A randomized phase III trial indicates that initial therapy with nivolumab alone or in combination with ipilimumab is significantly more effective than ipilimumab alone. Nivolumab alone more than doubled the average time to disease progression, compared to ipilimumab (6.9 months vs. 2.9 months), and the benefit was even greater when ipilimumab and nivolumab were combined (11.5 months). The response rates were also substantially higher in patients receiving the combination therapy (57.6%) and nivolumab (43.7%) alone, as compared to ipilimumab (19%).
"We're very encouraged that the initial observations about the efficacy of this combination held up in this large phase III trial," said lead study author Jedd Wolchok, MD, PhD, Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York, NY. "Our study also suggests that patients with a specific tumor marker appear to benefit the most from the combination treatment, whereas other patients may do just as well with nivolumab alone. This will help doctors provide important insight for patients on which treatment is right for them."
Nivolumab and ipilimumab are monoclonal antibodies that block two different immune checkpoints ─ PD-1 and CTLA-4, respectively. Both treatments, commonly referred to as checkpoint inhibitors, essentially boost the immune system's ability to fight cancer.
Prior research has shown that immune checkpoint inhibitors can improve survival for patients with melanoma and lung cancer. Both ipilimumab and nivolumab are FDA-approved for use as single agents in patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma that no longer responds to other drugs.
This study randomly assigned 945 patients with previously untreated, advanced melanoma to receive ipilimumab, nivolumab, or the combination of the two. After a follow-up period of at least nine months, the median progression-free survival was 2.9 months for ipilimumab, 6.9 months for nivolumab, and 11.5 months for the combination. The differences between the combination and ipilimumab groups, and nivolumab and ipilimumab groups were statistically significant.
The response rates for the combination, nivolumab, and ipilimumab groups were 57.6%, 43.7%, and 19%, respectively. The average reductions in tumor burden (depth of response) were 52% with the combination and 34% with nivolumab alone. In contrast, patients who received ipilimumab alone experienced a 5% increase in tumor burden.
As expected, the rate of serious drug-related side effects was the highest in the combination group (55%), and 36% of patients in this group had to stop the therapy due to side effects. Dr. Wolchok remarked that prior studies have shown that many patients who stop immunotherapy early still continue to do well.
This prolonged benefit is explained by the fact that immunotherapy works by activating the immune system rather than targeting the tumor directly. It is not yet clear how long patients need to be treated to fully activate the immune system, and the minimal duration of therapy probably varies from patient to patient.
Quality of life data were collected on the study, and the analysis of those results will be reported at a later time.
PD-L1 Status May Help Define Optimal Treatment
The PD-1 protein on immune cells attaches to another protein called PD-L1, which is sometimes found on the surface of some tumor cells. Prior research suggested that patients who had detectable PD-L1 levels in their tumor (PD-L1-positive tumors) typically had better responses to PD-1 therapy.
In this study, nivolumab alone seemed to be as effective against PD-L1-positive tumors as the combination of nivolumab and ipilimumab. For patients with PD-L1-negative tumors, however, the combination treatment was significantly more beneficial than nivolumab alone.
This study received funding from Bristol-Myers Squibb.