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 at Johns Hopkins Kimmel Cancer Center and 11 other institutions. All patients had experienced disease progression despite prior systemic therapies, and most had received two or more prior treatments.

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

Results of the study are published online March 3 in the Journal of Clinical Oncology.

"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," says study lead-author Suzanne Topalian, M.D., professor of surgery and oncology, and director of the melanoma program at Johns Hopkins.

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, that is expressed by some tumors and by cells in the immune system, is programmed death ligand (PD-L2), which was discovered by Johns Hopkins investigators in 2001.

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

Drug-related adverse events occurred in 84 percent of patients; 22 percent 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 1-3 percent of participants. There were no drug-related deaths in patients with melanoma receiving nivolumab.

Several companies also are investigating anti-PD1 agents or anti-PD-L1 agents in the treatment of cancers, including melanoma.

Ultimately, investigators envision boosting the effectiveness of the therapy by combining it with other anticancer agents, including cancer vaccines, other immunotherapies, or drugs that block enzymes called kinases, the researchers say.

In addition to Topalian, co-authors on the study were William Sharfman, Julie Brahmer, Evan Lipson, Janis Taube and Drew Pardoll from Johns Hopkins; Mario Sznol and Harriet Kluger from Yale's Smilow Cancer Center; David McDermott from Beth Israel Deaconess Medical Center; Donald Lawrence from Massachusetts General Hospital Cancer Center; F. Stephen Hodi from Dana Farber Cancer Institute; Richard Carvajal from Memorial Sloan-Kettering Cancer Center; Michael Atkins from Georgetown-Lombardi Comprehensive Cancer Center; John Powderly from Carolina BioOncology Institute; Philip Leming from The Christ Hospital Cancer Center; Igor Puzanov and Jeffery Sosman from Vanderbilt University Medical Center; David Smith from the University of Michigan Comprehensive Cancer Center; and Jon Wigginton, George Kollia and Ashok Gupta from Bristol-Myers Squibb.

Nivolumab is being developed and manufactured by Bristol-Myers Squibb, which provided funding for the trial along with Ono Pharmaceuticals Co., Ltd. Topalian has served as an uncompensated consultant to Bristol-Myers Squibb and has received research support from the company. Sharfman has served as a consultant to Merck. Brahmer has served as an uncompensated consultant and received research funding from Bristol-Myers Squibb. Pardoll has served as a consultant (uncompensated) to Bristol-Myers Squibb, Jounce Therapeutics, Amplimmune and sanfo-aventis; received research funding from Bristol-Myers Squibb and owns patents related to technology involved in the B7-DC antibody. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.