Complete pathologic response after neoadjuvant treatment with vemurafenib for malignant melanoma
Authors: Orit Kaidar-Person, Ayelet Eran, Gil Bar-Sela
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Invasive melanoma on the left arm was diagnosed in a 32-year-old male patient. The initial diagnosis was made by skin biopsy, which revealed a nonulcerated melanoma of 3 mm depth. The patient underwent reexcision and sentinel lymph node biopsy, both of which were negative for malignant melanoma. Two months later, the patient presented with a large mass (>7 cm) in his left arm and palpable axillary lymph nodes. Biopsy of the lesion with an 18-gauge Tru-Cut needle and automatically triggered biopsy gun was positive for melanoma and BRAF V600E mutation. After the biopsy, the tumor mass transformed to an open wound with constant bleeding (Fig 1), necessitating prolonged hospitalization. Fluorodeoxyglucose positron electron tomography (FDG-PET) examination showed uptake in the primary site and left axilla, and suspicious uptake in the left supraclavicular lymph nodes. Axillary cytology via fine-needle aspiration was positive for melanoma. The patient refused immediate surgery, which would have involved disarticulation amputation. Neoadjuvant treatment with vemurafenib (Zelboraf, Hoffmann-La Roche), 960 mg orally twice daily, was instituted. A follow-up visit 2 weeks later showed significant clinical improvement. After 8 weeks of treatment, the mass disappeared (Fig 2). There were no significant side effects of vemurafenib treatment. A multidisciplinary team decided to refer the patient to surgery. Vemurafenib was continued until 2 days before surgery. The patient underwent resection of the recurrent skin lesion and axillary lymph node dissection, all of which indicated complete pathologic response. Vemurafenib was not renewed after surgery. The patient was followed every 3 months by a physical examination and with FDG-PET every 6 months. At 18 months after surgery, he shows no evidence of disease.Fig 2Site of prior melanoma, shown in Fig 1, after 8 weeks of treatment with vemurafenib.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Neoadjuvant treatment for resectable/unresectable stage III melanoma remains an investigational approach; there are neither large prospective randomized trials nor recommended regimens or timelines for a treatment frame, in that none of the systemic therapies or radiotherapy for melanoma were proven to be sufficiently active to support this approach.1Moschos S.J. Edington H.D. Land S.R. Rao U.N. Jukic D. Shipe-Spotloe J. et al.Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses.J Clin Oncol. 2006; 24: 3164-3171Crossref PubMed Scopus (215) Google Scholar Vemurafenib was approved by the Food and Drug Administration in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation based on a large randomized study.2Food and Drug Administration. Vemurafenib. Available from: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm268301.htm. Accessed October 30, 2013.Google Scholar, 3Chapman P.B. Hauschild A. Robert C. Haanen J.B. Ascierto P. Larkin J. et al.BRIM-3 Study GroupImproved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6059) Google Scholar The majority of the patients (95%) had metastatic disease. Subgroup analysis of overall survival indicated that the nonmetastatic patients did not benefit from vemurafenib but a significant benefit to this subgroup was shown with regard to progression-free survival. It was not stated whether these patients became operable or were referred for surgical resection. There are no ongoing trials evaluating the role of vemurafenib in the neoadjuvant setting, and a literature review reveals that there are only 2 other reports of vemurafenib in the neoadjuvant setting.4Kolar G.R. Miller-Thomas M.M. Schmidt R.E. Simpson J.R. Rich K.M. Linette G.P. Neoadjuvant treatment of a solitary melanoma brain metastasis with vemurafenib.J Clin Oncol. 2013; 31: e40-e43Crossref PubMed Scopus (25) Google Scholar, 5Fadaki N. Cardona-Huerta S. Martineau L. Thummala S. Cheng S.T. Bunker S.R. et al.Inoperable bulky melanoma responds to neoadjuvant therapy with vemurafenib.BMJ Case Rep. 2012; (bcr2012007034)PubMed Google Scholar In the case presented, there was a pathologic complete response; however, the role of vemurafenib in locally advanced disease, whether in the neoadjuvant or adjuvant setting, is yet to be determined. A major concern of this approach is the possibility of gaining resistance to BRAF inhibition and losing it as potential treatment in the metastatic setting.