Kees Kraaij

Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study.

Abstract Objective: Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes. Methods: From October 2006 to January 2008, 1012 patients with advanced/metastatic NSCLC who completed or discontinued first-line treatment were enrolled in a multi-national, prospective observational cohort study (SELECTTION). Treatment cohorts were constructed based on the patients’ distribution across second-line treatments that were assigned by physician decision (pemetrexed, docetaxel, erlotinib, other treatments). This report presents a descriptive analysis of the baseline data collected, including patient/disease characteristics, treatment history and planned second-line treatments. Factors that may have affected treatment choice, selected by physicians from a range of options, were also identified. Results: Overall, 468 patients (46.2%) were enrolled in the pemetrexed cohort, 232 (22.9%) in docetaxel cohort, 206 (20.4%) in erlotinib cohort and 106 (10.5%) received other treatments. The profile of patients enrolled in the erlotinib cohort differed from those of patients enrolled in the pemetrexed or docetaxel cohorts in that erlotinib was more frequently planned for women, never-smokers and patients with adenocarcinomas. The primary reasons physicians gave for selection of the second-line treatment were tolerance and efficacy for pemetrexed, and preferred regimen for the particular patient and efficacy for the other treatments. Conclusions: In this observational study, pemetrexed, then docetaxel and erlotinib were the most frequently prescribed second-line treatments, which is in line with international guidelines. Erlotinib was most commonly prescribed to that subset of patients expected to gain the greatest benefit (those with adenocarcinoma, never-smokers and females). Pemetrexed was more frequently prescribed than docetaxel, with physicians most commonly choosing to prescribe the former agent because of its tolerability profile.

Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study.

OBJECTIVES We report on a post-hoc analysis of patients with brain metastases from a large prospective observational study of first-line treatment of non-small cell lung cancer (NSCLC). The aim was to describe baseline characteristics of NSCLC patients with brain metastases, understand their first-line treatment and report outcomes attained in real-world settings. MATERIALS AND METHODS This post-hoc analysis included all patients in the European observational FRAME study who had brain metastases at initiation of first-line treatment. Descriptive statistics were used for continuous and categorical variables and survival outcomes were assessed using the Kaplan-Meier approach. RESULTS Our data showed that 17% of patients (263/1564) had spread of the disease to the brain at initiation of first-line treatment. Patients with brain metastases were slightly younger, and more likely to have NSCLC of non-squamous histology than the overall study sample. 34% had received prior palliative radiotherapy to the brain. Our analysis showed a median overall survival (OS) of 7.2 months [95% confidence interval (CI) 6.1-8.2] for all patients with brain metastases treated with first-line platinum-based chemotherapy, ranging from 5.6 months for those treated with gemcitabine plus platinum up to 9.3 months for those treated with pemetrexed plus platinum. Further analysis showed that patients with brain metastases were more frequently treated with pemetrexed platinum-doublet therapy than with any other regimen. CONCLUSIONS Our analysis provides a unique set of real-world data which adds to current understanding about treatment decisions and outcomes for NSCLC patients with brain metastases for whom there is little clinical trial data available.

Second-line therapy for non-small cell lung cancer in clinical practice: final results and treatment pathways from the SELECTTION observational study

Abstract Objectives: SELECTTION was a multinational, prospective observational study to assess the choice of and the time from initiation of second-line treatment to treatment discontinuation for any reason in patients with non-small cell lung cancer. Methods: Treatment cohorts were constructed based on prescribed second-line treatments that were at the discretion of the treating physicians, for 1013 patients enrolled in 11 countries. Propensity score analysis was conducted to assess whether the cohorts were comparable. Time from initiation of second-line treatment to treatment discontinuation was the primary endpoint. Reasons for treatment discontinuation, overall survival, progression-free survival and choice of second-line treatment were secondary endpoints. Results: The treatment cohorts were pemetrexed (46.2%), docetaxel (22.9%), erlotinib (20.4%) and other treatments (10.5%). Analyses of baseline data and propensity scores showed that the erlotinib cohort comprised substantially different patients compared with the pemetrexed and docetaxel cohorts: patients in the erlotinib cohort were more likely to be women, never-smokers, have adenocarcinoma and worse performance status. Therefore, comparisons of outcomes between cohorts were not appropriate. Although disease progression was the most common reason for treatment discontinuation in all cohorts, erlotinib patients tended to continue treatment after disease progression, whereas in the docetaxel and pemetrexed cohorts, discontinuation occurred soon after disease progression. Conclusions: In real-world clinical practice the profiles of patients assigned to erlotinib were distinctly different from those assigned to pemetrexed or docetaxel. The most common reason for treatment discontinuation was progressive disease, reflecting adherence to clinical recommendations. It is difficult to extrapolate these findings to the present, as both clinical practice and the approved indications for NSCLC treatments have evolved substantially.

Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study.

OBJECTIVES To explore patient and disease factors, and reasons behind the physicians choice of platinum backbone for the first-line treatment of non-small cell lung cancer (NSCLC), as observed in a European prospective observational study of patients receiving platinum-based chemotherapy as first-line treatment for advanced or metastatic NSCLC (the FRAME study). Additionally, overall survival (OS) for patients who received cisplatin or carboplatin was evaluated. MATERIALS AND METHODS A post-hoc analysis of the prospective study population was conducted. Baseline characteristics of patients receiving cisplatin versus carboplatin were compared and summarized by propensity score. Survival for matched patients was summarized using the Kaplan-Meier approach. RESULTS Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. Patients treated with carboplatin were older than patients receiving cisplatin (mean age 67 versus 61 years; p<0.001), had poorer performance status (p<0.001), and more comorbidities (p<0.001). Cisplatin was most frequently combined with pemetrexed (47%), and carboplatin most frequently with taxanes (31%). Unadjusted median OS estimates for patients from the total prospective study sample were 11.5 months (95% confidence interval [CI] 10.1-12.9) for cisplatin recipients and 9.0 months (95% CI 8.1-10.6) for carboplatin recipients. Median (95% CI) overall survival for the matched cohorts was 10.8 months (8.8-14.3) for cisplatin versus 9.5 months (8.2-11.3) for carboplatin; p=0.086. CONCLUSION This post-hoc analysis illustrated real-life differences in patients with NSCLC prescribed platinum-based first-line treatment, and suggested that baseline patient and disease characteristics were associated with physicians choice of platinum agent, with cisplatin being more frequently prescribed to younger and fitter patients.

1252PNSCLC PATIENTS WITH BRAIN METASTASES TREATED WITH PLATINUM-BASED DOUBLETS AS FIRST-LINE THERAPY: ANALYSES FROM THE EUROPEAN FRAME OBSERVATIONAL STUDY

ABSTRACT Aim: Patients (pts) with brain metastases (mets) are often excluded from clinical trials and limited data exists. FRAME (2009-2012) was a prospective, non-interventional observational study of pts with advanced NSCLC receiving platinum (plt)-doublet chemotherapy as first-line treatment (FLT) across Europe. Thus, in FRAME unique real-life data could be collected on baseline characteristics, FLT and survival for NSCLC pts with brain mets. Methods: FLT decisions were at the discretion of the physicians under routine clinical practice. The primary objective of overall survival (OS) from FRAME was previously reported. Here, we describe baseline characteristics and survival for pts with brain mets at FLT initiation. Survival was estimated using Kaplan-Meier methods and unadjusted estimates are presented. Results: In FRAME overall, 1564 pts received plt in combination with: pemetrexed (pem; n = 569), gemcitabine (gem; n = 360), taxanes (tax; n = 295), vinorelbine (vin; n = 300), or other (n = 40); 263 (17%) of these pts had brain mets at FLT initiation. Pts with brain mets had a median age of 58 years [range: 33-84] (overall 64 years [range: 33-87], n = 1564), 64% were male (overall 72%), 84% had non-squamous histology (overall 72%), 21% had an ECOG performance status (PS) 2-3 (overall 17%), 58% received cisplatin as FLT plt backbone (overall 55%) and 34% received prior radiotherapy to the brain (overall 6%). Several baseline characteristics for pts with brain mets numerically varied among cohorts (Table 1, “other” cohort [n = 5] is not shown). For the overall study, median OS was 10.3 months (95% CI: 9.5-11.2). For pts with brain mets, median OS was 7.2 months (95% CI: 6.1-8.2); OS estimates for cohorts are shown in Table 1. Pts with brain mets FLT Baseline characteristics Pem n = 117 Gem n = 49 Tax n = 54 Vin n = 38 ≥70 yrs, % 12 25 20 21 ECOG PS 2-3, % 18 14 30 21 Never smoker, % 14 6 6 5 Non-squamous, % 97 69 70 82 Median OS, mos. (95% CI) 9.3 (6.2-11.9) 5.6 (4.1-8.4) 6.6 (3.7-7.8) 6.7 (5.2-9.3) Conclusions: Real-world data from the European FRAME study provide relevant information on NSCLC pts with brain mets, and may have implications on FLT management decisions for these pts. Disclosure: D. Moro-Sibilot: Consulting fees from Eli Lilly and Company, Roche, Astra Zeneca, Boehringer Ingelheim France, Amgen; J. De Castro Carpeno: Advisory board for Eli Lilly and Company, Roche and Pfizer; speakers bureau for Roche; K. Lesniewski-Kmak: Invited speaker for Eli Lilly and Company, Roche, Astra Zeneca, GSK, Amgen; J.G. Aerts: Research grant from and consultant for Eli Lilly and Company; advisory board for Eli Lilly and Company, Genentech, BMS; R. Villatoro: Speaker fee from Jansen, Pfizer; K. Kraaij: Employee and stockholder of Eli Lilly and Company; K. Nacerddine: Employee and stockholder of Eli Lilly and Company; Y. Dyachkova: Employee of Eli Lilly and Company; K. Smith: Employee and stockholder of Eli Lilly and Company; A. Girvan: Employee and stockholder of Eli Lilly and Company; C.M. Visseren-Grul: Employee and stockholder of Eli Lilly and Company; P.A. Schnabel: Research funding from Eli Lilly and Company. Speakers bureau for AstraZeneca, InterMune, Eli Lilly and Company, Novartis, Pfizer and Roche. Advisory board for Eli Lilly and Company, AstraZeneca, Novartis and Roche. All other authors have declared no conflicts of interest.

1247PANALYSIS OF PATIENTS TREATED WITH CISPLATIN OR CARBOPLATIN-BASED DOUBLET CHEMOTHERAPY IN THE EUROPEAN FRAME OBSERVATIONAL STUDY

ABSTRACT Aim: FRAME was a prospective observational study of patients (pts) receiving platinum (plt)-based chemotherapy as first-line treatment (FLT) for advanced or metastatic non-small cell lung cancer (NSCLC) across Europe between 2009 and 2012. Methods: The study primary objective of overall survival was previously reported. Here, we describe the association between baseline characteristics and the physicians choice of a cisplatin (cis) or carboplatin (cb) backbone for FLT observed in FRAME. The distribution of baseline characteristics was compared by t-test or k2-test and summarized by propensity of receiving cb estimated by logistic regression. Cohorts were matched by propensity score; survival for matched pts was compared using Kaplan-Meier approach. Results: In total, 1520 pts received either cis (n = 825) or cb (n = 695) in combination with either: pemetrexed, gemcitabine, taxanes or vinorelbine, and were analyzed here. Pts prescribed cb were on average older, had worse ECOG PS and were more likely to have squamous histology than pts who received cis (Table 1); they also had more pre-existing conditions (cardiovascular p Cis (n = 825) Cb (n = 695) p-value ≥70 yrs (%) 15 47 ECOG PS (%) Gr 0-1 Gr 2-3 87 12 77 22 FLT (+plt) (%) pemetrexed (n = 567) gemcitabine (n = 360) taxanes (n = 293) vinorelbine (n = 300) 47 23 9 21 26 24 31 19 Histology (%) Squamous (sq) Non-sq 23 75 26 70 .031 Conclusions: FRAME observed that age, ECOG PS, pre-existing conditions and pathological diagnosis have strong associations with the choice of cis or cb in FLT for advanced or metastatic NSCLC across Europe. Disclosure: D. Moro-Sibilot: Consulting fees from Eli Lilly and Company, Roche, Astra Zeneca, Boehringer Ingelheim France, Amgen; J. De Castro Carpeno: Speakers Bureau for Roche; Advisory board for Eli Lilly and Company, Roche and Pfizer; K. Kmak-Lesniewski: Invited speaker for Eli Lilly, Roche, Astra Zeneca, GSK, Amgen; J.G. Aerts: Research grant from and Consultant for Eli Lilly and Company. Advisory board for Eli Lilly and Company, Roche Genentech and BMS; R. Villatoro: Speaker fee from Jansen, Pfizer; K. Kraaij: Employee and stockholder of Eli Lilly and Company; K. Nacerddine: Employee and stockholder of Eli Lilly and Company; Y. Dyachkova: Employee and stockholder of Eli Lilly and Company; K. Smith: Employee of Eli Lilly and Company; A. Girvan: Employee and stockholder of Eli Lilly and Company; C.M. Visseren-Grul: Employee and stockholder of Eli Lilly and Company; P.A. Schnabel: Speakers Bureau for AstraZeneca, InterMune, Eli Lilly and Company, Novartis, Pfizer, Roche. Advisory board for AstraZeneca, Eli Lilly and Company, Novartis, Roche. Prior research funding from Eli Lilly and Company. All other authors have declared no conflicts of interest.

A phase II single-arm study of induction chemotherapy with cisplatin and gemcitabine followed by concurrent cisplatin and gemcitabine with thoracic radiation for unresectable locally advanced non-small cell lung cancer

Objectives: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin–gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: This was a phase II, multicenter, open-label, single-arm trial in treatment-naïve patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m2 plus cisplatin 80 mg/m2, two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m2, cisplatin 80 mg/m2, and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. Results: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2–53.8%). Median TtPD was 11.4 months (95% CI 9.4–12.9). Median OS was 21.8 months (95% CI 17.5–26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. Conclusions: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m2) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis.