Nivolumab, Ipilimumab Combination Effective in Advanced Melanoma; Cost Questions Raised

Nivolumab, Ipilimumab Combination Effective in Advanced Melanoma; Cost Questions Raised

Dr. Jedd D. Wolchok
The combination of nivolumab and ipilimumab significantly increased progression-free survival (PFS) for patients with advanced melanoma compared with ipilimumab alone, according to a randomized, double-blind, phase III trial (Abstract LBA1). Nivolumab monotherapy also performed better than ipilimumab alone. Though this was a positive trial, a Discussant also noted the extreme high costs of these drugs, and others like them.

Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, presented results of the CheckMate 067 trial during the Plenary Session on Sunday, May 31. The trial involved two immunotherapy approaches: Nivolumab, a PD-1 checkpoint inhibitor, and ipilimumab, a CTLA-4 checkpoint inhibitor.

“The immune system is regulated by a dynamic interplay of positive and negative signaling pathways,” Dr. Wolchok said. Both the individual drugs have yielded improvements in survival in melanoma, and preclinical and earlier stage studies have indicated a synergistic effect with the combination.

 The study included 945 patients with treatment-naive, advanced melanoma who were randomly assigned to one of three treatment groups: 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for four doses followed by 3 mg/kg of nivolumab every 2 weeks (314 patients); 3 mg/kg of nivolumab every 2 weeks plus ipilimumab-matched placebo (316 patients); or 3 mg/kg of ipilimumab every 3 weeks for four doses plus nivolumab-matched placebo (315 patients).

The coprimary endpoints were PFS and overall survival (OS), on an intent-to-treat basis. The OS data is not yet available. The median PFS in the group treated with combination therapy was 11.5 months compared with 6.9 months in the nivolumab monotherapy group and 2.9 months in the ipilimumab monotherapy group.

The hazard ratio (HR) for PFS with the combination versus ipilimumab alone was 0.42 (99.5% CI [0.31, 0.57]; p < 0.00001). Nivolumab alone was also significantly better than ipilimumab, with an HR for progression of 0.57 (99.5% CI [0.43, 0.76]; p < 0.00001). Although this was considered an exploratory endpoint and the study lacked statistical power for the comparison, the combination group was also better than nivolumab alone, with an HR for PFS of 0.74 (95% CI [0.60, 0.92]).

In patients with PD-L1 expression of at least 5%, the median PFS was similar among the combination (14.0 months) and nivolumab monotherapy (14.0 months) arms, whereas the PFS was 3.9 months in the ipilimumab monotherapy arm. In contrast, patients with expression levels below 5% experienced benefit with the combination, which resulted in a median PFS of 11.2 months compared with 5.3 months for nivolumab monotherapy and 2.8 months for ipilimumab monotherapy.

Response rates were also better with the combination therapy option, and the median duration of response was not reached in any of the three groups.

Grade 3 to 4 adverse events were more common with the combination therapy, occurring in 55.0% of patients compared with 27.3% of patients who received ipilimumab and 16.3% of patients who received nivolumab.

In the group receiving combination therapy, 36.4% of patients discontinued treatment because of adverse events. The majority of these patients (67.5%) still experienced a response; 50% of these responses occurred after treatment discontinuation. Dr. Wolchok pointed out that there were no treatment-related deaths in the combination arm of the study, although it was carried out at 137 sites globally.

Dr. Michael B. Atkins
 Discussant Michael B. Atkins, MD, of Georgetown University Medical Center, described this as another “breakthrough” in melanoma therapy. Given these results and results of an earlier study comparing pembrolizumab and ipilimumab, he said, nivolumab monotherapy and in combination with ipilimumab—along with pembrolizumab—should be considered new standards of care for advanced melanoma.

Though the efficacy of these regimens is clear in this study, their value in terms of cost and associated benefits is still in question, according to Leonard Saltz, MD, of Memorial Sloan Kettering Cancer Center, who discussed “Perspectives on Value” during the Plenary Session. He noted that current prices for nivolumab and ipilimumab—$28.78 per mg and $157.46 per mg, respectively—push the total cost of the regimen in the CheckMate 067 trial into the hundreds of thousands of dollars. The price of ipilimumab, Dr. Saltz said, is “approximately 4,000 times the cost of gold.”

This reflects a decades-long trend in rising oncology drug costs, a trend that Dr. Saltz called “unsustainable.” He said that the rising costs of these drugs do not reflect development costs, nor do they help drive innovation. “Cancer drug prices are not related to the value of the drug, rather the prices are based on what has come before, and what the seller believes the market will bear.”

He said that the U.S. Food and Drug Administration’s inability to consider costs and the Centers for Medicare and Medicaid Services’ inability to negotiate those costs with drug companies is contributing to the problem. To begin to change this, Dr. Saltz said, the community must start by acknowledging there is an upper limit to what we pay to treat each patient with cancer. “It’s a very unpleasant discussion. It’s very uncomfortable,” but it is a necessary one to have, he said.  

Watch the session: Visit the ASCO Virtual Meeting website.