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M. Fukuoka



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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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      O03.07 - Investigation of risk factors for developing interstitial lung disease (ILD) and poor prognostic factors for ILD death in Japanese patients with non-small-cell lung cancer (NSCLC): a final analysis of a large-scale erlotinib surveillance study (POLARSTAR) (ID 2208)

      11:35 - 11:45  |  Author(s): M. Fukuoka

      • Abstract
      • Presentation
      • Slides

      Background
      A large-scale surveillance study (POLARSTAR) was implemented to investigate erlotinib safety and efficacy in Japanese patients, focusing on the pattern of occurrence of interstitial lung disease (ILD) and specific factors that may contribute to the onset of ILD in patients receiving erlotinib. The following risk factors for erlotinib-induced ILD have been previously reported: concurrent/previous ILD (adjusted hazard ratio [HR] =3.2), existing emphysema/chronic obstructive pulmonary disease (COPD) (HR=1.9) or lung infection (HR=1.6), smoking status (HR=2.2) and ECOG performance status 2–4 (HR=1.4). These were identified as the primary risk factors for ILD by multivariate analysis. The current analysis was carried out to identify factors linked with poor prognosis in terms of ILD-related death within the POLARSTAR surveillance study.

      Methods
      Enrolment of all patients in Japan receiving erlotinib for NSCLC took place between December 2007 and October 2009; the observation period was 12 months. All ILD-like events were assessed by an independent ILD review committee. ILD was defined as all ILD-like events excluding those events deemed non-ILD by the independent ILD review committee. Risk factors for poor prognosis concerning ILD death were analyzed by multivariate analysis using a logistic regression model.

      Results
      A total of 10,708 patients were enrolled by the data cut-off of 12 October 2009, with data available for 9,909 patients. The majority of ILD cases were reported within 4 weeks of receiving erlotinib. Among the 491 patients who experienced ‘ILD-like’ events, 93 could not be evaluated by the independent ILD review committee due to lack of imaging data; the remaining 398 patients were referred to the committee for evaluation. A total of 310 patients had confirmed ILD by the ILD review committee, based on image evaluation or clinical investigation; 125 had died as a result of ILD. These patients were assessed by multivariate analysis. Sixty-two events were deemed non-ILD and 26 events could not be evaluated due to a lack of clear clinical evidence (e.g. ILD could not be distinguished from progression or pneumonitis, or insufficient imaging data were available). The multivariate analysis identified ECOG performance status 2–4 (adjusted odds ratio [OR] =2.45 [95% CI 1.41–4.27]; p=0.0016), <50% remaining normal lung area (OR=3.12 [1.48–6.58]; p=0.0029) and interstitial pneumonia with concomitant honeycomb lung (OR=6.67 [1.35–32.94]; p=0.02) as poor prognostic factors for ILD death. However, pre-existing interstitial pneumonia by grade of severity was not identified as one of these factors. This result could be attributed to practical bias in this surveillance study, such as selection or treatment bias for patients with pre-existing interstitial pneumonia within the condition of careful dosage specified in the erlotinib label.

      Conclusion
      These final data from this large surveillance study in Japanese patients with recurrent and advanced NSCLC provide further information on the risk factors for poor prognosis with ILD, identifying those patients at greatest risk of ILD-related death. Improved awareness of these prognostic factors will help clinicians in monitoring those patients at highest risk.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-020 - Dose adjustment of single agent amrubicin in lung cancer patients with impaired hepatic function (ID 1348)

      09:30 - 09:30  |  Author(s): M. Fukuoka

      • Abstract

      Background
      The pharmacokinetics (PK) of amrubicin (AMR) in lung cancer patients with impaired hepatic function have not been reported. The objectives of this study were to evaluate the PK of AMR and its major metabolite, amrubicinol (AMR-OH), in lung cancer patients with or without impaired hepatic function, and to assess the validity of dose adjustment of AMR based on hepatic function.

      Methods
      Eligibility criteria included the presence of histologically or cytologically proven lung cancer, an ECOG PS of 0 to 2, age 20 to 70 years old, and no evidence of hepatitis B virus infection. The dose was adjusted from 25 to 45 mg/m[2]/day (iv, days 1-3, q3w) based on the history of prior treatment and baseline values of total bilirubin (T-bil), AST and ALT (Table 1). Figure 1

      Results
      Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) were enrolled. Terminal half-life (t~1/2~) and clearance of AMR in plasma, and t~1/2~ of AMR-OH in blood did not differ between the two arms. Area under the curve (AUC~0-24~) of AMR in plasma and AUC~0-120~ of AMR-OH in blood in arm I were similar or lower compared to those in arm N (Table 2). The dose-adjusted AUCs of AMR and AMR-OH did not show a tendency to increase with increases in baseline T-bil, AST and ALT. Two deaths occurred in arm I (one due to disease progression, and the other due to an unspecified reason), but the toxicities in arm I were not severe compared with those in arm N. Figure 1

      Conclusion
      These data show the validity of dose adjustment of AMR in patients with impaired hepatic function.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-028 - Efficacy and safety of erlotinib in elderly versus non-elderly patients: analysis of the POLARSTAR study of 9,909 Japanese non-small cell lung cancer (NSCLC) patients treated with erlotinib. (ID 1591)

      09:30 - 09:30  |  Author(s): M. Fukuoka

      • Abstract

      Background
      Compared with younger patients, elderly NSCLC patients are often considered unfit for standard chemotherapy due to increased chemotherapy-related toxicity, more comorbidities, and the consequent deterioration in patient quality of life. Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated survival benefits with good tolerability in previously treated NSCLC patients regardless of EGFR mutation status. Erlotinib has become a standard treatment for this indication. As it is well tolerated compared with cytotoxic agents, erlotinib is also expected to be a valid treatment option for previously treated elderly NSCLC patients. This analysis of the POLARSTAR surveillance study compared the efficacy and safety of erlotinib treatment for elderly versus non-elderly patients.

      Methods
      From December 2007 to October 2009 all recurrent/advanced NSCLC patients in Japan treated with erlotinib were enrolled onto the POLARSTAR surveillance study. Erlotinib efficacy and safety data were analyzed by age group: Group A <75 years; Group B 75–84 years; and Group C ≥85 years. Kaplan–Meier methods were used to estimate median progression-free survival (PFS). All adverse event reports were collected and graded using the NCI-CTCAE version 3.0 and coded using MedDRA version 14.1.

      Results
      Of 9,909 patients evaluated, 9,907 were eligible for safety assessment (Group A, n=7,848; Group B, n=1,911; Group C, n=148). Baseline characteristics (including histology, smoking status and performance status [PS]) were well-balanced between groups. Non-hematologic toxicities are shown (Table). Grade 1–4 hematologic toxicities (neutropenia/leukopenia/anemia/thrombocytopenia) were observed at <1.0% in each group. One patient had grade 5 anemia (Group A) and one patient had grade 5 thrombocytopenia (Group B). A total of 9,651 patients were eligible for efficacy assessment. The median PFS was 65 days for Group A (n=7,701), 74 days for Group B (n=1,815) and 72 days for Group C (n=135). In patients with clinical features associated with better EGFR TKI efficacy (adenocarcinoma/non-smoker/PS 0–2/second- or third-line setting/EGFR TKI naïve) the median PFS was 176 days (Group A, n=651), 213 days (Group B, n=180), and 341 days (Group C, n=14). Figure 1

      Conclusion
      Efficacy and tolerability of erlotinib treatment for elderly patients (≥75 years) with previously treated NSCLC was similar to that seen in younger patients. Erlotinib could be considered as standard therapy for elderly NSCLC patients in second- or later line treatment settings.

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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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      P3.10-007 - Avastin® for advanced or recurrent non-squamous non-small cell lung cancer: A nested case control study exploring risk factors for hemoptysis in Japan (ID 782)

      09:30 - 09:30  |  Author(s): M. Fukuoka

      • Abstract

      Background
      A nested case control (NCC) study was conducted to assess the incidence of hemoptysis (Grade 2 cases that used an injectable hemostatic or Grade 3+ cases) and to explore risk factors for hemoptysis in patients receiving Avastin[®] (bevacizumab) in real-life-practice in Japan.

      Methods
      From November 2009 to August 2011 patients intending to use bevacizumab were pre-enrolled, and we calculated incidence of hemoptysis in the 6774 patients actually receiving bevacizumab. Excluding one patient of unspecified age, we selected a control group from the 6773 patients by matching each patient who developed hemoptysis (cases) to four patients who did not (controls) by sex and age. We selected 92 controls for the 23 cases and performed conditional logistic regression analysis of a total 113 patients (23 cases and 90 controls) to investigate risk factors for hemoptysis. A third party including radiologists performed blind assessment of imaging characteristics for the 104 patients with evaluable baseline computerized tomography images.

      Results
      In the 6774 patients receiving bevacizumab, incidence of hemoptysis was 0.33%. To perform conditional logistic regression analysis of the 113 patients in the case control study, we included the following factors in the model: smoking history, stage (7th ed.), PS (baseline), present metastasis, previous lung disease, concurrent lung disease, previous thoracic radiotherapy, concomitant drugs (anticoagulant, aspirin preparation, non-steroidal anti-inflammatory drug, antiplatelet drug), concomitant thoracic radiotherapy, treatment line, macrovascular (arterial) invasion, and central airway tumor exposure extending to segmental bronchus. Analysis using the stepwise method identified presence of previous thoracic radiotherapy (odds ratio [OR], 2.76; 95% confidence interval [CI], 0.61–12.43), concomitant thoracic radiotherapy (OR, 6.19; 95% CI, 0.63–60.47), and central airway tumor exposure extending to segmental bronchus (OR, 5.29; 95% CI, 1.22–22.89).

      Conclusion
      At 0.33%, the incidence of hemoptysis in this study was low, and three risk factors were identified. Because this was a case control study in patients receiving Avastin, these risks cannot necessarily be attributed to Avastin treatment, and further study of safety risks is needed.