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G. Scagliotti



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 2
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      P1.11-018 - An Open-Label, Multicenter, Randomized, Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 1449)

      09:55 - 10:25  |  Author(s): G. Scagliotti

      • Abstract
      • Slides

      Background
      Pemetrexed combined with cisplatin is an approved first-line treatment regimen for patients with advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). New targets are needed to further improve first-line therapy outcomes. Cixutumumab, a fully human IgG1 monoclonal antibody, specifically blocks the insulin-like growth factor-type 1 receptor, inhibiting its activation and signal transduction. Early studies have reported clinical efficacy and safety with cixutumumab. However, the clinical benefit of adding cixutumumab to conventional chemotherapy is yet to be established. This study assessed whether pemetrexed and cisplatin combined with cixutumumab was superior to pemetrexed and cisplatin as first-line therapy.

      Methods
      This open-label, multicenter, randomized, phase II study (N=172) enrolled patients ≥18 years of age with stage IV nonsquamous NSCLC and ECOG performance status 0–1. Patients were randomized (1:1) to receive cixutumumab 20 mg/kg combined with pemetrexed 500 mg/m[2] and cisplatin 75 mg/m[2] (cixutumumab arm; n=87) or pemetrexed and cisplatin (control arm; n=85) every 21 days up to 6 cycles of induction therapy. Patients eligible for maintenance therapy received pemetrexed and cixutumumab (cixutumumab arm) or pemetrexed (control arm). The primary endpoint was progression-free survival (PFS) based on radiographic assessments. To test for superiority (1-sided significance level 20%; study power 80%), a median PFS of 7.16 months in the cixutumumab arm (HR cixutumumab/control=0.74) was expected. Secondary endpoints included objective response rate (ORR), duration of response, and overall survival (OS). Adverse events (AEs) were assessed using CTCAE version 4.0. Between-arm comparisons of unstratified data are presented.

      Results
      Baseline patient and disease characteristics were similar between arms in the intent-to-treat population. The mean age of the population was 59 years (range, 32 to 83). Dose intensity for all treatments was ≥90% during both study phases. Median PFS was 5.45 months (95% CI, 3.88–6.05) vs. 5.22 months (95% CI, 4.24–6.74) in the cixutumumab and control arms, respectively (HR 1.15, 95% CI, 0.81–1.61; P=0.440). ORR did not significantly differ between treatments (37.9% cixutumumab vs. 30.6% control; P=0.338); however, the median duration of response was numerically greater in the cixutumumab arm (4.9 months; 95% CI, 4.17–6.28) than in the control arm (3.91 months; 95% CI, 2.92–6.41), although differences were not significant (HR 0.74, 95% CI, 0.40–1.38; P=0.340). Median OS was 10.68 months (95% CI, 8.74–not evaluable) in cixutumumab vs. 10.38 months (95% CI, 7.43–14.39) in control patients (HR 0.85, 95% CI, 0.56–1.30; P=0.450). Common AEs reported in ≥10% of patients were nausea, hyperglycemia, fatigue, vomiting, and anemia. A greater proportion of patients in the cixutumumab arm (74.1%) had grade 3/4 AEs than patients in the control arm (61.7%). Grade 3/4 hyperglycemia occurred at a higher rate in the cixutumumab arm than the control arm (11.8% vs. 1.2%). One possibly cixutumumab-related death occurred during the study.

      Conclusion
      Superior PFS was not achieved in nonsquamous NSCLC patients when cixutumumab was added to the pemetrexed and cisplatin treatment regimen, and no significant improvement for any other endpoint was observed. Pemetrexed combined with cisplatin and cixutumumab was tolerable, with no new safety concerns reported.

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      P2.11-024 - Efficacy Analysis for Molecular Subgroups in MARQUEE: a Randomized, Double-blind, Placebo-controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib versus Placebo plus Erlotinib in Previously Treated Patients with Locally Advanced or Metastatic, Non-squamous, Non- small Cell Lung Cancer (NSCLC) (ID 2909)

      09:55 - 10:25  |  Author(s): G. Scagliotti

      • Abstract
      • Slides

      Background
      MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.

      Methods
      Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.

      Results
      From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.

      Conclusion
      Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.

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    MS13 - Statistics of Personalised Medicine (ID 30)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Statistics
    • Presentations: 1
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      MS13.3 - Clinical Trial Designs for Biomarker Driven Therapies in Early Disease (Adjuvant) (ID 518)

      14:00 - 15:30  |  Author(s): G. Scagliotti

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      P1.10-034 - Weight Gain as a Prognostic Factor on Patient Outcomes<br /> In Advanced, Nonsquamous, Non-small Cell Lung Cancer (ID 1905)

      09:30 - 16:30  |  Author(s): G. Scagliotti

      • Abstract

      Background
      Patients with advanced/metastatic non-small cell lung cancer (NSCLC) have a poor prognosis and low survival rates. One of the first notable symptoms of advanced lung cancer is unexplained weight loss. We evaluated weight gain (> 5% post baseline), as an early prognostic factor for clinical outcome, in advanced nonsquamous, NSCLC patients.

      Methods
      This retrospective analysis reports on three randomized phase III studies with survival and response data from a total of 2301 advanced, nonsquamous NSCLC patients who received pemetrexed or other chemotherapy plus a platinum or targeted agent, as first-line therapy. Body weight was recorded before and after treatment by each study’s schedule. Baseline weight was defined as the last non-missing weight measure before first treatment. Post baseline weight was defined as the maximum weight measured after starting treatment. Patients were analyzed using log-rank test and adjusted Cox modeling to assess the relationship between weight gain and overall survival (OS) and progression-free survival (PFS). Logistic regression was used to assess the association between baseline covariates and post-baseline weight gain.

      Results
      Patients were a mean age of 61 years (range 26 – 86) and most were of Caucasian descent (77.0%). A majority of patients had adenocarcinoma (73.8%), were male (59.8%) with an ECOG performance status (PS) of 0/1/2 (38.5%/60.2%/1.4%). Many patients were smokers or former smokers (55.7%) with Stage IV disease (83.1 %), according to the American Joint Committee on Cancer, editions. 5/6 and had an average weight at baseline of 71.4 kg. A total of 421 (18.3%) patients had a >5% increase in weight (>5% subgroup) after baseline with a statistically significant increase in OS and PFS. Median OS was 16.7 months for patients in the >5% subgroup versus 10.7 months for patients who gained <5% weight (< 5% subgroup; [n=1880]; p<0.001). PFS was 6.9 months for the >5% subgroup versus 4.8 months for <5% subgroup; p<0.001). Differences in overall response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were also significant. ORR was 50.8% for >5% subgroup versus 25.4% for < 5% subgroup (p<0.001). DCR was 91.5% for >5% subgroup and 63.6% for <5% subgroup (p<0.001). Cox modeling revealed patients in the >5% subgroup had significantly longer survival (HR=0.56, [95% CI 0.49-0.64]; p<0.001) than patients with <5% subgroup, after adjusting for baseline age (<65 versus 65), sex, ECOG PS (0 versus 1/2), histology (adenocarcinoma versus others), and study. Similar significant results were also found for PFS. Logistic regression indicated a significant association between weight gain and age. More patients aged <65 had a >5% weight gain (p<0.001).

      Conclusion
      This exploratory analysis showed that substantial weight gain (>5%) occurred after initiation of platinum-based chemotherapy in approximately 20% of advanced/metastatic, nonsquamous NSCLC patients. There was a positive correlation between weight gain and improved, OS, PFS and response in patients treated in these phase III studies.

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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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      P3.11-039 - Exploration of patient health status as measured by the generic preference-based questionnaire EQ-5D alongside the START trial of tecemotide (L-BLP25) in non-small cell lung cancer (ID 2744)

      09:30 - 16:30  |  Author(s): G. Scagliotti

      • Abstract

      Background
      Tecemotide (L-BLP25) is a mucin 1 (MUC1) antigen-specific cancer immunotherapy investigated in patients not progressing after primary chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC) in the phase III START study. The objective of this analysis was to explore patients’ health status alongside the study.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC that did not progress after chemo-radiotherapy (platinum-based chemotherapy and ≥50 Gy) were randomized (2:1; double-blind) to tecemotide (806 μg lipopeptide) or placebo SC weekly x 8 then Q6 weeks until disease progression or withdrawal. The analysis population (n=1239) was defined prospectively to account for a clinical hold of the study. The impact on patient health status was assessed as an exploratory endpoint using the EuroQoL 5 Dimensions (EQ-5D), a widely used generic preference-based questionnaire covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). EQ-5D index score can be calculated for which perfect health is given a value of 1 and death a value of 0. EQ-5D was collected at baseline, weeks 2, 5 and 8 and then every 6 weeks until end of treatment (EOT) visit (i.e. at time of disease progression), the EOT visit and every 12 weeks afterwards. Analysis of covariance (ANCOVA) was carried out to explore the change of EQ-5D index score over time in the overall population for patients on treatment. The change of EQ-5D to EOT visit was also estimated. Change of EQ-5D index score was explored using all data (i.e. collected both before and after EOT visit) using a linear growth curve model, with random intercept and slope, considering time as a continuous variable.

      Results
      EQ-5D compliance rates (percentage of patients still in the study who completed the questionnaire) were consistently above 85% for all visits of the treatment period in both treatment arms. Mean baseline EQ-5D score was 0.79 (sd=0.19) for both tecemotide and placebo arms. The results from ANCOVA on the overall population did not show any significant difference between the two arms during the treatment phase. Change in the EQ-5D index score from baseline to EOT visit was –0.102 (95%CI: –0.134, –0.071) for tecemotide and –0.136 (95%CI: –0.177, –0.095) for placebo. The linear growth model including the EQ-5D assessments before and after EOT showed that the EQ-5D index score decreased significantly over time in both treatment arms, but that the decrease was slightly slower in the tecemotide than in the placebo arm: –0.0076 per month in tecemotide patients vs. –0.01 in placebo (p=0.0498).

      Conclusion
      During treatment, there was no statistical difference in health status with tecemotide vs. placebo. This supports the good tolerability profile of tecemotide, with a lack of significant toxicity as compared to placebo. Disease progression was associated with a notable deterioration of patient health status, regardless of the treatment. Considering data from both before and after disease progression, patients’ health status appeared to worsen slightly over time, at a slower rate for patients treated with tecemotide.