A 29-Year-Old Man Presents With Stage IV, Poorly Differentiated Malignant Melanoma
A 29-year-old man was presented early in this series as an example of stage IV, poorly differentiated malignant melanoma. As noted previously, evaluation disclosed the presence of multifocal metastatic disease (lungs, lymph nodes).
There is only one viable answer for this case presentation. Toceranib is a veterinary drug used to manage mast cell tumors in dogs. Brentuximab vedotin is indicated for the treatment of several types of human lymphoma. Ondansetron is administered to decrease nausea and vomiting associated with chemotherapy. Vismodegib has not yet been approved by the US Food and Drug Administration, but is under consideration for use with advanced basal-cell carcinoma. The correct choice is therefore ipilimumab.
As noted in a previous feature that focused on a different aspect of this case, no consensus has been reached as to the optimal management of metastatic malignant melanoma. Complete response rates to either traditional single-drug or multi-drug chemotherapeutic regimens have been poor (< 6 %), including only modest increases in the median survival.[1-3] Palliative surgery is always a valuable option to consider, if for no other reason than to improve quality of life.
However, the outlook for management of advanced, inoperable, and metastatic melanoma has improved dramatically with the approval of several new drugs. For example, ipilimumab (Yervoy) is now available as a first- or second-line treatment for patients with metastatic melanoma. This is an intravenously administered recombinant human monoclonal antibody which binds to, and thus inactivates, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); the latter is a molecule on T cells that suppresses the immune response. Blockade of CTLA-4 thus augments T-cell activation and proliferation. Therefore, ipilimumab works by increasing T-cell mediated antitumor immune responses. Analysis of data from multiple trials indicates that neither overall survival rate nor treatment-related adverse events depend upon HLA subtype.
Regardless of the measurement criteria (median survival rates, durable disease control rate, complete and partial responder rates), a variety of phase II and phase III, single-center and multi-center studies have verified the beneficial effects of ipilimumab; these benefits extend even to very heavily pretreated patients with progressive disease.[7-9] The combination of ipilimumab and dacarbazine (DTIC) appears to be better than either drug administered alone (in previously untreated patients), with higher overall median survival rates detectable even at 3 years.[10-11] It has been pointed out that response to ipilimumab may be highly atypical, with some delayed responders not being apparent up to and beyond one year of therapy. An increase in absolute peripheral lymphocyte count may portend better clinical response and/or overall survival.
Adverse events are largely autoimmune in nature, and consist primarily of nonspecific cutaneous eruptions, colitis, thyroiditis, hematologic cytopenias, and hepatitis. Grade 3–4 adverse events occur in 10% to 20% of patients. Although side effects may be severe, long-lasting, and even fatal, most are reversible with appropriate therapy.[7,8]
1. Legha SS, Ring S, Papadoupoulos N, et al: A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer. 1989;64:2024–2029.
2. McClay EF, Mastrangelo MJ, Berd D, et al: Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials. Int J Cancer. 1992;50:553–556.
3. Reinhard D, Garbe C, Thompson JA, et al: Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma. J Clin Onc. 2006;2–4:1188–1194.
4. Wornom IL III, Smith JW, Soong SJ, et al: Surgery as palliative treatment for distant metastases of melanoma. Ann Surg. 1986;204:181–185.
5. Tarhini A, Lo E, Minor DR. Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Cancer Biother Radiopharm. 2010;25:601–613.
6. Wolchok JD, Weber JS, Hamid O, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immunol. 2010;10:9.
7. Hodi FS. O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723.
8. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: A multicenter, single-arm phase II study. Ann Oncol. 2010;21:1712–1717.
9. Di Giacomo AM, Danielli R, Calabro L, et al. Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol Immunother. 2011;60:467–477.
10. Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29:489–498.
11. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526.
12. Boasberg P, Hamid O, O’Day S. Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin Oncol. 2010;37:440–449.