Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: Evidence from an individual patient analysis

Authors

  • George R. Simon MD,

    Corresponding author
    1. Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
    • Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 903, MSC 635, Charleston, SC 29425-6350

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    • George Simon and Gerold Bepler were at H. Lee Moffitt Cancer Center and Research Institute when this work was performed.

    • George R. Simon generated the study concept and contributed to data tabulation, statistical analysis, and patient accrual; he is a guarantor of the article and takes responsibility for the integrity of the work as a whole, from inception to publication.

    • Fax: (843) 792-0644

  • Michael J. Schell PhD,

    1. Biostatistics Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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    • Michael J. Schell contributed to statistical analysis of the data. Mubeena Begum contributed to data compilation and analysis.

  • Mubeena Begum MD MSPH,

    1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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  • Jongphil Kim PhD,

    1. Biostatistics Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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    • Jongphil Kim contributed to statistical analysis of the data.

  • Alberto Chiappori MD,

    1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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    • Alberto Chiappori contributed to the accrual of patients and conceptualization of studies in the standard-of-care arms.

  • Eric Haura MD,

    1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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    • Eric Haura contributed to the accrual of patients and conceptualization of studies in the standard-of-care arms.

  • Scott Antonia MD,

    1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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    • Scott Antonia contributed to the accrual of patients and conceptualization of studies in the standard-of-care arms.

  • Gerold Bepler MD, PhD

    1. Department of Thoracic Oncology Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
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    • Gerold Bepler conceptualized the studies and contributed to the analysis of molecular determinants.


Abstract

BACKGROUND:

Excision repair cross complementing 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) are molecular determinants that predict sensitivity or resistance to platinum agents and gemcitabine, respectively. Tailored therapy using these molecular determinants suggested patient benefit in a previously reported phase 2 trial. Here, we report an individual patient analysis of prospectively accrued patients who were treated with the “personalized therapy” approach versus other “standard,” noncustomized approaches.

METHODS:

Patients who had nonsmall cell lung cancer (NSCLC) with extranodal metastatic disease and an Eastern Cooperative Oncology Group performance status of 0/1 were accrued to 4 phase 2 clinical trials conducted at the H. Lee Moffitt Cancer Center: Trial A (first-line carboplatin/gemcitabine followed by docetaxel), Trial B (docetaxel and gefitinib in patients aged ≥70 years), Trial C (combination therapy with carboplatin/paclitaxel/atrasentan), and Trial D (personalized therapy based on ERCC1 and RRM1 expression). Patients with low RRM1/low ERCC1 expression received gemcitabine/carboplatin, patients with low RRM1/high ERCC1 expression received gemcitabine/docetaxel, patients with high RRM1/low ERCC1 expression received docetaxel/carboplatin, and patients with high RRM1/high ERCC1 expression received vinorelbine/docetaxel. Patients who were treated on Trials A, B, and C were pooled together and analyzed as the “standard therapy” group. Patients accrued to Trial D were called the “personalized therapy” group. Individual patient data were updated as of February 8, 2011. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method.

RESULTS:

There were statistically significant improvements between the personalized therapy group versus the standard therapy group in response (44% vs 22%; P = .002), OS (median: 13.3 months vs 8.9 months; P = .016), and PFS (median: 7.0 months vs 4.3 months; P = .03).

CONCLUSIONS:

The results from individual patient analyses suggest that ERCC1 and RRM1/tailored selection of first-line therapy improved survival over standard treatment-selection approaches. Cancer 2012. © 2011 American Cancer Society.

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