Results from a phase III clinical trial indicate that the addition of Genasense® (oblimersen) to dacarbazine provides a significant survival benefit in patients with stage III or IV melanoma. The benefit, however, was only present in patients with normal levels of the enzyme lactate dehydrogenase (LDH). These results were presented at the 2005 annual Chemotherapy Foundation Symposium in New York.
Melanoma is a cancer of the skin that usually begins in the form of a mole. The cancer can grow deep into the skin and spread to different parts of the body through blood or lymph vessels. It usually spreads first to lymph nodes that are near the site of cancer origin and, when advanced, can spread to organs and other lymph nodes throughout the body.
The prognosis for patients diagnosed with metastatic melanoma is poor since this disease typically does not respond well to standard therapies. In an effort to improve outcomes for metastatic melanoma, new drugs and new drug combinations are being explored.
Dacarbazine is a chemotherapy drug that is FDA approved for the treatment of metastatic melanoma. It belongs to a class of drugs known as alkylating agents. Dacarbazine works against cancer by causing a chemical reaction that damages the DNA in a cell. The DNA damage caused by dacarbazine inhibits protein synthesis and results in cellular death.
Genasense is a drug that targets the bcl-2 protein. This protein is crucial for melanoma cells to survive and is overexpressed in more than 80% of patients with melanoma. Laboratory studies also suggest that bcl-2 may be involved in cancer resistance to chemotherapy.
In order to evaluate whether treatment of metastatic melanoma with the combination of Genasense and dacarbazine results in better survival than treatment with dacarbazine alone, researchers conducted a multi-national phase III clinical trial. The trial enrolled 771 patients with stage III or IV melanoma who had not received prior chemotherapy. Patients were randomly assigned to receive Genasense plus dacarbazine or dacarbazine alone. All patients have been followed for at least two years since the start of the study. The study included measurement of blood levels of the enzyme LDH. High levels of LDH are linked to tissue damage.
- Overall, there was not a significant difference in survival between the two groups of patients-median survival was 9 months for patients treated with Genasense plus dacarbazine versus 7.8 months for patients treated with dacarbazine alone.
- Among patients with normal LDH levels, survival was better among patients treated with Genasense plus dacarbazine (11.4 months) than among patients treated with dacarbazine alone (9.7 months). Furthermore, 17.2% of the patients treated with Genasense plus dacarbazine had a reduction in detectable cancer, compared to 9.3% of patients treated with dacarbazine alone.
- Among patients with high LDH levels, survival was similar in the two study groups (4.5 months in both groups), as were response rates (5.7% among patients receiving Genasense plus dacarbazine and 4.6% among patients receiving dacarbazine alone).
The researchers concluded that the combination of Genasense and dacarbazine offers promise for the treatment of metastatic melanoma among patients with normal LDH levels, but does not appear to benefit patients with high LDH levels.
Reference: Haluska F, Kirkwood J, Bekikian A, et al. Final Results of a Randomized Multinational Phase 3 Trial of Dacarbazine (DTIC) with or without Oblimersen Sodium (BCL-2 Antisense;Genasense) in Patients with Advanced Melanoma. Proceedings from the 2005 Chemotherapy Foundation Symposium. New York. Abstract #23.