By John Carruthers, assistant editor, May 01, 2013
Dermatologists treating advanced cases of metastatic melanoma had for years struggled with a lack of options to improve the survival rate of their patients. In 2011, the U.S. Food and Drug Administration (FDA) approved two groundbreaking new drugs for the treatment of these advanced melanoma cases, ipilimumab and vemurafenib. The two drugs came out within months of each other, and immediately sparked hopes for a future of effective targeted therapies (see “Targeted therapies take aim at skin cancer”). After another year of the top dermatologic and oncologic minds examining the drugs and their effects, dermatologists look forward to further improved patient outcomes and therapeutic combinations as they better develop the use of these therapies.
Targeted therapies, improved outcomes
Once melanoma progresses to stage IV, according to the American Cancer Society, patient survival rates at the five- and 10-year intervals drop significantly, from stage IIIC levels of 40 and 24 percent to levels approaching 15 to 20 and 10 to 15 percent, respectively. Ipilimumab and vemurafenib approach this advanced stage in two different ways.
Ipilimumab is a monoclonal antibody that blocks the CTLA-4 antigen that is thought to inhibit the immune system’s response to the melanoma cells. This allows the immune system to more effectively fight the development and spread of melanoma cells throughout the body. The therapy, as demonstrated in a 2010 New England Journal of Medicine article (2010;363(8):711-23), is the first to improve overall survival in stage IV melanoma patients. [pagebreak]
Vemurafenib is a targeted genetic therapy that blocks the function of the V600E BRAF gene mutation that is present in about half of melanomas. The drug shuts down the MAP-kinase pathway that allows melanoma cells to grow at uncontrollable rates. In a separate NEJM study (2011;364(26):2507-16), advanced melanoma patients showed a 48 percent response rate to the drug.
Taken together or separately, the two drugs are the most promising developments in the effort to improve melanoma treatment in some time, according to dermatologist Matthew Fox, MD, who works on the University of Michigan’s Multidisciplinary Melanoma Clinic.
“Patients are finally living longer with advanced disease. The therapies continue to be effective for a subset of patients with metastatic melanoma,” Dr. Fox said. “We are seeing a measurable, sustained clinical response to treatment for patients that was uncommon before the development of these therapies.”
Discovering benefits, limits
While both therapies have been demonstrated to improve outcomes in a manner unmatched by any other therapy, the limits of their effectiveness are now coming more clearly into focus, according to Brown University dermatologist Martin Weinstock, MD, PhD, who runs a multidisciplinary melanoma program at Rhode Island Hospital.
“We know that they both do improve prognosis to a degree, but that neither one cures a substantial number of patients. There’s an increase in survival, but most patients still end up succumbing to the disease,” Dr. Weinstock said. [pagebreak]
Continued research has shown that while ipilimumab has a low patient response rate, those patients who do find success with the therapy have significantly lasting results, according to Providence Cancer Center oncologist and internist Walter Urba, MD, PhD. This stands in contrast to the experience with vemurafenib, which has a higher percentage of patients respond but also sees many treated tumors eventually demonstrate resistance.
“Vemurafenib in BRAF mutation patients is a very potent drug. More than half the patients will have their tumors shrink,” he said. “There are great responses, and great improvement in survival, but ultimately, all the patients that we treat we know that one day in the future, seven or eight months later is the median time, that the tumors will develop resistance to vemurafenib and patient tumors will progress despite continued treatment.”
While Dr. Urba said that he and other researchers knew of these traits at the time that both agents were approved, another year’s worth of observation has seen those early opinions largely confirmed. A great deal has been learned about the biological mechanisms by which the tumor cells become resistant to vemurafenib, Dr. Urba said, but unfortunately there’s no “magic bullet” to address the process. Rather, he said, a number of mechanisms pose a challenge to continued therapy with the drug, and to identifying best therapy practices after resistance is demonstrated.
Dealing with adverse events
As with any new therapy, the need to establish and manage the side effects has been of paramount importance over the last year. Perhaps the most significant side effect of vemurafenib, according to Dr. Fox, is the development of secondary non-melanoma skin cancers, including squamous cell carcinomas. This, he said, may occur in as many as one in four patients treated with the drug. The secondary cancers, however, are most often treatable, and combining vemurafenib with a targeted pathway inhibitor has shown promising results. [pagebreak]
“Typically, among patients who are found to have secondary squamous cell carcinoma, one to two lesions develop with a mean time to development around eight weeks. These tumors are generally amenable to conventional treatment, and to our knowledge, no unresectable non-melanoma skin cancers have developed among patients treated with vemurafenib,” Dr. Fox said. “Interestingly, the risk of squamous cell carcinoma development is decreased when vemurafenib is used in combination with targeted MEK inhibitors, which in early studies have also demonstrated benefit for patients with metastatic melanoma. Low dose systemic retinoid therapy may be considered for patients with a large number of secondary tumors.”
Another year of administering and monitoring patient response to ipilimumab has led to a greater ability to understand and manage the drug’s side effects, according to Omid Hamid, MD, director of the Melanoma Center at the Angeles Clinic and Research Institute.
“Since the main mechanism of activity for this drug is to remove the body’s inhibition of an ongoing immune response, the adverse events associated with the administration of ipilimumab primarily consist of reactions that are immune in nature,” Dr. Hamid said. “Immune toxicities usually involve the skin, liver, gastrointestinal tract, and endocrine glands and appear in the form of fatigue, diarrhea, nausea, rash, and pruritus. Among almost 3,000 patients treated with ipilimumab, approximately 50 percent of patients reported some form of adverse immune-related event; however only 12 percent were serious adverse immune-related events. Almost all severe immune-related adverse events were managed with supportive care or corticosteroids and resolved without sequelae.” [pagebreak]
While dermatologists and researchers continue to study patient response to both drugs, continued improved outcomes may derive from the combination of both therapies with either outside therapies. However, a recent study combinining them with each other was stopped due to concerns about toxicity.
“I think we all share in the investigator’s disappointment that combined therapy with these two drugs as attempted in this study proved too toxic to move forward,” Dr. Urba said. “These are two very important drugs for patients with advanced melanoma that will continue to be used safely as single agents and other strategies to combine them sequentially, or on a different schedule, are likely to be developed. I don’t think we have heard the last comment about how these two drugs might be combined safely for the benefit of patients with advanced melanoma,” he said, and it may also be possible to combine vemurafenib with other targeted agents, like an MEK inhibitor, he said. “The big question is after a year, or two, or three, has the combined approach led to more disease-free survivors, or have tumors developed resistance to two targeted agents instead of one? All those studies are a bit early to evaluate, but the results appear to be better than what we have seen with single-agent therapy.”
Study of ipilimumab and vemurafenib, according to Dr. Fox, has motivated researchers to further invest time and hope in patient-targeted therapies with powerful new drugs. [pagebreak]
“These therapies continue to exemplify the advances of bench-to-bedside translational medicine. More and more is being discovered about the molecular profiles of melanoma, and a future of patient-specific targeted therapy is increasingly in focus,” Dr. Fox said. “Several novel targeted therapies are on the horizon, including novel BRAF inhibitors; MEK-inhibitors, which target the BRAF pathway downstream of vemurafenib; and targeted immunomodulatory agents such as PD-1 inhibitors, which have been shown to enhance anti-tumor immunity. Clinical trials investigating the effectiveness of these and other therapies are currently underway.” Apart from advanced melanoma, researchers have seen promising patient responses in lung and ovarian cancer cases — diseases not typically known as responsive to immune system manipulation — treated with PD-1 inhibitors.
“We’re making progress, bit by bit,” Dr. Weinstock said. “Obviously, we’re still hoping for a treatment that’s a cure, but with at least one of these agents, combination therapy seems to be showing quite a bit of promise. Ultimately, that could be the way that we use both [ipilimumab and vemurafenib]. This is all wonderful news for our patients, and for us as physicians in being able to increase their survival rates and work toward a cure.”
Editor’s note: Dr. Hamid has received grants from Bristol-Myers Squibb and Medarex and served as an advisor and consultant to Bristol-Myers Squibb, Lilly, and Medarex. Dr. Urba is an advisor and consultant to Bristol-Myers Squibb and Medarex. Dr. Weinstock is a consultant to Abbott, Celgene, Genentech, Idera Pharmaceuticals, Merck & Co., and Roche Laboratories. Dr. Fox has no financial interests related to his comments.
Dermatologists are required by law to report all new cases of melanoma to their state’s central cancer registry, but regional studies, including a recent one in Arizona (see January Dermatology World, p. 6) demonstrate significant underreporting to state registries. Underreporting of melanoma results in the underestimation of the true incidence of this disease, which in turn inhibits governmental ability to respond in a timely fashion with public health initiatives.
This reporting requirement is separate from the Medicare Physician Quality Reporting System (PQRS), and is mandated by state laws in all 50 states. These laws require that all cases of melanoma be reported to the state registry when diagnosed by a health care provider, laboratory, or hospital. Required reporting enables states to identify disease trends, track disease outbreaks, and aid in preventive measures.
To learn more about the requirements and find your state’s registry, visit the Academy’s melanoma registry finder at www.aad.org/education-and-quality-care/performance-measurement-and-quality-reporting/melanoma-reporting-to-state-cancer-registries.