Adjuvant Ipilimumab in Melanoma: Future in Doubt

Liam Davenport

October 10, 2017

The future of adjuvant ipilimumab (Yervoy, Bristol-Myers Squibb) for the treatment of resected stage III melanoma could be in doubt, as a combination of "astronomically high" costs and better outcome data with another treatment threaten its position as the standard of care, argues an expert.

Ipilimumab, a monoclonal antibody that blocks CTLA-4, was shown to significantly improve recurrence-free and overall survival vs placebo when used after surgery. These data, from the EORTC 18071 trial, led to its approval by the US Food and Drug Administration (FDA) as an adjuvant therapy for patients with stage III melanoma in October 2015. This extended its original approval in 2011 to treat late-stage melanoma in patients who are not candidates for surgery.

However, this adjuvant use of ipilimumab is hugely expensive ― costs are estimated to be more than $1.8 billion per patient.

This is "far more expensive than other highly priced cancer drugs," comments Daniel A. Goldstein, MD, from the Winship Cancer Institute, Emory University, Atlanta, Georgia, and the Davidoff Cancer Center, Rabin Medical Center, Petach Tikvah, Israel, in an editorial published online October 5 in JAMA Oncology.

Moreover, recent results presented at the 2017 annual meeting of the European Society of Medical Oncology (ESMO) show that patients have substantially better outcomes with the checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) than with ipilimumab in this clinical setting.

As reported by Medscape Medical News, adjuvant nivolumab increased relapse-free survival by a significant 35% vs ipilimumab, and the rate of grade ≥3 adverse effects was reduced by approximately a third. This is particularly relevant, given that questions had already been raised over the levels of toxicity associated with ipilimumab, especially at the recommended dose of 10 mg/kg.

Dr Goldstein estimates that the average cost of a nivolumab regimen would be far lower than that of ipilimumab.

Consequently, the future of adjuvant ipilimumab in resected stage III melanoma would appear to be under threat. Currently, adjuvant ipilimumab is approved only in the United States for this indication.

In his editorial, Dr Goldstein points out that until the results of the EORTC 18071 trial became available, interferon had been the standard of care for patients with resected melanoma. These results showed a significant improvement in both 5-year recurrence-free and 5-year overall survival compared with placebo, and led to the FDA approval of adjuvant ipilimumab in 2015.

He also highlights the finding that, during the 5 years of the study, 11 of 100 lives were saved with ipilimumab, which he describes as a "major and important improvement.

"Many modern FDA-approved therapies in the metastatic setting prolong life merely by a number of weeks, without potential for cure. This treatment has the potential to cure 11% of this group of patients, and we must applaud this as a major breakthrough," he writes.

I would want this therapy because it would increase my chance of cure from this fatal disease. Dr Daniel Goldstein

"If I were a patient with resected stage III melanoma, I would want this therapy because it would increase my chance of cure from this fatal disease," he adds.

However, he notes that the ipilimumab regimen used in the EORTC 18071 trial was four doses of 10 mg/kg every 3 weeks, then every 3 months for up to 3 years or until either disease recurrence or the level of toxicity became unacceptable.

For an adult of average weight in the United States (82 kg), the average dose would therefore be 820 mg; at a cost of $145 per mg, the cost for an average dose would be $120,000.

The regimen stipulates that patients receive 15 treatments, resulting in a maximum cost of approximately $1.77 million per patient. With the 4.3% markup that Medicare reimburses to healthcare providers, the cost would be $1.85 million per patient.

However, this is a theoretical cost estimate. In the real world, some patients would be given fewer than the recommended 15 doses, Dr Goldstein points out. Even in the EORTC 18071 trial, the median number of doses was four, and 53% of patients discontinued treatment with ipilimumab because of an adverse event, he points out.

Moreover, the patients in the trial were only those with Eastern Cooperative Oncology Group disease (ECOG) status 0 or 1. It is likely that treatment of patients with a worse performance status would affect rates of toxic events and discontinuation, as well as drug cost and efficacy.

Dr Goldstein also underlined that, for the approximately 11% of patients who are "spared metastatic recurrence, there will be significant cost savings because these patients would not require subsequent expensive therapy."

However, these cost savings would be offset by the "additional costs for the management of adverse events, which may be significant."

Dr Goldstein calculates that, given an average number of treatments in the real world of 10 and a total cost of $120 million, the average cost to save one life would be approximately $10.9 million if the cure rate from the EORTC 18071 trial were extrapolated to the real-world setting.

He continues: "The median age of patients in the trial was 51 years and life expectancy in the United States is 79. So we can estimate that 28 years of full quality life were saved, per life saved. Therefore the cost is $390,000 per quality adjusted life year (QALY) saved."

This makes ipilimumab a "poor value intervention," Dr Goldstein comments, although he concedes that this may not make it "of worse value than other FDA-approved cancer therapies."

One way around this issue of poor value could be to use a lower dose of ipilimumab, such as 3 mg/kg, although the current data supporting that "are felt to be immature."

Dr Goldstein believes a price reduction for ipilimumab is unlikely. Although it is "far more expensive" than other cancer drugs, "current competition and reimbursement rules provide no incentive for the manufacturer to reduce the price."

While looking forward to the results of other trials with adjuvant immunotherapies, he concludes: "The cost of adjuvant ipilimumab is astronomically high. The value of ipilimumab is poor, but it is not astronomically poor. In the adjuvant setting, given the potential for cure, perhaps high drug prices are more justified?"

In an interview with Medscape Medical News, Dr Goldstein pointed out that he wrote the editorial approximately 3 months ago, before the presentation of the CheckMate 238 data at the ESMO 2017 Congress and the simultaneous publication of that study in the New England Journal of Medicine.

He said: "Ipilimumab has been the standard of care in the adjuvant setting for melanoma for the past 2 or so years. It looks now like nivolumab will probably now become the new standard of care, given the findings from ESMO.

"The question is: Is the nivolumab regimen going to be as expensive as the ipilimumab regimen?"

Dr Goldstein believes that the likely answer is no, given the fact that 1-year regimen of nivolumab "won't be anywhere near as expensive as that $1.8 billion regimen for ipilimumab."

Indeed, he estimates that the cost for treatment with nivolumab would likely be between $120,000 to $150,000 per patient, given that the drug costs around $10,000 to $15,000 per patient per month.

The results with nivolumab are "really excellent news for patients, because [they show] that nivolumab is better than ipilimumab," he said. "It's also excellent news for payers, because it's going to be a much cheaper regimen."

Dr Goldstein did underline, however, that there is an important caveat to that, which is that in the comparison of nivolumab with ipilimumab, the duration of therapy with ipilumab was 1 year, whereas in the EORTC 18071 trial, the duration of therapy was 3 years.

He nevertheless emphasized that, in that earlier ipilimumab vs placebo trial, "the median number of doses was only about approximately 1 year or so probably [CheckMate 238] was a justifiable trial design."

Another major question is whether in the future, ipilimumab will have a role in the adjuvant setting for resected melanoma, he said.

Dr Goldstein said: "It's a very toxic regimen, so I think nivolumab is going to be the next standard of care. Whether it will remain the standard of care forever, I don't know."

Dr Goldstein has disclosed no relevant financial relationships.

JAMA Oncol. Published online Ocrtober 5, 2017. Editorial

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