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A. Urman

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    Best of Posters - IASLC Selection - Part 1 (ID 262)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P1.11-008 - A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) in patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). (ID 976)

      09:55 - 10:25  |  Author(s): A. Urman

      • Abstract
      • Slides

      AUY922 is an HSP90 inhibitor that degrades client onco-proteins including mutant EGFR. Preclinical studies utilizing cell lines and xenografts harboring EGFR T790M demonstrate that HSP90 inhibition is effective in models of AR. This phase II study combines AUY922 and E for the treatment of patients with EGFR-mutant lung cancer and RECIST-progression on EGFR TKIs.

      Eligible patients had EGFR mutations and developed AR (per Jackman, JCO 2010) after treatment with EGFR TKIs. Patients underwent tumor biopsies after developing AR and prior to study entry. Tumor tissue from re-biopsy was analyzed for EGFR T790M and other mechanisms of resistance. Patients received AUY922 70 mg/m[2 ]IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment was done at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%).

      The trial has completed accrual, and twenty-five patients have been treated (18 women, median age 59 (range 42-76)). The median time on EGFR TKI prior to the development of AR was 11 mo (range 3-26 mo). Ten patients (40%) had EGFR T790M identified by tumor re-biopsy. In the 25 patients evaluable for response, ORR was 4/25 (16%, 95% CI 6-35%). Three of four patients with PR had EGFR T790M. An additional four patients had stable disease for at least 8 weeks. To date, four patients were on study drug for ≥ 4 cycles, and four patients currently remain on study. Adverse events reported in ≥ 20% of patients were diarrhea, fatigue, myalgias, nausea, mucositis, and night blindness. Sixty-eight percent (17/25) experienced night blindness (grade 1-2 only), and three patients came off study due to eye-related toxicity. Grade 3 toxicities included elevated liver function tests, diarrhea, fatigue, constipation and anemia.

      AUY922 and E is an active, well-tolerated regimen for patients with EGFR-mutant lung cancer. Visual disturbances, particularly night blindness, were common, but resolved with drug discontinuation. AUY922 and erlotinib demonstrate activity as combination therapy for patients with EGFR mutant lung cancers and AR to EGFR TKI. Activity is not limited to patients with EGFR T790M. Supported by Novartis, Inc.

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