Investigational drug may increase survival of advanced melanoma

An experimental drug aimed at restoring the immune system's ability to spot and attack cancer halted cancer progression or shrank tumors in patients with advanced melanoma, according to a multisite, early-phase clinical trial. All patients had experienced disease progression despite prior systemic therapies, and most had received two or more prior treatments.

The patients who showed responses to the drug, nivolumab (anti-PD-1; BMS-936558; MDX-1106; ONO-4538), survived for an average of 16.8 months following initiation of treatment. Overall, 62% of patients (66 of 107) were alive 1 year following treatment initiation, and 43% (46 of 107) were alive 2 years later. Average survival among 33 patients (31%) whose tumors shrank significantly was 2 years. The drug is now being tested in three larger, phase 3 trials in melanoma, which generally compare a new therapy with a standard one currently in use.

Results of this study were published in the Journal of Clinical Oncology (2014; doi:10.1200/JCO.2013.53.0105).

"The results seen here are remarkable for these patients with treatment-resistant, advanced metastatic melanoma, who had limited life expectancies when they joined the trial," said study lead-author Suzanne Topalian, MD, professor of surgery and oncology, and director of the melanoma program at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

The immune-based therapy aims not to kill cancer cells directly, but to block a pathway that shields tumor cells from immune system components that are potentially able and poised to fight cancer. The pathway includes two proteins called programmed death-1 (PD-1), expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), expressed on cancer cells.

When PD-1 and PD-L1 join together, they form a biochemical shield protecting tumor cells from being destroyed by the immune system. Another protein involved in the pathway, which is expressed by some tumors and by cells in the immune system, is programmed death ligand (PD-L2).

A total of 107 people with advanced melanoma were given the medication, which is administered intravenously in an outpatient clinic every 2 weeks. Results suggest that some patients can safely remain on the treatment for up to 2 years. Participants received doses of 0.1, 0.3, 1, 3, or 10 mg/kg in 12 or fewer 8-week cycles of treatment. Investigators observed responses at all doses, though the highest response rate was in 7 of 17 (41%) patients receiving 3 mg/kg, the dose now being tested in phase 3 trials. Participants given that amount survived an average 20.3 months following treatment initiation.

Drug-related adverse events occurred in 84% of patients; 22% had serious side effects. Among the most common serious side effects were lymphopenia (low levels of infection-fighting white blood cells circulating in the blood), diarrhea, fatigue, and endocrine disorders. Each affected 1% to 3% of participants. There were no drug-related deaths in patients with melanoma receiving nivolumab.

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