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Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab

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Abstract

Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78% objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation. As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway. To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays. Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected.

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Acknowledgments

We would like to thank Dr. Rachel Humphrey and Dr. Maria Jure-Kunkel for their critical review of the paper and Dr. Ping Zhan for her contribution to the data analysis in this paper.

Conflict of interest

Vafa Shahabi, Gena Whitney, Scott D. Chasalow, Suresh Alaparthy, and Jeffrey R. Jackson are employees of Bristol-Myers Squibb, the manufacturer of ipilimumab. Omid Hamid and Henrik Schmidt declare that they have no conflict of interest.

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Authors and Affiliations

  1. Bristol-Myers Squibb Company, Princeton, NJ, USA

    Vafa Shahabi, Gena Whitney, Scott D. Chasalow, Suresh Alaparthy & Jeffrey R. Jackson

  2. The Angeles Clinic and Research Institute, Santa Monica, CA, USA

    Omid Hamid

  3. Aarhus University Hospital, Aarhus, Denmark

    Henrik Schmidt

Authors
  1. Vafa Shahabi
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  2. Gena Whitney
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  3. Omid Hamid
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  4. Henrik Schmidt
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  5. Scott D. Chasalow
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  6. Suresh Alaparthy
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  7. Jeffrey R. Jackson
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Correspondence to Vafa Shahabi.

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Shahabi, V., Whitney, G., Hamid, O. et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother 61, 733–737 (2012). https://doi.org/10.1007/s00262-012-1227-3

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  • DOI: https://doi.org/10.1007/s00262-012-1227-3

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