In the last 20 years, the survival and quality of life outcomes for patients with metastatic melanoma have been poor, with unsatisfactory results of chemotherapy and immunotherapy-based regimens. No drug or combination of drugs had any impact on survival until 2011, when ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), was approved for clinical use. Phase III trials have shown, for the first time ever, an overall survival benefit of ipilimumab compared with standard treatment, with a manageable toxicity profile. This review will discuss the mechanism of action of ipilimumab and the clinical trials that led to its approval.
LensM.B., DawesM.: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol, 150: 179–185, 2004.
2.
AgarwalaS.S.: Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther, 9: 587–595, 2009.
3.
KornE.L., LiuP.Y., LeeS.J., ChapmanJ.A., NiedzwieckiD., SumanV.J., MoonJ., SondakV.K., AtkinsM.B., EisenhauerE.A., ParulekarW., MarkovicS.N., SaxmanS., KirkwoodJ.M.: Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol, 26: 527–534, 2008.
4.
RosenbergS.A., LotzeM.T., MuulL.M., LeitmanS., ChangA.E., EttinghausenS.E., MatoryY.L., SkibberJ.M., ShiloniE., VettoJ.T., SeippC.A., SimpsonC., ReichertC.M.: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med, 313: 1485–1492, 1985.
5.
HodiF.S., O'DayS.J., McDermottD.F., WeberR.W., SosmanJ.A., HaanenJ.B., GonzalezR., RobertC., SchadendorfD., HasselJ.C., AkerleyW., van den EertweghA.J., LutzkyJ., LoriganP., VaubelJ.M., LinetteG.P., HoggD., OttensmeierC.H., LebbéC., PeschelC., QuirtI., ClarkJ.I., WolchokJ.D., WeberJ.S., TianJ., YellinM.J., NicholG.M., HoosA., UrbaW.J.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 363: 711–723, 2010.
6.
WolchokJ.: How recent advances in immunotherapy are changing the standard of care in patients with metastatic melanoma. Ann Oncol, 23(suppl 8): 15–21, 2012.
7.
ThompsonC.B., AllisonJ.P.: The emerging role of CTLA-4 as an immune attenuator. Immunity, 7: 445–450, 1997.
8.
KormanA.J., PeggsK.S., AllisonJ.P.: Checkpoint blockade in cancer immunotherapy. Adv Immunol, 90: 297–339, 2006.
9.
LeachD.R., KrummelM.F., AllisonJ.P.: Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271: 1734–1736, 1996.
10.
AcharyaU.H., JeterJ.M.: Use of ipilimumab in the treatment of melanoma. Clin Pharmacol, 5(Suppl 1): 21–27, 2013.
11.
AgarwalaS.S.: Novel immunotherapies as potential therapeutic partners for traditional or targeted agents: cytotoxic T-lymphocyte antigen-4 blockade in advanced melanoma. Melanoma Res, 20: 1–10, 2010.
12.
DowneyS.G., KlapperJ.A., SmithF.O., YangJ.C., SherryR.M., RoyalR.E., KammulaU.S., HughesM.S., AllenT.E., LevyC.L., YellinM., NicholG., WhiteD.E., SteinbergS.M., RosenbergS.A.: Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res, 13: 6681–6688, 2007.
13.
RosenbergS.A., YangJ.C., RestifoN.P.: Cancer immunotherapy: moving beyond current vaccines. Nat Med, 10: 909–915, 2004.
14.
SchwartzentruberD.J., LawsonD., RichardsJ., ConryR.M., MillerD., TriesmanJ., GailaniF., RileyL.B., VenaD., HwuP.: A phase III multi-institutional randomized study of immunization with the gp100: 209–217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol, 27(Suppl): 463s (abstr), 2009.
15.
HershE.M., O'DayS.J., PowderlyJ., KhanK.D., PavlickA.C., CranmerL.D., SamlowskiW.E., NicholG.M., YellinM.J., WeberJ.S.: A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naíve patients with advanced melanoma. Invest New Drugs, 29: 489–498, 2011.
16.
PattD., JudayT., PenrodJ.R., ChenC., WongS.L.: A community-based, real world study of treatment-naíve advanced melanoma (AM) patients treated with 3 mg/kg Ipilimumab in the United States. Proc European Cancer Congress 2013, Amsterdam; abstract 3751, 2013.
17.
MargolinK.A., WongS.L., PenrodJ.R., SongJ., ChangI.F., JohnsonD.B., JangS., ClarkJ., McDermottD.: Effectiveness and safety of first-line Ipilimumab 3 mg/kg therapy for advanced melanoma: evidence from a U.S. multisite retrospective chart review. Proc European Cancer Congress 2013, Amsterdam; abstract 3742, 2013.
18.
Di GiacomoA.M., GrimaldiA.M., AsciertoP.A., QueiroloP., Del VecchioM., RidolfiR., De RosaF., De GalitiisF., TestoriA., CognettiF., BernengoM.G., SavoiaP., GuidaM., StrippoliS., GalliL., MandalaM., ParmianiG., RinaldiG., AgliettaM., Chiarion-SileniV.: Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access program (EAP). J Clin Oncol, 31(Suppl): abstract 9065, 2013.
19.
QueiroloP., SpagnoloF., AltomonteM., Chiarion-SileniV., PigozzoJ., Del VecchioM., Di GuardoL., RidolfiR., ScoppolaA., FerrucciP.F., FerraresiV., BernengoM.G., GuidaM., MarconciniR., MandalàM., ParmianiG., RinaldiG., AgliettaM., SimeoneE., AsciertoP.A. Italian cohort of ipilimumab expanded access programme (EAP): Efficacy, safety, and correlation with mutation status in metastatic melanoma patients. J Clin Oncol, 31(Suppl) abstract 9070, 2013.
20.
ManganaJ., GoldingerS.M., SchindlerK., RozatiS., FrauchigerA.L., RechsteinerM., MochH., RomanoE., KaehlerK.C., MichielinO., HauschildA., HoellerC., DummerR.: Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: association with overall survival?J Clin Oncol, 31 (Suppl): abstract 9025, 2013.
