according to previously published criteria. Association between ILD development and clinical factors was evaluated.

      Results
      From February 2008 to July 2012, a total of 1214 patients who received EGFR-TKI as single therapy for NSCLC were screened. Patients who developed severe ILD and needed hospitalization (grade 3-5) were included. Consequently, 9 of 1214 patients (0.7%) were diagnosed to have severe EGFR-TKI related ILD. The median age of the patients with ILD was 61.0 years and 6 were male (66.7%). The median time interval from EGFR-TKIs use to onest of ILD was 31 days (range: 10-75 days). The most common symptom of EGFR-TKIs related ILD was dyspnea (88.9%). The most common radiological manifestation was bilateral ground glass opacity (GGO), which was noted in 5 patients (55.6%). All patients discontinued EGFR-TKIs immediately when ILD was suspected and 8 patients (88.9%) received systemic steroids. Six of nine patients (67%) patients died from ILD.

      Conclusion
      EGFR-TKIs, both gefitinib and erlotinib may cause fatal ILD in Taiwanese NSCLC patients. Physicians should be aware of this rare but severe side effect of EGFR-TKI and monitor this pulmonary toxicity closely.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-033 - Brain Metastasis Features and Association with Tumor EGFR mutation in Patients with Adenocarcinoma of the Lungs (ID 2516)

      09:30 - 16:30  |  Author(s): C. Tsai

      • Abstract

      Background
      More than half of pulmonary adenocarcinoma patients present with locally advanced or metastatic disease. Most patients with brain metastases suffered from poor quality of life and poor survival time. Epidermal growth factor receptor (EGFR) mutations were most frequently found in patients with pulmonary adenocarcinoma and were associated with a better prognosis than patients with EGFR wild-type tumors. However, the association between tumor EGFR mutation and whether or not more frequent brain metastasis is still unclear.

      Methods
      We retrospectively reviewed the data of our pulmonary adenocarcinoma patients who have brain metastasis, and record the characteristics of brain metastasis. The association between tumor EGFR mutation and clinical characteristics of brain metastasis were analyzed.

      Results
      374 cases were reviewed. There are 239 patients with EGFR mutations, 69 patients with initial diagnosis of brain metastasis, and 82 patients with brain metastasis after treatment. Older patients (more than 70 years old) had fewer brain metastasis than younger (less than 70 years old) patients (25.8% v.s 48%, P<0.001). Patients with higher N stage of TNM staging system had higher proportion of brain metastasis (P=0.006). Patients with exon 19 deletion had more chance to suffer from brain metastasis than those with EGFR wild type (48.1% v.s. 34.1%, P=0.021). Patients with exon 19 deletion didn’t have significantly higher chance to have initial diagnosis of brain metastasis (P=0.216). However, patients with exon 19 deletion had higher chance to suffered from brain metastasis after treatment than those with EGFR wild type (35.6% v.s. 21.2%, P=0.019). Patients with exon 19 deletion survived longer than those with EGFR wild type (1-yr survival rate 95.8% vs. 78.7%, P=0.003). Thus, longer survival time may lead to higher proportion of brain metastasis occurrence in patients with exon 19 deletion than those with EGFR wild type.

      Conclusion
      There is no significant difference in frequency of initial brain metastases in patients with EGFR mutation or wild type. However, there are statistically significant association between brain metastasis and EGFR mutations in pulmonary adenocarcinoma patients in their disease process.