Results from a phase I trial combining two immunotherapy antibodies—the already-approved ipilimumab (Yervoy) and the still experimental nivolumab—suggest combining the agents may benefit advanced melanoma patients even more than either agent alone. Jedd Wolchok, MD, PhD, medical oncologist and immunotherapy and melanoma expert at the Memorial Sloan Kettering Cancer Center in New York City presented the data at an American Society of Clinical Oncology (ASCO) press meeting on May 15, 2013. The full results from the trial will be presented at the annual ASCO meeting this June.
Based on the findings, a phase III clinical trial in advanced melanoma patients who have not been previously treated for their metastatic disease will directly compare the combination therapy to either ipilimumab or nivolumab alone. The trial will enroll more than 900 patients and is slated to open this year.
In the ongoing phase I trial, 52 melanoma patients received combination therapy. Patients were divided into subgroups and were treated with different dosage combinations. Seventeen patients received a 1-mg/kg dose of nivolumab combined with the FDA-approved 3-mg/kg dose of ipilimumab. Fifty-three percent of these patients had an objective response—meaning at least 50% shrinkage of existing tumors. At other dosage combinations, response rates ranged from 21% to 53%. Of the patients who responded to the combination, 90% have continued to have a response. Because the 1 mg/kg nivolumab plus 3 mg/kg ipilimumab combination was most successful, it will be tested in the phase III trial.
In contrast to the 53% objective response results, the average objective response in previously treated late-stage melanoma patients treated with ipilimumab alone is about 11%, according to a phase III trial. Response rates in a similar patient population treated with nivolumab are 41%, according to a large phase I trial published last year.
These new results show that more patients can achieve a complete response with the combination compared to less than 3% for patients in trials of ipilimumab or nivolumab alone. “What was unique here was that most responding patients had rapid and deep regressions, with many showing more than 80% tumor regression by the time of [first patient evaluation],” Wolchok said.
Both nivolumab and ipilimumab are antibodies that block distinct but related molecules on T cells—immune cells that help the body fight infections, as well as cancer. Nivolumab blocks activity of the PD-1 molecule while ipilimumab inhibits the CTLA-4 molecule. Nivolumab as a single-agent immunotherapy is not yet FDA-approved—it is being evaluated in several phase III trials, including one for metastatic melanoma patients.
Both antibodies promote full activity of molecular pathways that enhance antitumor T-cell responses by blocking two molecular breaks of the immune system. “By blocking these breaking pathways, ipilimumab and nivolumab each result in immune activation in different ways,” Wolchok said during the press briefing.
The researchers reasoned that, because both antibodies modulate the immune system in different ways, the combination could work better than either agent alone. “The rationale for combining [the two therapies] is based on preclinical and animal studies showing that the combination produces better results than either one alone,” Wolchok said.
Patients treated with ipilimumab or nivolumab can have immune-related side effects such as colitis, skin rash, and hepatitis. It was initially not clear whether combining these two immunomodulators would magnify these types of side effects. The data so far shows that the combination is indeed safe—all toxicities were manageable and reversible with either dose lowering or prolonging the time between doses. Grades III-IV toxicities that were immune system-related occurred in 53% of the patients. The most common ones were elevation in lipase and in the liver enzymes AST and ATL, which occurred in 11% to 13% of patients. Patients did not experience symptoms from these liver-related effects.
“The antitumor activity in this trial is reaching levels we did not expect any immunotherapy would ever be able to reach,” said Antoni Ribas, MD, PhD, melanoma clinician and researcher at the Jonsson Comprehensive Cancer Center in Los Angeles, California. Ribas cautioned that there are significant toxicities in more than half of the patients. “It will be of great importance to understand if the antitumor activity is higher than what would be expected with nivolumab alone, or a sequence of nivolumab and ipilimumab, since it is quite clear that the toxicities are higher when [the agents are given together].”