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D.R. Spigel



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

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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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)

      10:00 - 10:05  |  Author(s): D.R. Spigel

      • 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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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-038 - Efficacy of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with previously treated advanced non-small cell lung cancer (NSCLC): subpopulation response analysis in a phase 1 trial (ID 2751)

      09:30 - 09:30  |  Author(s): D.R. Spigel

      • Abstract

      Background
      Lung cancer is the leading cause of cancer deaths globally, and NSCLC comprises 85% of lung cancers. Patients with advanced (stage IIIB or IV) NSCLC have a poor prognosis. Current second-line chemotherapeutics demonstrate a median overall survival (OS) of 8 months and 1-year survival of 30%. Factors that may influence clinical activity include age, ECOG performance status (PS), number of prior therapies, and EGFR- and KRAS-mutation status. The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands PD-L1 and PD-L2. Nivolumab, a fully human IgG4, PD-1 receptor blocking monoclonal antibody, was evaluated in a phase 1 study (CA209-003; NCT00730639) in patients with various tumors, including previously treated advanced NSCLC. In this study, treatment with nivolumab demonstrated durable objective responses and prolonged stable disease in a portion of patients from this NSCLC cohort (Topalian S, et al. N Engl J Med. 2012;366:2443-54). We present the updated findings from assessment of clinical activity to nivolumab in subpopulations of the NSCLC cohort from this study.

      Methods
      Patients received nivolumab (1–10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. An analysis of clinical activity by select patient characteristics was performed from the NSCLC cohort of this trial.

      Results
      129 patients with NSCLC (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) received nivolumab at 1, 3, or 10 mg/kg as of March 2013 (Table). Association of clinical activity with baseline characteristics will be assessed for the following subgroups: age ≥70 and <70 years, gender, ECOG PS 0 and ≥1, number of prior therapies 1–2 and ≥3, prior tyrosine kinase inhibitor (TKI) therapy, EGFR-mutation status, and KRAS-mutation status.

      Table
      Baseline characteristic[a] NSCLC patient population (n=129)
      Median age (range), y 65 (38–85)
      Gender, n (%)
      Male 79 (61)
      Female 50 (39)
      ECOG PS, n (%)
      0 27 (21)
      1 100 (78)
      2 2 (2)
      Number of prior therapies, n (%)
      1 25 (19)
      2 34 (26)
      3 27 (21)
      ≥4 43 (33)
      Prior therapy, n (%)
      Platinum-based chemotherapy 128 (99)
      TKI 36 (28)
      [a]Data on EGFR- and KRAS-mutation status are pending.

      Conclusion
      Nivolumab demonstrated encouraging clinical activity in patients with previously treated advanced NSCLC. Clinical activity by patient subgroups may provide insights into the influence of patient and tumor characteristics on response to nivolumab. An update of the data regarding clinical activity of nivolumab therapy in these subgroups of the NSCLC cohort will be presented.