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V.M. Vukovic



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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 12:00  |  Author(s): V.M. Vukovic

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-007 - Antimetastatic activity of ganetespib: preclinical studies and assessment of new lesion growth in the GALAXY-1 NSCLC trial (ID 2789)

      09:30 - 16:30  |  Author(s): V.M. Vukovic

      • Abstract

      Background
      Heat shock protein 90 (Hsp90) maintains the stability and activity of numerous signaling proteins involved in cancer metastasis. Interim results of the GALAXY-1 trial (NCT01348126) showed an improvement in overall survival in patients with non-small cell lung cancer (NSCLC) treated with an Hsp90 inhibitor, ganetespib (G), plus docetaxel (D) compared to D alone. We evaluated the antimetastatic activity of ganetespib in preclinical models, and compared time to appearance of new lesions in patients with radiologic progression in the two arms of the GALAXY-1 trial.

      Methods
      Preclinical effects of ganetespib were investigated on the: (1) migration and invasion of cancer cells via scratch and Boyden chamber assays, (2) expression of metastatic factors using protein array and gene profiling, (3) architecture of NSCLC xenografts by IHC, and (4) metastasis to the lung in tail vein and orthotopic breast cancer mouse models assessed by bioluminescence and histology. GALAXY-1 is a Synta sponsored randomized, international open-label study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m2 on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m2 on days 1 and 15. Time to appearance of new lesions (TTNL) was measured using serial computed tomography scans, starting from randomization and until a new metastatic lesion was reported. Patient enrollment completed in November 2012.

      Results
      Ganetespib blocked the directional migration of NSCLC cells in a monolayer of cancer cells, significantly reduced their invasion into type I collagen and induced the degradation of metastasis drivers including HIF-1α, activated FAK and MET. In mouse models, ganetespib significantly reduced tumor angiogenesis and proliferation in NSCLC xenografts; significantly blocked (>8X, p<0.005) the development of lung cancer metastases in a tail vein model; and significantly reduced multi-organ metastasis in an orthotopic model and blocked extramedullary hematopoiesis induced by the primary tumor. In GALAXY-1 trial patients, the population that exhibited the strongest survival improvement (diagnosis of advanced disease >6 months, N=175), median TTNL increased from 6.9 months (D) to 11.3 months (G+D), with hazard ratio 0.5 (p=0.0053) at time of abstract submission.

      Conclusion
      Ganetespib induces the degradation of key drivers of metastasis, resulting in the reduction of cancer cell migration and invasion in vitro and tumor angiogenesis and new lesion formation in vivo. Preliminary data from the GALAXY-1 study suggests that ganetespib treatment may reduce the risk of emergence of new metastatic lesions by 50% in advanced NSCLC patients.