Juliane Lungershausen

Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations

PURPOSE Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. PATIENTS AND METHODS Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. RESULTS Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P = .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P < .001) and dyspnea (P < .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P < .001), role (P = .004), and cognitive (P = .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P < .01). CONCLUSION In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.

The Economic Burden of Head and Neck Cancer: A Systematic Literature Review

BackgroundThis systematic literature review aimed to evaluate and summarize the existing evidence on resource use and costs associated with the diagnosis and treatment of head and neck cancer (HNC) in adult patients, to better understand the currently available data. The costs associated with HNC are complex, as the disease involves multiple sites, and treatment may require a multidisciplinary medical team and different treatment modalities.MethodsDatabases (MEDLINE and Embase) were searched to identify studies published in English between October 2003 and October 2013 analyzing the economics of HNC in adult patients. Additional relevant publications were identified through manual searches of abstracts from recent conference proceedings.ResultsOf 606 studies initially identified, 77 met the inclusion criteria and were evaluated in the assessment. Most included studies were conducted in the USA. The vast majority of studies assessed direct costs of HNC, such as those associated with diagnosis and screening, radiotherapy, chemotherapy, surgery, side effects of treatment, and follow-up care. The costs of treatment far exceeded those for other aspects of care. There was considerable heterogeneity in the reporting of economic outcomes in the included studies; truly comparable cost data were sparse in the literature. Based on these limited data, in the US costs associated with systemic therapy were greater than costs for surgery or radiotherapy. However, this trend was not seen in Europe, where surgery incurred a higher cost than radiotherapy with or without chemotherapy.ConclusionsMost studies investigating the direct healthcare costs of HNC have utilized US databases of claims to public and private payers. Data from these studies suggested that costs generally are higher for HNC patients with recurrent and/or metastatic disease, for patients undergoing surgery, and for those patients insured by private payers. Further work is needed, particularly in Europe and other regions outside the USA; prospective studies assessing the cost associated with HNC would allow for more systematic comparison of costs, and would provide valuable economic information to payers, providers, and patients

Health-related quality of life and utility in patients with advanced non-small-cell lung cancer: a prospective cross-sectional patient survey in a real-world setting.

Background: Non–small-cell lung cancer (NSCLC) has a significant impact on patients’ health-related quality of life (HRQOL). This study aimed to measure health state utility values representing the individual’s preferences for specific health-related outcomes in advanced NSCLC patients and to assess predictive parameters. Methods: We conducted a prospective quality-of-life survey on advanced NSCLC patients in 25 hospitals in Europe, Canada, Australia, and Turkey. HRQOL was assessed using the EuroQol (EQ-5D) questionnaire and EQ-5D utility and EQ-visual analog (EQ-VAS) scores were estimated. Results: Three hundred nineteen patients were recruited of which 263 had evaluable data. Mean utility for progression-free (PF) patients on first-, second-, and third-/fourth-line treatment was 0.71 (SD = 0.24), 0.74 (SD = 0.18), and 0.62 (SD = 0.29), respectively. Mean utility for patients with progressive disease (PD) while on first-, second- and third-/fourth-line treatment was 0.67 (SD = 0.2), 0.59 (SD = 0.34), and 0.46 (SD = 0.38), respectively. Overall, patients with PD had lower mean utility scores than PF patients (0.58 versus 0.70). The results of the EQ-VAS showed that the score decreased with later treatment lines. Patients with PD had a 10-point decrease in VAS scores compared with PF patients (53.7 versus 66.6). The regression analysis revealed that stage IV disease, higher lines of treatment, and health state were significant predictors of utility at the 10% level. Conclusion: The results presented indicate a substantial impact of lung cancer on patients’ HRQOL, with stage IV disease, line of treatment, and PD, resulting in considerable deterioration of utility. The values obtained here will inform evaluations of cost-utility for NSCLC therapies.

Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non–small-cell Lung Cancer

Introduction: In the phase III, LUX-Lung 6 trial, afatinib prolonged progression-free survival (PFS) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive non–small-cell lung cancer (NSCLC). This article provides detailed assessments of patient-reported outcomes (PROs), a LUX-Lung 6 secondary end point, and explores the relationship between PFS and health-related quality of life (QoL) in these patients. Methods: Patients (n = 364) were randomized (2:1) to oral afatinib (40 mg/day) or up to six cycles of cisplatin/gemcitabine (21-day cycle; cisplatin 75 mg/m2 [d1]; gemcitabine 1000 mg/m2 [d1,8]). QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its lung cancer-specific module. The relationship between PFS (investigator assessment and independent review) and QoL was evaluated using analysis of covariance and a longitudinal model. Results: More patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL (p < 0.0001) and physical (p < 0.0001), role (p = 0.013), and social (p < 0.001) functioning scales. Delayed symptom deterioration and better QoL over time was also observed with afatinib. QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression, with significant differences in mean scores at multiple assessment time points. Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL (p < 0.0001). Conclusion: Afatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients. Progression was associated with statistically significant worsening in QoL measured before tumor assessment, underscoring the value of PFS as a clinically relevant end point.

Afatinib in the treatment of EGFR mutation-positive NSCLC - A network meta-analysis

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA). MATERIALS AND METHODS A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods. RESULTS The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40-1.16) and compared with erlotinib was 0.86 (0.50-1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42-1.24) for afatinib compared with erlotinib and 0.60 (0.34-0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments. CONCLUSIONS In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits.

Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial

The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were €126 (95% uncertainty interval (UI) €55–195) and €170 (95% UI €77–260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010–0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of €87 (95% UI €19–157). The incremental cost-effectiveness ratio was €1,961 per exacerbation avoided from the SHI perspective and €2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were €3,488 from the SHI perspective and €8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.

Treatments for EGFR Mutation-Positive (M+) NSCLC Patients – A Network Meta-Analysis (NMA) by Mutation Type

1Royal Marsden Hospital, London, UK; 2National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; 3Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Guangdong Lung Cancer Institute, Guangzhou, China Treatments for EGFR Mutation-positive (M+) NSCLC Patients – A Network Meta-Analysis (NMA) by Mutation Type PCN8

1268PEVALUATION OF ASSOCIATION OF PROGRESSION-FREE SURVIVAL (PFS) WITH HEALTH-RELATED QUALITY OF LIFE (HRQOL) IN LUNG CANCER PATIENTS (PTS)

ABSTRACT Aim: PFS is a common primary endpoint in oncology trials. However, there is limited evidence supporting a positive association between PFS extension and HRQoL improvement and whether PFS improvement translates into pt-relevant benefits. Methods: LUX-Lung 6 trial data comparing afatinib with cisplatin/gemcitabine in EGFR mutation-positive NSCLC pts were analysed to determine whether tumour progression is accompanied by worsening of HRQoL (prior to providing new tumour information to the pt). HRQoL was assessed by using the cancer-specific European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (global health status [GHS]/QoL), the EuroQol EQ-5D UK utility and EuroQol EQ visual analogue scale (VAS). The relationship between tumour progression by investigator assessment (irrespective of treatment arm) and HRQoL was evaluated using analysis of covariance and a longitudinal model. Results: HRQoL questionnaire completion on study treatment was high (>85%). HRQoL was considerably poorer for pts with progression versus pts without progression at the same timepoint. Differences in mean scores from baseline to progression were shown independent of time of progression, but more pronounced for pts progressing more rapidly (Table). For all three HRQoL measures, results from the longitudinal analysis consistently showed that progression had a significant negative impact on HRQoL: for GHS/QoL (EORTC QLQ-C30) the effect of progression was –7.69 (95% CI –9.22, –6.17; p Effect of progression on HRQoL for GHS/QoL (EORTC QLQ-C30) Week Effect of progression (SE) p-value 6 –8.78 (4.41) 0.047 12 –11.84 (6.54) 0.071 18 –11.65 (4.24) 0.007 24 –12.02 (3.28) 30 –4.51 (3.98) 0.259 36 –3.31 (4.80) 0.491 42 0.18 (4.38) 0.968 48 –3.18 (4.70) 0.499 Conclusions: Tumour progression in EGFR mutation-positive NSCLC is associated with a statistically significant, clinically meaningful worsening in HRQoL at time of progression. These findings confirm those from previous analyses of afatinib and underline the value of PFS as a pt-relevant endpoint. Disclosure: M. Palmer: Stock ownership with AstraZeneca Corporate sponsored research for Boehringer Ingelheim, payment for statistical analyses; I. Griebsch: Other substantive relationships Employee of Boehringer Ingelheim GmbH; J. Lungershausen: Other substantive relationships Employee of Boehringer Ingelheim GmbH. All other authors have declared no conflicts of interest.

1265PPATIENT-REPORTED OUTCOMES (PROS) IN PATIENTS (PTS) WITH ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) RECEIVING AFATINIB (A) MONOTHERAPY FOLLOWED BY A + PACLITAXEL (A + P) VS INVESTIGATOR'S CHOICE OF SINGLE-AGENT CHEMOTHERAPY (IC): LUX-LUNG 5 (LL5)

ABSTRACT Aim: A is an irreversible ErbB family blocker. In Part A of the open-label LL5 study, pts with advanced NSCLC who had failed ≥1 line of chemotherapy and erlotinib/gefitinib received A (50 mg/day; n = 1154). In Part B, pts with >12 weeks of clinical benefit on A were eligible for randomisation and received A + P (40 mg/day, 80 mg/m2/week; n = 132) or IC (n = 60). A + P significantly improved progression-free survival (PFS) vs IC (5.6 vs 2.8 months; HR 0.6; p = 0.003); overall survival was similar (12.2 vs 12.2 month; HR 1.0; p = 0.994). Pre-specified PRO analyses are presented here. Methods: Lung cancer symptoms were assessed every 28 days until progression using the EORTC (QLQ-C30/LC13) questionnaires. Analyses of cough, dyspnea and pain were preplanned, including percentage of patients improved on therapy, time-to-deterioration (TTD) of symptoms and change in symptoms over time. Results: Baseline symptom burden was low. Median TTD in Part A was 2.8, 2.8 and 4.5 months for dyspnea, pain and cough, respectively. In Part B, compared with IC, A + P showed a trend delaying TTD for dyspnea (3.1 vs 1.8 months; HR [95% CI] 0.78 [0.55, 1.09]; p = 0.144) and pain (4.3 vs 3.5 months; HR [95% CI] 0.80 [0.56, 1.14]; p = 0.212) but not cough (5.7 vs 6.5 months; HR [95% CI] 1.13 [0.79, 1.62]; p = 0.505). Numerically, more A + P than IC patients showed improvements in dyspnea (45% vs 35%; p = 0.222) and cough (46% vs 36%; p = 0.225). Differences in mean scores over time also numerically favored A + P over IC for dyspnea (-2.9; p = 0.191) and cough (-3.8; p = 0.201). There was no significant change in the global health status (GHS)/quality of life (QoL) scale of QLQ-C30 over time with A + P (p = 0.767). Conclusions: A + P showed trends for symptom improvement and delayed TTD vs IC in heavily-pretreated NSCLC patients. GHS/QoL was maintained over time despite a doubling of median treatment time and PFS with A + P. Disclosure: D. Planchard: I have attended Advisory Boards for: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer and Roche; K. Park: Advisory Boards for: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Eli Lilly, Roche, Novartis, Kyowa Hakko Kirin; J. Yang: Advisory Boards for: AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Merck Serono, Pfizer, Clovis Oncology, Novartis, Eli Lilly, Takeda, Innopharma, Bayer Corporate sponsored research for: Boehringer Ingelheim; J. Kim: Sponsor initiated trials for: Pfizer, Boehringer Ingelheim, Lilly and Roche; F. De Marinis: Advisory Board for: Pfizer, Boehringer Ingelheim and Roche; Y. Chen: Advisory Boards for: Roche, AstraZeneca; J. Feng: Corporate sponsored research for Boehringer Ingelheim; C. Chouaid: Advisory Boards for: Lilly, Boehringer Ingelheim, Amgen and Roche; S. Lu: Advisory Boards for: AstraZeneca and Boehringer Ingelheim; R. Wiewrodt: Advisory Boards for: Boehringer Ingelheim, Grifols, Lilly, Novartis, Roche, Talecris Corporate sponsored research for: Bayer, Boehringer Ingelheim, Lilly, Genentech, Roche; C. Zhou: Advisory Boards for: Boehringer Ingelheim, Roche and Lilly; J. Bennouna: Advisory Boards for: Boehringer Ingelheim, Roche and Novartis; J. Lungershausen: Employee of Boehringer Ingelheim; B. Wang: Employee of: Boehringer Ingelheim; V. Chand: Corporate sponsored research: Boehringer Ingelheim Employee of: Boehringer Ingelheim; M. Schuler: Advisory Board for: AstraZeneca, Boehringer Ingelheim, Novartis and Pfizer Corporate sponsored research: Boehringer Ingelheim and Novartis Patents for: University Duisburg-Essen. All other authors have declared no conflicts of interest.