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B.A. Dicarlo



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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-092 - A Phase IB Dose-Escalation Study of Pemetrexed and AUY922 in Previously Treated Metastatic Non-Squamous, Non-Small Cell Lung Cancer (ID 2164)

      09:30 - 09:30  |  Author(s): B.A. Dicarlo

      • Abstract
      • Slides

      Background:
      Despite advances in targeted therapy, treatment options for metastatic NSCLC progressing after initial therapy remains limited. HSP90 is an ATP-dependent molecular chaperone that plays a vital role in protein stabilization. Some HSP90 client proteins are key regulators in cell proliferation and survival. Many mutant oncoproteins are more dependent on HSP90 for proper folding and stability compared to their wildtype counterparts. AUY922 potently inhibits HSP90, showing preclinical activity in a wide range of cancer cell lines, including NSCLC (1). Phase I clinical trials established 70 mg/m[2] as the dose for further development (2). A single agent phase II trial demonstrated clinical activity of AUY922 in NSCLC, particularly molecular subsets with driver mutations in the known HSP90 client proteins, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (3). Pemetrexed is a folate antimetabolite chemotherapeutic approved for use in advanced non-squamous, NSCLC. In pre-clinical models, mRNA for dihydrofolate reductase (DHFR), a target of pemetrexed, reliably decreased in response to AUY922 exposure (1). These findings suggest that the combination of AUY922 and premetrexed in NSCLC is worthy of investigation.

      Methods:
      Adult patients with previously treated stage IV non-squamous, NSCLC, measureable disease per RECIST 1.1, ECOG performance status < 2, and life expectancy > 3 months are eligible for this open label phase Ib clinical trial (NCT01784640). A standard 3 x 3 design will evaluate 3 cohorts, all with pemetrexed at the standard 500 mg/m[2] dose, plus: AUY922 40 mg/m[2], 55 mg/m[2], and 70 mg/m[2] qwk. Enrollment of the 70 mg/m[2] qwk cohort has been open since November 2014 and is currently ongoing. After the optimal dose for further evaluation is determined, an additional 20 patients will be enrolled at that dose. This expansion phase will focus on patients with EGFR mutations and ALK gene rearrangements. The primary endpoint is safety and tolerability of AUY922 combined with pemetrexed in patients with previously treated non-squamous NSCLC. [Funding by Novartis, K23CA149079, Wolfen Family, One Ball Matt Memorial Golf Tournament]. References 1) Garon EB et. al. Mol Cancer Ther. 2013 2) Sessa C et. al. Clin Cancer Res. 2013 3) Garon EB et. al. ASCO 2012

      Results:
      Not applicable

      Conclusion:
      Not applicable

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