Melanoma and Ipilimumab

Ipilimumab, the first cancer immunotherapy for metastatic melanoma, is the first drug to be FDA approved in many years. Ipilimumab is sold as Yervoy by Bristol-Meyers Squibb. Interleukin-2, the last drug to have been approved for treating melanoma was approved in 1998 and only benefits 10-15% of patients with advanced disease. Dacarbazine, a chemotherapy approved in 1975, shows similar efficacy.

Zelboraf – the targeted cancer therapy vemurafenib – benefits ~80% of the patients who test positive for the B-raf mutation. Vemurafenib was also FDA approved in 2011 for metastatic melanoma. There are ongoing tests for the combination of vemurafenib (Zelboraf) and ipilimumab (Yervoy) with optimism for finding a very effective treatment for melanoma.

Cancer immunotherapy works by promoting the normal body immune system attempts to kill foreign cells, but not the body’s own cells. Tumor cells are the body’s own cells, but the changes that lead to excessive growth make the cells slightly different. If that difference were identified, then the body’s immune system could kill those tumor cells. Normally CTLA-4 blocks the immune response and protects the body’s regular cells. Ipilimumab binds to the receptors on immune cells in place of the CTLA-4 and dials down the prevention of immune cells from killing the regular cells. The goal is for the immune system to now kill the tumor cells preferentially over the regular cells, which was observed for 20-30% of the patients. There is a difficult balance where the more powerful immune system does attack the body’s regular cells as well and leads to auto-immune disorder side effects like rashes and trouble with digestion.

Read more details about Ipilimumab.

Ipilimumab (sold as Yervoy) has side effects that come from the activation of T-cells and the body’s immune responses. The most common are side effects are very much like auto-immune disorders and include a number of adverse reactions including diarrhea, rash, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. In the clinical trials, Ipilimumab use was stopped in 10% of the patients due to the severity of the side effects. Ipilimumab side effects varied widely with the test population, and can appear after the drug use is stopped. Sensitive patients were given hydrocortisone to reduce the immune system activity.^1,3,4,7,9

1. "Ipilimumab." U S Food and Drug Administration Home Page. 25 Mar. 2011. Web. 02 Nov. 2011. <http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm>.
2. Peggs, KS, SA Quezada, AJ Korman, and JP Allison. "Principles and Use of Anti-CTLA4 Antibody in Human Cancer Immunotherapy." Current Opinion in Immunology(2006): 206-13. Http://www.ncbi.nlm.nih.gov. Pub Med, 18 Apr. 2006. Web. 04 Nov. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/16464564?dopt=Citation>.
3. Wolchok, Jedd D., Jeffrey S. Weber, and Omid Hamid. "Ipilimumab Efficacy and Safety in Patients with Advanced Melanoma: a Retrospective Analysis of HLA Subtype from Four Trials." Cancer Immunology (2010). Print.
4. Robert, C., L. Thomas, and I. Bondarenko. "Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma." New England Journal of Medicine 364.26 (2011): 2517-526. Print.
5. "Dacarbazine, DTIC Dome, DIC - Chemotherapy Drugs, Chemo Drug Side Effects."Chemotherapy Drugs and Side Effects Information - Chemo Care. Web. 02 Nov. 2011. <http://www.chemocare.com/bio/dacarbazine.asp>.
6. Jelic, S., N. Babovic, and V. Kovcin. "Comparison of the Efficacy of Two Different Dosage Dacarbazine-based Regimens and Two Regimens without Dacarbazine in Metastatic Melanoma: a Single-centre Randomized Four-arm Study." Melanoma Results. Pub Med, 12 Feb. 2002. Web. 02 Nov. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/11828263>.
7. Brockey, Mike. "I Am Now on Vemurafenib and Feeling Pretty Good." SMelanoma, Cancer Stinks! Blogger.com, 22 Aug. 2011. Web. 02 Nov. 2011. <http://www.smelanoma.com/2011/08/i-am-now-on-vemurafenib-and-feeling.html>.
8. "Melanoma (stage III or IV) - Ipilimumab: Appraisal Consultation Document." Http://guidance.nice.org.uk. National Institute for Clinical Excellence, 14 Oct. 2011. Web. 04 Nov. 2011. <http://guidance.nice.org.uk/TA/WaveCRS2/48/Consultation/DraftGuidance>.
9. "Yervoy (patient Information)." Www.yervoy.com. Bristol-Meyers Squibb. Web. 2 Nov. 2011. <http://www.yervoy.com/patient.aspx>