Combination immunotherapy significantly more effective for patients with advanced melanoma

The power of the immune system if we can remove the “brakes”
May 4, 2015

A melanoma (credit: Wikimedia Commons)

Researchers from Memorial Sloan Kettering Cancer Center (MSK) are reporting exciting results in the field of cancer immunology.

Positive results from a clinical trial published in The New England Journal of Medicine show that the combination of the immunotherapy drugs ipilimumab (Yervoy) and nivolumab (Opdivo) produced significantly better outcomes than ipilimumab alone in patients with advanced melanoma.

A second piece in the same issue from MSK details a dramatic response occurring after a single dose of the combination therapy.

The response rate based on significant tumor shrinkage was 61 percent in patients receiving the combination therapy compared with 11 percent in patients receiving ipilimumab plus placebo. Patients receiving both drugs also lived longer without their disease progressing. Side effects of the combination therapy were more than those for patients receiving ipilimumab alone, but side effects were manageable.

High chance of significantly shrinking melanoma

“The incredibly high response rate seen in this trial for patients receiving the combination, approximately 60 percent, now lets us tell patients that they have a high chance of significantly shrinking their melanoma with this treatment.” said lead author Michael Postow.

“More research is still needed, however, to know if it is necessary to give all patients this combination or if patients should receive drugs like nivolumab and ipilimumab in sequence.”

“We are excited about these results and believe they support the principle that rationally combining effective medicines is an approach to achieving better outcomes for patients,” explained senior author Jedd Wolchok.

Power of the immune system: tumor disappears in three weeks

In addition to this study, NEJM published a letter written by medical oncologists Paul Chapman, Sandra D’Angelo, and Jedd Wolchok that describe the remarkable effect of the ipilimumab-nivolumab combination in a single patient whose melanoma had returned after surgery. The patient had a large tumor under her breast, but a single treatment with the two drugs caused the entire mass to disappear in only three weeks.

”This is one of the most astonishing responses I have seen,” said medical oncologist Paul Chapman. “It reminds us of the potential power of the immune system if we can remove the “brakes” that keep it from attacking cancer cells.”

Abstract of Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma


In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.


In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.


Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation–positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.


The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; number, NCT01927419.)