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From OncoLog, January 2011, Vol. 56, No. 1

Compass: Metastatic Melanoma
Experimental treatments could be preferable to standard therapies for metastatic melanoma

By Sunni Hosemann

Introduction

Melanomas, which arise from melanocytes, are the most aggressive form of skin cancer.

Fortunately, most melanomas are discovered at an early stage when they are highly curable by surgery alone. According to data from the U.S. Surveillance, Epidemiology, and End Results program, 84% of cutaneous melanomas are discovered while localized, and for these patients, the 5-year relative survival rate is 98%.

Patients whose melanoma has spread to regional lymph nodes (stage III; about 8% of cases) have a 5-year relative survival rate of about 62%, and patients whose cutaneous melanoma is unstaged at diagnosis (about 4% of cases) have a 5-year relative survival rate of 76%. Patients who present with metastatic disease (stage IV; about 4% of cases) have a 5-year relative survival rate of only about 16%.

Types of melanoma

Although most melanomas occur on the skin surface, approximately 7% of primary melanomas are noncutaneous, according to Scott Woodman, M.D., Ph.D., an instructor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center. Noncutaneous melanomas occur most often in the eye and mucous membranous sites such as the anus, rectum, vulva, vagina, nasal sinuses, and mouth. These tumors are associated with poorer prognoses than are cutaneous melanomas.

Noncutaneous melanomas tend to go undetected until they reach an advanced stage because they are hidden deep in the eye or in mucosa, where they cause no early symptoms. These locations also offer access to relatively rich vascular and/or lymphatic environments, enabling noncutaneous melanomas to spread more quickly than their cutaneous counterparts. Furthermore, genetic differences between cutaneous and noncutaneous melanomas cause them to have different biological behaviors and to respond differently to treatment.

According to Kevin Kim, M.D., an associate professor in the Department of Melanoma Medical Oncology, even cutaneous melanomas can differ significantly depending on where on the skin they occur and the degree of sun damage to the skin. In addition, the invasiveness of cutaneous melanomas may vary according to histological subtype; nodular melanomas are more invasive—and therefore more aggressive—than are superficial spreading, lentigo, and acral lentiginous melanomas. “Melanoma is not a single entity,” Dr. Kim said, “and this means that more tailored treatments are needed.”

Standard treatment options

“The average survival for patients with stage IV metastatic melanoma is 6–10 months,” said Michael Davies, M.D., Ph.D., an assistant professor in the Department of Melanoma Medical Oncology, “and this hasn’t changed for 30 years.”

The current standard treatment for metastatic melanoma is chemotherapy with dacarbazine, which has been shown to shrink tumors in only 10%–15% of patients who receive it. Unfortunately, this effect rarely persists more than a few months as chemoresistance develops. “In short, even though dacarbazine’s toxicity is relatively mild and the drug may prolong survival by a short time for a few patients, it’s not much better than supportive care for the majority of patients with metastatic melanoma,” Dr. Davies said.

High-dose bolus interleukin-2 (IL-2) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 1998. IL-2 is an immunomodulatory agent that acts by stimulating the immune system to attack the cancer cells. IL-2 has been shown to achieve rates of tumor reduction similar to those with dacarbazine, but about half the patients who respond to IL-2 have a complete response—a durable disease remission for more than 10 years. Most patients who achieve a complete response subsequently remain free of melanoma for the rest of their lives. However, according to Dr. Davies, IL-2 is among the most toxic of cancer treatments, with marked side effects and a significant risk of life-threatening adverse events. For these reasons, treatment with high-dose IL-2 requires hospitalization in a cardiac monitoring or intensive care setting at a center experienced in the agent’s administration, with cardiopulmonary specialists available. Despite these precautions and the use of IL-2 being limited to patients with excellent health and functionality, the treatment itself has a 1%–2% mortality rate.

“IL-2 is a wonderful treatment for those patients who are able to achieve a complete response and may therefore be cured of this aggressive disease,” Dr. Davies said. “Unfortunately, however, we don’t yet know how to identify those rare patients who have the best chance to benefit from this highly toxic treatment.”

Currently, IL-2 treatment can be considered only for patients who are in otherwise excellent health and only after extensive discussion of the risks and benefits of this treatment. Patients with brain metastases should be monitored with extra caution while receiving IL-2 because of the potential for edema at the tumor sites and because historical data reveal particularly low response rates to IL-2 in these patients. Interferon alfa-2b—which, like IL-2, is an immunotherapy agent—is approved by the FDA as an adjuvant treatment for patients with stage II melanoma and primary tumors more than 4-mm thick or with stage III melanoma.

Interferon alfa-2b has been shown to delay recurrence in these patients, but in most clinical studies it has not improved overall survival durations. Current studies are exploring whether interferon alfa-2b could be effective against metastatic melanoma if used in combination with chemotherapeutic agents or new immunotherapies.

Like IL-2, interferon alfa-2b involves a challenging and lengthy treatment. Interferon therapy consists of an induction phase requiring intravenous infusions five times a week for 4 weeks followed by a 48-week course of subcutaneous injections three times a week. This treatment is associated with a variety of side effects, such as flu-like symptoms, liver toxicity, and psychiatric disturbances. “With the questionable benefits of interferon therapy for improving survival in patients,” Dr. Davies said, “the side effect profile and quality of life are important considerations for patients and physicians.”

Clinical trials

Because of the limited survival benefits from the FDA-approved treatments, most experts agree that clinical trials are the best option for patients with metastatic melanoma. However, even in clinical trials, progress has been slow. Not only have some promising approaches failed, but because metastatic melanoma is relatively uncommon, there have been few large, randomized trials. Nevertheless, investigators strive to develop treatment approaches that have the greatest chance of success, building upon research that has provided an improved understanding of the molecular underpinnings of melanoma.

“We want to be able to match the right patients with the right treatments,” Dr. Davies said. To make this possible, researchers at MD Anderson and other institutions have been working to identify the molecularly defined subtypes of melanoma and the ideal treatment for patients in each group.

According to Dr. Woodman, researchers have recently identified key genetic mutations in melanoma. “This is important because it provides us with the opportunity to target these tumors with specific agents,” he said.

Approximately 60% of patients with cutaneous melanomas have mutations in the BRAF gene. These mutations occur most frequently in tumors arising from skin surfaces with intermittent sun damage. Another 20% of cutaneous melanomas have NRAS mutations (which exclude BRAF). There are fewer BRAF mutations in tumors arising from non–sun-damaged areas of the skin (i.e., palms of hands, soles of feet), from chronically sun-damaged skin, and from mucosal sites. Mutations in the KIT gene are found in some of these less common melanomas, including mucosal and acral melanomas.

The identification of KIT mutations in these subtypes of melanoma has led to multiple ongoing phase II clinical trials in which melanoma patients are treated with FDA-approved agents that inhibit activated KIT in other cancers. For example, Drs. Kim and Woodman have designed a novel phase II trial to test the molecular effect of dasatinib in patients with mucosal and acral melanoma.

Other studies are under way to test experimental agents that target the mutant BRAF protein in patients with melanoma. PLX4032, an oral medication that selectively and potently inhibits the most common BRAF mutation, achieved clinical responses in more than 80% of patients with stage IV or unresectable stage III melanoma in a recent phase I clinical trial. “These results are unprecedented,” Dr. Davies said. “When you consider that the FDA-approved therapies for metastatic melanoma achieve clinical responses in only 10%–15% of patients, this trial demonstrates the dramatic potential of personalized, targeted therapies to revolutionize the treatment of this disease.” The results of the trial supported the specificity of PLX4032 for the mutant BRAF protein, as no patients who had a normal BRAF gene responded to the medication. The treatment was extremely well tolerated; a rash was the most common side effect. Phase II and III trials of PLX4032 are under way.

In early studies of another BRAF inhibitor, GSK2118436, researchers have reported similar efficacy and toxicity to that of PLX4032. While the clinical activity and limited toxicity of these targeted therapies are promising, investigators are working to improve these treatments further.

Some patients have developed new cancers of the skin as a side effect of the BRAF inhibitors. Although these tumors—which were not melanomas—were controlled with surgical removal and have not required any responding patient to discontinue BRAF inhibitor therapy, investigations are ongoing to understand why these tumors develop and how to prevent them. Another concern is that although the overwhelming majority of melanoma patients with BRAF mutations who have received BRAF inhibitors initially responded to the medication, most patients eventually develop clinical resistance to the drugs, and their tumors start growing again. “Resistance appears to develop in some patients after 7–8 months,” Dr. Davies said, “so we are looking into why that might be and considering ways to make the effects last, perhaps with combinations.”

There are a variety of combinatorial approaches being considered to combat resistance to the BRAF inhibitors, including the addition of targeted therapies against other pathways that may be activated concurrently with BRAF. Other combinations might include agents with completely different mechanisms of action, such as immunotherapy agents. Ipilimumab, a monoclonal antibody, activates T cells and has shown promise against metastatic melanoma when used alone and in combination with vaccine therapy. In a phase III trial comparing ipilimumab to the GP100 peptide vaccine in patients whose metastatic melanoma had not responded to first-line treatments, the average survival duration increased from 6 months to 10 months. “It was the first time in melanoma that an experimental drug increased survival over the control drug,” said Dr. Kim, who believes ipilimumab may have a role in future combination therapies. While ipilimumab does have the potential to cause autoimmune side effects, it does not pose the same acute cardiovascular risks as IL-2; therefore, ipilimumab can be administered safely as an outpatient treatment and potentially made available to more patients than is IL-2.

Another immune-based approach, adaptive T cell therapy, is being developed at MD Anderson under the direction of Patrick Hwu, M.D., a professor in and chair of the Department of Melanoma Medical Oncology. Dr. Kim explained that the therapy involves harvesting T cells from the patient’s tumor. The T cells are multiplied in the laboratory, and then billions of the cells are transfused back into the patient. These T cells specifically target the tumor but are not numerous or strong enough to eradicate it. To help these tumor-specific T cells proliferate in the bloodstream, patients are given chemotherapy to deplete ordinary T cells prior to the tumor-specific T cells’ reintroduction and given high-dose IL-2 to stimulate T cell growth after the T cells’ reintroduction. “Nearly 50% of patients with metastatic melanoma have had a clinical response to adaptive T cell therapy so far,” said Dr. Kim, who added that the therapy is still experimental.

These avenues of research represent important advances for patients with metastatic melanoma, for whom the current standard treatments have been woefully ineffective and/or highly toxic.

“This is a very exciting time in the history of a disease for which there have been few options,” said Dr. Woodman. “I’m optimistic that the treatment choices in 5–10 years will be very different than the ones I’ve seen thus far in my career as an oncologist.”

References

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Melanoma V1.2011.
Altekruse SF, Kosary CL, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2007. Bethesda, MD: National Cancer Institute, 2010.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-723. Erratum in: N Engl J Med 2010;363(13):1290.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363(9):809-819.
Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24(26):4340-4346.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Michael Davies, M.D., Ph.D.
Assistant Professor, Melanoma Medical Oncology

Kevin Kim, M.D.
Associate Professor, Melanoma Medical Oncology

Scott Woodman, M.D., Ph.D.
Instructor, Melanoma Medical Oncology

For more information on this topic or for questions about MD Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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