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D.A. Proia

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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): D.A. Proia

      • Abstract

      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.

      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.

      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.

      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.