Nivolumab-Based Treatments Delay Progression of Advanced Melanoma

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Results from an international, double-blind, randomized phase III trial show that patients with advanced melanoma who received nivolumab (Opdivo®) and ipilimumab (Yervoy®) had longer progression-free survival than patients who received ipilimumab alone. Progression-free survival was also longer among patients who received nivolumab alone than among those who received ipilimumab alone.


New England Journal of Medicine, May 31, 2015 (See the abstract.)


Nivolumab and ipilimumab block the activity of certain proteins, called immune checkpoint proteins, that limit the strength of immune responses. When activated, these checkpoint proteins serve as a brake on the immune system, preventing overly strong immune responses that could harm normal cells as well as abnormal cells. Treatments that block the activity of checkpoint proteins may remove this brake, enabling the immune system to destroy cancer cells.

Nivolumab inhibits the activity of a protein receptor called PD-1 on immune cells called T cells. When PD-1 on T cells binds to another protein called PD-L1, which is present on the surface of some melanoma cells, the T cells become inactive. Nivolumab blocks PD-1 binding to PD-L1 and prevents T cell inactivation, allowing the immune system to attack the tumor cells.

Some previous studies have suggested that patients whose tumors test positive for the PD-L1 protein tend to have better responses to anti-PD-1 therapy than patients whose tumors test negative. Nivolumab has been approved by the Food and Drug Administration (FDA) for the treatment of certain patients with melanoma and lung cancer.

Ipilimumab binds to a checkpoint protein on the surface of T cells called CTLA-4. Ipilimumab was the first immune checkpoint inhibitor to be approved by the FDA (in 2011) to treat advanced melanoma. Both nivolumab and ipilimumab are monoclonal antibodies that are given as intravenous infusions  by a doctor or nurse in a hospital or medical facility.

An early-phase study demonstrated that the combination of nivolumab and ipilimumab was safe and led to tumor regression in some patients with advanced melanoma. More recently, a phase III study showed that nivolumab improves overall survival compared with the chemotherapy dacarbazine in certain patients with the disease. The current study is the first phase III trial to compare a combination of immune checkpoint inhibitors with ipilimumab alone.

The Study

In the CheckMate 067 trial, 945 patients with previously untreated advanced melanoma were randomly assigned to receive nivolumab plus ipilimumab, nivolumab alone, or ipilimumab alone. The three regimens were given as follows:

Patient Group Treatment Regimen
nivolumab alone 3 milligrams per kilogram of body weight of nivolumab every 2 weeks (plus ipilimumab-matched placebo)
nivolumab plus ipilimumab 1 milligram per kilogram of body weight of nivolumab plus 3 milligrams per kilogram of body weight of ipilimumab every 3 weeks for four doses, followed by 3 milligrams per kilogram of body weight of nivolumab alone every 2 weeks
ipilimumab alone 3 milligrams per kilogram of body weight of ipilimumab every 3 weeks for four doses (plus nivolumab-matched placebo)

The primary endpoints of the study were progression-free survival and overall survival. The current report includes only progression-free survival data, as the results on overall survival were not available at the time of publication. Secondary endpoints included the objective response rate, safety, and tumor expression of the protein PD-L1 as a predictive biological marker of treatment efficacy.

James Larkin, M.D., Ph.D., of the Royal Marsden Hospital in London was the first author of the study, which was sponsored by Bristol-Myers Squibb, the maker of ipilimumab and nivolumab.


After a median follow-up of approximately 12 months, patients treated with the combination therapy and with nivolumab alone had longer progression-free survival than patients treated with ipilimumab alone. The median progression-free survival was 11.5 months in the combination therapy group, 6.9 months in the nivolumab-alone group, and 2.9 months in the ipilimumab-alone group.

Among patients with PD-L1-negative tumors, median progression-free survival was longer for patients in the nivolumab-plus-ipilimumab group than for those in either of the single treatment groups. Among patients with PD-L1-positive tumors, those receiving the combination therapy and nivolumab alone had similarly higher median progression-free survival compared with those receiving ipilimumab alone.

The objective response rates—the percentages of patients whose cancers shrank or disappeared after treatment—were higher in the combination-therapy group and the nivolumab-alone group than in the ipilimumab-alone group. Patients with PD-L1-positive tumors had higher objective response rates than patients with PD-L1-negative tumors.

The percentage of patients with a complete response was also higher in the combination-therapy group than in either the nivolumab-alone group or the ipilimumab-alone group.

Patient Group Objective Response Rate Complete Response Rate
  PD-L1-Negative PD-L1-Positive Overall Overall
nivolumab alone 41.3 percent 57.7 percent 43.7 percent 8.9 percent
nivolumab plus ipilimumab 54.8 percent 72.1 percent 57.6 percent 11.5 percent
ipilimumab alone 17.8 percent 21.3 percent 19.0 percent 2.2 percent

Treatment-related side effects of grade 3 or 4 occurred in 55 percent of patients in the combination-therapy group, 16.3 percent of patients in the nivolumab group, and 27.3 percent of patients in the ipilimumab group. There was one death in each of the two single-agent groups due to toxic effects of the study drug, but none in the combination-therapy group. In the combination-therapy group, 36.4 percent of the patients stopped treatment because of side effects of any grade.

The most common side effects among patients in the combination-therapy group included diarrhea, rash, and fatigue. “Adverse events were manageable with established treatment guidelines, and most select adverse events were resolved with the use of immune-modulatory agents,” the study authors wrote. 


The duration of response for patients receiving the combination therapy is not yet known. More data are needed to determine if the improvement in progression-free survival seen for the combination therapy in this trial will translate into an overall survival benefit for patients.

As the study authors noted, there is no consensus about the most effective method for measuring PD-L1 expression and defining “positive” PD-L1 expression, and the clinical usefulness of this protein as a biomarker has not been established. 


“This study is a major advance for the field of immunotherapy and for the treatment of cancer in general,” said Dr. James C. Yang, M.D., of NCI’s Center for Cancer Research, who studies immunotherapy and melanoma but was not involved in this trial. “These findings confirm several other studies showing that nivolumab does cause the dramatic regression of melanoma in a significant portion of patients.”

The new study also helps to reinforce the idea that many melanomas are “primed to be rejected by the immune system,” explained Dr. Yang. “But a major way that tumors are avoiding that rejection is through the PD-1 pathway. Until recently, we didn’t realize that this pathway was so dominant in this disease.”

Dr. Yang pointed out that adding ipilimumab to nivolumab increases the toxic side effects for some patients considerably, yet the durability of the combination therapy is not known. In the future, he noted, “the decision to use the combination therapy rather than nivolumab alone may depend on whether the long-term benefit from adding ipilimumab is worth the cost of the additional side effects for individual patients.”

The take-home message of this study “is that ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma,” said Michael B. Atkins, M.D., of Georgetown University Medical Center, who was the discussant when the CheckPoint 067 study findings were presented at the 2015 American Society of Clinical Oncology annual meeting.

Based on the new results and previous studies, Dr. Atkin said that nivolumab alone and in combination with ipilimumab—along with pembrolizumab (Keytruda®)—should be considered the new standards of care for patients with advanced melanoma.

Noting that tests for assessing PD-L1 expression are technically difficult to do and imperfect, Dr. Atkins also cautioned that more research is needed on PD-L1 before it should be used as a biomarker to guide the selection of treatments for patients.

  • Posted: June 26, 2015

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