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A. Rademaker



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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. Rademaker

      • Abstract
      • Slides

      Background
      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.

      Methods
      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%).

      Results
      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.

      Conclusion
      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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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-006 - Review of 10 Years of ASCO Abstracts for Non-Small Cell Lung Cancer (NSCLC) and the Impact of Molecular Biomarkers (MB) in Clinical Trial Selection Criteria (ID 901)

      09:30 - 16:30  |  Author(s): A. Rademaker

      • Abstract

      Background
      Over the last decade, incorporation of new cytotoxic chemotherapeutics, introduction of maintenance therapy, and integration of targeted therapies have altered treatment paradigms for patients with metastatic NSCLC (mNSCLC). In a disease that was largely treated empirically, therapy is now tailored based upon histology and MB. We sought to analyze whether outcomes of clinical trials in mNSCLC reported over 10 years at the ASCO Annual Meeting reflected perceived gains in the treatment of patients with mNSCLC.

      Methods
      Data were collected from ASCO abstracts of Phase II–IV clinical trials for patients with mNSCLC from 2004–2013. Trials in Progress abstracts were excluded. Data collected included author names, histology and MB selection criteria, phase, primary endpoint, outcomes, and drugs used. We hypothesized that rates of positive clinical trial outcomes would increase over time and that trials using MB selection criteria would have higher rates of positive outcomes. Statistical comparisons were made using Fisher’s exact test with two-sided p-values. Trends were compared using Spearman’s rank correlation.

      Results
      711 of 2,540 identified mNSCLC category abstracts met selection criteria. Over 50% were published by the top 10% of 841 unique first/last authors. Annual abstracts fitting selection criteria declined from 107 to 41 from 2004–2013. Common primary endpoints were: not specified (31%), response rate (24%), progression-free survival (PFS, 22%), and overall survival (OS, 14%). Few phase II trials had primary endpoints of PFS or OS (20.4%, 6.0%). The proportion of trials with positive PFS outcomes increased from 3.7% to 26.8% despite decreases in total annual abstracts (correlation coefficient = –0.67, p=0.033) (see Figure). Positive OS outcomes increased from 0.9% to 4.9%. Trials with MB selection criteria (5.6%) or non-squamous (NS) histology (13% of trials without MB selection) increased from 0% to 22% and 18% annually, respectively, and were more likely to result in an improvement in PFS (20.0% vs. 9.2%, p=0.0482 and 23.0% vs. 7.3%, p=0.0001, respectively). These criteria had no significant association with OS or QOL outcomes. Figure 1

      Conclusion
      Despite fewer phase II–III clinical trials presented at ASCO annually, there was a significant increase in those with positive PFS outcomes. Increases in trials selective for MB or NS histology may account for the improved PFS results. These data suggest better trial design and efficient use of resources. These data may also reflect bias in selecting abstracts for presentation, which could result in missed learning opportunities for future trial design. Additionally, it is unclear whether PFS endpoints are as meaningful as OS.