Author of

• 12441

  +

  P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12444

    +

    P3.06-003 - Correlative Analysis of Circulating Biomarkers from a Phase 1b/2 trial of Cabozantinib (C) with or without Erlotinib (E) in Patients (Pts) with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (ID 266)

    09:30 - 09:30  |  Author(s): M.B. Wax
    • Abstract

    Background
    Cabozantinib (C) is a potent ATP-competitive inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2) along with KIT, RET, AXL, TIE2, and FLT3. Hepatocyte growth factor (HGF), the ligand of MET, and VEGF act synergistically to promote angiogenesis. There are currently no widely accepted prognostic or predictive biomarkers for anti-angiogenic agents.

    Methods
    This is a retrospective correlative biomarker study from the phase 1b/2 trial of C+/-E in stage IIIB-IV NSCLC. All pts had to fail prior therapy with E. Both drugs are oral and dosed daily. C dosing is in the free-base equivalent weight. In phase I, there was a 2 week lead in with E and the cohorts included: 1A (60 mg C+150 mg E), 2A (60 mg C+100 mg E), 3A (100 mg C+100 mg E), 4A (100 mg C+50 mg E), and 2B (40 mg C+150 mg E). In phase II, both drugs started simultaneously: Arm A (100 mg C) and Arm B (100 mg C+50 mg E). Pts were included in the study if a pre-E+C and post-C > day 29 plasma sample was available. The Milliplex 13-plex and Luminex 51-plex assays were used. For this preliminary analysis, select markers previously implicated in angiogenesis (bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12, IL-17, PDGF-BB, ICAM-1, VCAM-1) and those of interest (ligands of KIT and MET- SCF and HGF, respectively) were analyzed. Log transformed mean fluorescence intensity (MFI) values and Wilcoxon Rank paired sum tests were used to detect changes from day 1-29. A change from baseline was noted to be significant if at least 15% (median) with α<0.05 (2-sided) and a trend if 10-15% (median) with α<0.08 (2-sided).

    Results
    73 pts included: 52 phase I and 21 phase II; median age 60 years; 23M/50F; 56.2% nonsmoker; 91.8% adenocarcinomas. The pts with samples from both time points were divided into two groups due to limited sample size and included: Group R (complete/partial response and stable disease> 6 months; n=22) and Group NR (stable disease< 6 months and progressive disease; n=51). The only marker that changed in a single direction in all subjects within a group was sVEGFR2 in group R. Overall, significant decreases were noted in sVEGFR1-3, IL-6, PDGF-BB, and trended in IL12p70 and IL-17. By subgroups: Group R had significant decreases in bFGF, VEGF, sVEGFR1-3, IL-6, IL-8, IL-12(p40+p70), IL-17, PDGF-BB, SCF, and trended in HGF (median 10.1% ↓, p=0.0275); and Group NR had significant decreases in sVEGFR2-3, IL-6, PDGF-BB, and trended in sVEGFR-1, IL-6, and IL-17.

    Conclusion
    Both groups R+NR had a decrease in sVEGFR-2, suggesting that this is a marker of treatment with C rather than a marker of response. However, overall group R had larger dynamic decreases of immune markers than group NR. HGF, which is targeted downstream by C and plays a role in angiogenesis and E resistance, had a trend to decrease in group R but not group NR. This study is retrospective with a small sample size, imbalanced numbers per response subgroup, and is exploratory in nature.