Nivolumab Improves Survival for Some Patients with Advanced Melanoma
Results from an international double-blind, randomized phase 3 trial show that patients with advanced melanoma who received nivolumab (Opdivo®) or a combination of nivolumab and ipilimumab (Yervoy®) had longer progression-free survival and overall survival than patients who received ipilimumab alone.
New England Journal of Medicine, September 11, 2017 (See the abstract.)
Nivolumab and ipilimumab are drugs known as immune checkpoint inhibitors. By blocking checkpoint proteins—proteins that limit the strength of immune responses that could harm normal as well as abnormal cells—these drugs enable the immune system to destroy cancer cells.
Nivolumab binds to a receptor protein called PD-1 on immune cells called T cells. When PD-1 on T cells attaches to another protein called PD-L1, which is present on the surface of some cancer cells, the T cells become inactive. By preventing PD-1 from binding to PD-L1, nivolumab prevents T-cell inactivation, allowing the immune system to attack the tumor cells.
Some studies have suggested that patients whose tumors have low levels of PD-L1 protein tend to have better responses to anti-PD-1 therapy than patients whose tumors have higher levels of PD-L1. Nivolumab has been approved by the Food and Drug Administration (FDA) for the treatment of certain patients with melanoma regardless of PD-L1 status, as well as several other cancers.
Ipilimumab binds to a checkpoint protein on the surface of T cells called CTLA-4. In so doing, it blocks an inhibitory signal that prevents the T cells from responding to the cancer.
Ipilimumab was the first immune checkpoint inhibitor to be approved by 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. The current study was the first phase III trial to compare a combination of immune checkpoint inhibitors with ipilimumab alone.
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 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|
|nivolumab alone||3 milligrams per kilogram of body weight of nivolumab every 2 weeks (plus ipilimumab-matched placebo)|
|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. 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 lead author of the study, which was sponsored by Bristol-Myers Squibb, the maker of both ipilimumab and nivolumab.
ResultsAfter a minimum follow-up of 36 months, patients treated with either the combination therapy or with nivolumab alone had longer progression-free survival than patients treated with ipilimumab alone. The median overall survival was longer in the nivolumab-alone group than the ipilimumab-alone group and had not been reached in the combination-therapy group.
|Patient Group||Median Progression-Free Survival||Median Overall Survival|
|nivolumab plus ipilimumab||11.5 months||not yet reached|
|nivolumab alone||6.9 months||37.6 months|
|ipilimumab alone||2.9 months||19.9 months|
The percentage of patients whose cancers shrank or disappeared after treatment (objective response rate) and the percentage of patients who saw the disappearance of all signs of cancer after treatment (complete response rate) were higher in the combination-therapy group and the nivolumab-alone group than in the ipilimumab-alone group.
|Patient Group||Objective Response Rate||Complete Response Rate|
|nivolumab plus ipilimumab||58%||19%|
The progression-free and overall survival rates were also higher in both groups that received nivolumab than in the ipilimumab-alone group.
|Patient Group||Progression-Free Survival Rate||Overall Survival Rate|
|nivolumab plus ipilimumab||39%||58%|
The researchers also analyzed the findings in subgroups of patients with different PD-L1 levels. Among patients whose tumors express low levels of PD-L1, preliminary data suggested that combination therapy may improve survival better than either drug alone. But in patients with higher levels of PD-L1, overall survival was similar in the combination and nivolumab groups.
Treatment-related side effects of grade 3 or 4 occurred in 55% of patients in the combination-therapy group, 21% of patients in the nivolumab group, and 28% 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, and two patients in the combination-therapy group died more than 100 days after receiving their last doses due to side effects the investigators considered to be related to a study drug. In the combination-therapy group, 39.3% 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.
LimitationsThe duration of response for patients receiving the combination therapy is not yet known. And, 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. Moreover, the available data "indicate that the level of tumor PD-L1 expression alone is a poor predictive biomarker of overall survival," they added.
"This study is a major advance for the field of immunotherapy," said James C. Yang, M.D., of NCI’s Center for Cancer Research, who studies immunotherapy and melanoma but was not involved in this trial. The study results also help to reinforce the idea that many melanomas are "primed to be rejected by the immune system," he said, "but the findings show that a major way that tumors are avoiding that rejection is through the PD-1 pathway."
"Although expression of PD-L1 ligand on tumors is not a reliable predictor of benefit overall," Dr. Yang continued, "the available data suggest that patients with this biomarker may do as well with nivolumab alone as opposed to the more toxic combination therapy."
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 earlier findings from the CheckPoint 067 study were presented at the 2015 American Society of Clinical Oncology annual meeting.
Based on these results and previous studies, Dr. Atkins 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.