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J. Von Pawel



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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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      MO06.07 - Daily administration of oral vinorelbine: data from a phase I trial in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2395)

      16:15 - 17:45  |  Author(s): J. Von Pawel

      • Abstract
      • Presentation
      • Slides

      Background
      Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower treatment-associated toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose tumour cells continuously to the drug, preventing recovery between cycles and possibly improving tumour control. We present the clinical and pharmacokinetic data of a phase I dose finding study in which the maximum tolerated dose (MTD) of daily oral vinorelbine was determined in pretreated patients with advanced NSCLC.

      Methods
      Patients (pts) were treated daily with oral vinorelbine (Navelbine® Oral) at fixed doses of 20 mg/d, 30 mg/d, 40 mg/d or 50 mg/d for 21 days of each four-week cycle. Blood sampling for pharmacokinetic assessment was carried out in the first cycle just before drug intake (trough concentrations) on days 1, 8, 15 and 21 and additionally at 1 h, 3 h and 24 h after drug intake on days 1 and 21.

      Results
      Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any dose limiting toxicities (DLT). At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. The MTD was reached at 50 mg/d when three out of six pts experienced DLT in cycle one. The reported DLTs included febrile and non-febrile neutropenia (6 DLTs) as well as fatigue (1 DLT). One patient had an exceptionally good clinical response with a long-lasting tumour remission. Twenty-one pts were evaluable for pharmacokinetic analysis. Blood concentrations of vinorelbine increased with escalating dose levels. Pts were continuously exposed to the drug over the 21-day treatment period as indicated by measurable trough concentrations on days 8, 15 and 21. A slight accumulation of vinorelbine was observed until day 8 based on residual concentrations (ratio c~24h ~ranged 1.96-2.03 between day 1 and either day 8, 15 or 21). The accumulation had no impact on global exposure at repeated dosing, as only minor differences in blood concentrations were detected between day 1 and day 21 (ratio d21/d1 median AUC~0h-24h~: 0.81, 0.92, 1.07, 0.56 at 20 mg/d, 30 mg/d, 40 mg/d and 50 mg/d, respectively). Data on four pts experiencing DLT were available (1 pt at 40 mg/d, 3 pts at 50 mg/d). Only one DLT correlated with an evidently high 24 h blood exposure to vinorelbine.

      Conclusion
      The recommended dose for daily administration of oral vinorelbine is 30 mg in cycle 1 followed by 40 mg in subsequent cycles in the absence of DLT. Further studies are necessary to determine the clinical impact, and possible anti-angiogenic profile of the daily administration schedule of vinorelbine.

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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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      P3.11-040 - Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomized, double-blind, placebo-controlled phase 3 study in second-line advanced non-small cell lung cancer (NSCLC) patients (ID 2812)

      09:30 - 16:30  |  Author(s): J. Von Pawel

      • Abstract

      Background
      Nintedanib is an oral, twice-daily angiokinase inhibitor targeting VEGFR-1–3, PDGFR-α/β and FGFR-1–3. LUME-Lung 1 is a placebo-controlled phase III trial investigating nintedanib plus docetaxel in advanced NSCLC patients after failure of first-line chemotherapy.

      Methods
      Stage IIIB/IV or recurrent NSCLC patients were randomised to receive nintedanib 200 mg bid plus docetaxel 75 mg/m[2] q21d (n=655), or placebo plus docetaxel (n=659). The primary endpoint was centrally reviewed progression-free survival (PFS) analysed after 714 events; the key secondary endpoint was overall survival (OS) analysed hierarchically after 1121 events, first in adenocarcinoma patients and then all patients. Quality of Life (QoL) was included as a secondary endpoint. Lung cancer symptoms and health-related QoL were assessed every 21 days until the first follow-up visit using the EORTC (QLQ-C30/LC13) and EQ-5D questionnaires. Changes of ≥10 points as compared with baseline were considered clinically significant. Analyses of cough, dyspnoea and pain symptoms were prespecified. Time to deterioration (TTD, first 10-point worsening from baseline) was analysed using a stratified log-rank test. An exploratory analysis of all subscales/items from the EORTC QLQ-C30/LC13 questionnaires estimated the respective hazard ratios for TTD using a Cox proportional hazards model.

      Results
      LUME-Lung 1 showed that nintedanib in combination with docetaxel significantly prolonged PFS for all patients regardless of histology (3.4 vs 2.7 months; HR 0.79, 95% CI: 0.68–0.92; p=0.0019), with a trend for improved median OS (10.1 vs 9.1 months; HR 0.94, 95% CI: 0.83–1.05; p=0.272) and significantly improved OS in patients with adenocarcinoma (HR: 0.83; p=0.0359; median 10.3 to 12.6 months). The most common AEs were diarrhoea and reversible ALT elevations. With respect to the QoL assessment, there was a high compliance rate of >80% until treatment course 25 for QLQ-LC13 and QLQ-C30 in both treatment arms. The addition of nintedanib to docetaxel did not influence TTD for cough (HR 0.90; 95% CI: 0.77–1.05; p=0.1858), dyspnoea (HR 1.05; 95% CI: 0.91–1.20; p=0.5203) or pain (HR 0.95; 95% CI: 0.82–1.09; p=0.4373), and maintained global health status/QoL (HR 0.952; 95% CI: 0.83–1.10). There was a significant deterioration in scores for nausea and vomiting, appetite loss and diarrhoea. The results were similar for adenocarcinoma patients with respect to cough (HR 0.97; 95% CI: 0.78–1.20; p=0.7744), dyspnoea (HR 1.04; 95% CI: 0.86–1.26; p=0.6813) and pain (HR 0.93; 95% CI: 0.76–1.13; p=0.4785); however, there was a trend for improved global health status/QoL (HR 0.86; 95% CI: 0.71–1.05). For squamous cell carcinoma patients, there was a trend for delayed TTD for cough (HR 0.84; 95% CI: 0.66–1.07; p=0.1561) and a maintained global health status/QoL (HR 0.975; 95% CI: 0.788–1.206). Further analyses are ongoing and will be presented at the congress.

      Conclusion
      In second-line NSCLC patients, docetaxel plus nintedanib did not result in any significant improvements in cough, dyspnoea or pain compared with placebo and docetaxel. However, PFS was improved in patients of all histologies receiving docetaxel and nintedanib, and OS was improved in patients with adenocarcinoma histology without adversely affecting self-reported QoL.