Phase I clinical trial results indicate that concurrent nivolumab and ipilimumab can produce rapid and long-lasting regression of metastatic melanoma. The findings, published in the New England Journal of Medicine on June 2 and presented at the 2013 meeting of the American Society of Clinical Oncology (ASCO), also indicated that these results were achieved with a manageable safety profile.This kind of deep and rapid tumor regression has never been seen in melanoma using immunotherapy, and suggests that these two drugs might be better used in combination than alone.
Preclinical testing indicated that the two agents would prove to be complementary, with ipilimumab (CTLA-4) blocking the inhibitory marker, activating the immune system, and prompting T cells to start attacking the tumor. By blocking PD-1, nivolumab further activates T cells in a different manner, allowing them to continue the immune system attack.
The US Food and Drug Administration approved ipilimumab for the treatment of advanced melanoma in 2011.
Fifty-three percent of participants in one cohort, which had concurrent nivolumab at 1 mg/kg combined with ipilimumab at 3 mg/kg, experienced tumor shrinkage of more than 80 percent within 12 weeks of receiving the drug combination, and the shrinkage was long-lasting.
Forty percent of the participants who received varying concurrent dosages had a more than 50 percent reduction in tumor size.
Side effects from the drug combination were manageable and often reversible.
Eighty-six participants were enrolled and assigned to one of the following protocols between December 2009 and February 2013.
Successive cohorts of patients were treated concurrently with nivolumab and ipilimumab every three weeks for four doses, followed by nivolumab alone every three weeks for four doses. Combined treatment was subsequently continued every 12 weeks for up to eight doses.
Two cohorts of patients previously treated with ipilimumab received nivolumab alone every two weeks.
After treatment, participants without confirmed disease progression were followed for up to 2.5 years.
Participants who experienced a complete response, a partial response, or a stable disease for more than 24 weeks and subsequent disease progression were given the option of being retreated with the original regimen.
A randomized phase III trial of the nivolumab-ipilimumab combination for patients newly diagnosed with advanced melanoma is scheduled to begin in June 2013.
The current research was supported by Bristol-Myers Squibb Inc. and Ono Pharmaceutical Company Ltd.