A Phase III randomized study found that first-line treatment with a combination of the immunotherapy drug ipilimumab (Yervoy?, Bristol-Myers Squibb) and the standard chemotherapy drug dacarbazine (DTIC) improves overall survival in patients with previously untreated metastatic melanoma.

The results were presented today at the 47th annual meeting of the American Society of Clinical Oncology (ASCO). This is the first study to show that combining chemotherapy and immunotherapy is safe and effective for patients with advanced melanoma. At the 2010 Annual ASCO Meeting, ipilumumab was shown to improve survival when compared to a melanoma vaccine, gp100.

?These findings show the same kind of important results announced last year with the use of ipilimumab alone in improving overall survival in metastatic melanoma,? said lead author Jedd Wolchok, MD, director of immunotherapy clinical trials and associate attending physician at Memorial Sloan-Kettering Cancer Center in New York. ?This trial?s three-year endpoint is significant. No randomized trial for metastatic melanoma has followed patients for this long, and it demonstrates the durability of this survival benefit, now out to three years in this population, and even four years in some cases. It?s one of the advantages of immunotherapy. The immune system is a ?living drug,? able to adapt itself to changes in the tumor that might otherwise lead to resistance when treated with chemotherapy or a pathway inhibitor.?

Advanced melanoma is one of the most deadly forms of cancer, and over the past three decades, melanoma incidence has climbed faster than any other cancer type. Ipilimumab is a monoclonal antibody that represents a new class of drugs that activate the immune system?s T cells, which then seek and destroy melanoma cells. The drug, which recently received U.S. Food and Drug Administration approval for use as a single-drug therapy in advanced melanoma, targets the cytotoxic T-lymphocyte associated antigen 4, which acts like a brake on the T-cell. Ipilimumab removes this brake, enabling T cells to attack the cancer.

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In this study, 502 patients with metastatic melanoma were randomized to ipilimumab plus dacarbazine (250) or placebo and dacarbazine (252). The overall survival rate for the combination after one year was 47.3% compared to 36.3% for DTIC alone. After two years, the overall survival rate was 28.5% for the two drugs, versus 17.9% for DTIC alone. At three years, overall survival was 20.8% for the combination compared to 12.2% for chemotherapy alone.

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Investigators found that the median overall survival was 11.2 months for patients who received ipilimumab and DTIC versus 9.1 months for those given only DTIC. The median progression-free survival times, however, were nearly the same: 2.8 months for the combination compared to 2.6 months for DTIC. Wolchok attributed this finding to the way ipilimumab ? and immunotherapy ? may work. The effects of immunotherapy treatment can take much longer to be seen than those from traditional chemotherapy or targeted therapies, and patients? scans may sometimes even get worse before they improve, he said. As a result, overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival.

The combination of ipilimumab and dacarbazine had a good safety profile, with no gastrointestinal perforations and a lower rate of colitis than was expected based upon prior studies with ipilimumab alone. Still, approximately 56 percent of patients in the ipilimumab-DTIC group and 27% of those who received only DTIC had significant grade 3/4 adverse events from their therapy, including elevated liver enzymes.

The next step in the research, according to Wolchok, is to investigate combinations of different therapies with ipilimumab, such as the targeted drug vemurafenib in melanoma patients with BRAF mutations, and to test other combinations of targeted agents and immune-modifying agents together as well.

For more information:
Study Authors: Wolchok JD, Thomas L, Bondarenko IN, O’Day S, Weber JS, et al.
Abstract title: Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs DTIC alone as first line treatment in patients with unresectable stage III or IV melanoma
Abstract: # LBA5

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