Evolving melanoma treatments: Field is 'work in progress'; hope is on the horizon

July 1, 2008

Despite years of clinical trials involving cytotoxics, DNA-damaging agents, immunomodulatory therapies and other interventions, the natural history of melanoma has changed very little. However, new treatments offer hope.

Key Points

National report- Despite years of clinical trials involving cytotoxics, DNA-damaging agents, immunomodulatory therapies and other interventions, the natural history of melanoma has changed very little. Even the two agents approved by the Food and Drug Administration (FDA) - interleukin-2 and dacarbazine (DTIC) - produce responses in only about 15 percent of patients.

"Melanoma is the malignant histology that gives oncology a bad name," says Jeffrey S. Weber, M.D., head of the Melanoma Center of Excellence at H. Lee Moffitt Cancer Center, Tampa, Fla.

New hope

Much of the optimism is being pinned on the monoclonal antibodies directed against cytotoxic T-lymphocyte antigen-4 (anti-CTLA4 antibodies), ipilumumab and tremelimumab.

Jedd Wolchok, M.D., of Memorial Sloan-Kettering Cancer Center, New York, describes CTLA-1 as a "brake" on the immune system cells that prevents hyperactivation of the immune system. Anti-CTLA4 antibodies temporarily release this brake to enable the immune system to fight the tumor.

Such agents work differently from chemotherapy, and may take longer to have an effect, says Dr. Wolchok, who has conducted studies on ipilimumab.

Advanced melanoma patients treated with ipilimumab had one-year projected survival rates ranging from 47 percent to 53 percent, depending on dose, and median overall survival of 10.2 to 14.6 months.

In treatment-naïve patients, survival approached 60 percent, and median overall survival has not been reached, according to studies reported at the meeting by the Global Ipilimumab Melanoma Study Group at the Angeles Clinic and Research Institute, Santa Monica, Calif.

"These studies are particularly important in light of recent literature showing median overall survival of six to nine months and one-year survival rate of 25 percent to 35 percent for patients with stage III or IV metastatic melanoma," says Steven J. O'Day, M.D., one of the investigators and chief of research at the institute.

"The ipilimumab data offer insights that we can potentially harness the immune system to fight cancer," Dr. O'Day tells Dermatology Times.

The news for tremelimumab, however, was not so good. The agent failed to show an improvement in overall survival compared to standard therapy, and a phase 3 study by Ribas et al was stopped early due to treatment futility.

Negative results were also reported for the adjuvant ganglioside GM2-KLH21 vaccine in the EORTC 18961 trial.

But outcomes were better for the GM-CSF-encoding oncolytic virus OncoVex, which, when directly injected into the tumor, produced a 32 percent response rate (even in distant metastases) and durable effects.

The tyrosine kinase inhibitor axitinib also produced impressive results, with a median survival of 13 months in an unselected population.

New focus of drug development

Progress has not occurred without fits and starts. The focus of drug development has traditionally been on the Ras/Raf/mitogen-activated protein (MAP) kinase cascade, but clinical trials of agents targeting this pathway have been disappointing.

Attention has turned to other approaches.

Recently, the molecular alterations within melanoma cells have become better understood. Two categories to target include metabolic enzymes expressed in the tumor microenvironment, and developmental signaling pathways active in aggressive tumors.

Strategies to interfere with these signals are posed for translation into the clinic, says Thomas F. Gajewski, M.D., Ph.D., associate professor of pathology and medicine, University of Chicago, who discussed novel pathways at an ASCO educational session.

Factors involved in metabolic alterations in the microenvironment, and possible therapeutic targets, include inducible nitric oxide synthase (iNOS), indoleamine-2, 3-dioxygenase (IDO) and arginase.

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