Full Spectrum: Efficacy and Toxicity of Immunotherapy in Metastatic Melanoma

View More View Less
  • 1 From the Medical Oncology Department, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Restricted access

Metastatic melanoma is a devastating disease that has been increasing in incidence and until relatively recently had few effective treatment options. With the approval in 2011 of ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), however, that has begun to change. Ipilimumab is an immune checkpoint inhibitor, a type of immunotherapy that can down-regulate inhibitory signals affecting T-cell activation to unleash more dramatic anti-tumoral responses and offer the possibility of deep and durable remissions in up to 20% of patients. Use of this and similar agents can lead to characteristic and varied immune-related adverse events (irAEs); however, experience has shown that these can be managed with patient education, early recognition, and judicious use of systemic steroids. Newer immune checkpoint inhibitors such as those that block PD-1 or PDL-1 have shown impressive results in early studies. Most recently, pembrolizumab, an anti-PD-1 antibody, was approved by the FDA for the treatment of patients with melanoma after progression on a CTLA-4 inhibitor and, if clinically relevant, a BRAF inhibitor. This supplement presents the case of a 60-year-old man with an enlarging right neck mass who was found to have disseminated metastatic melanoma. He was started on treatment with the CTLA-4 inhibitor ipilimumab (3 mg/kg intravenous). After the third dose, the patient developed grade 3 uveitis/retinitis and immune-mediated nephritis requiring hospitalization and systemic corticosteroids. Both conditions were considered irAEs secondary to ipilimumab. The patient recovered completely from all toxicities but did not receive further doses of ipilimumab. Nonetheless, the patient experienced a complete radiographic response and at time of writing was 19 months from diagnosis without evidence of disease.

Correspondence: Anthony J. Olszanski, MD, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail: Anthony.Olszanski@FCCC.edu

Editors’ note:

A new tool for health care professionals to communicate with patients regarding the safe and appropriate use of immune-based medicines in the treatment of cancer is available. See “Patient Education Tool” at right.

  • 1.

    Bleyer A, O’Leary M, Barr R. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-200. Betheseda, MD: National Cancer Institute; 2006.

    • Search Google Scholar
    • Export Citation
  • 2.

    American Cancer Society. Cancer Facts and Figures 2014. Available at http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/. Accessed September 26, 2014.

    • Search Google Scholar
    • Export Citation
  • 3.

    McDermott D, Lebbe C, Hodi FS. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev 2014; 40:10561064.

    • Search Google Scholar
    • Export Citation
  • 4.

    Levison VB: Spontaneous regression of a malignant melanoma. Br Med J 1955;1:458459.

  • 5.

    Sumner WC. Spontaneous regression of melanoma. Cancer 1953;6:10401043.

  • 6.

    Rosenberg SA, Mule JJ, Spiess PJ. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985;161:11691188.

    • Search Google Scholar
    • Export Citation
  • 7.

    Atkins MB, Kunkel L, Sznol M. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000;6(Suppl 1):S11S4.

    • Search Google Scholar
    • Export Citation
  • 8.

    Atkins MB, Lotze MT, Dutcher JP. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:21052116.

    • Search Google Scholar
    • Export Citation
  • 9.

    Rosenberg SA, Yang JC, Topalian SL. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994;271:907913.

    • Search Google Scholar
    • Export Citation
  • 10.

    Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2. Oncology 2002;16:1120.

  • 11.

    Dunn GP, Bruce AT, Ikeda H. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991998.

  • 12.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252264.

  • 13.

    Hodi FS, O’Day SJ, McDermott DF. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711723.

  • 14.

    Robert C, Thomas L, Bondarenko I. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:25172526.

  • 15.

    Lebbe C, Weber J, Maio M. Five-year survival rates for patients (pts) with metastatic melanoma (MM) treated with ipilimumab (IPI) in phase II trials, Asia Pac J Clin Oncol 2012;8:309309.

    • Search Google Scholar
    • Export Citation
  • 16.

    Maio M, Bondarenko I, Robert C. Four-year survival update for metastatic melanoma patients treated with ipilimumab plus dacarbazine in phase 3 study CA184-024. Ann Oncol 2012;23:1127.

    • Search Google Scholar
    • Export Citation
  • 17.

    Agarwala SS. Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther 2009;9:587595.

  • 18.

    Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30:26912697.

    • Search Google Scholar
    • Export Citation
  • 19.

    Chapman PB, Hauschild A, Robert C. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:25072516.

  • 20.

    Hauschild A, Grob J-J, Demidov LV. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358365.

    • Search Google Scholar
    • Export Citation
  • 21.

    Flaherty KT, Infante JR, Daud A. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:16941703.

  • 22.

    Ackerman A, Klein O, McDermott DF. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014;120:1695701.

    • Search Google Scholar
    • Export Citation
  • 23.

    Brahmer JR, Drake CG, Wollner I. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:31673175.

    • Search Google Scholar
    • Export Citation
  • 24.

    Topalian SL, Hodi FS, Brahmer JR. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:24432454.

  • 25.

    Hamid O, Robert C, Daud A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134144.

  • 26.

    Ribas A, Hodi FS, Kefford R. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma. Presented at the ASCO Annual Meeting, Chicago, IL, 2014.

    • Search Google Scholar
    • Export Citation
  • 27.

    Wolchok JD, Kluger H, Callahan MK: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122133.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 423 210 43
PDF Downloads 84 38 0
EPUB Downloads 0 0 0