As FDA Considers Approval, Weber Discusses Adjuvant Ipilimumab in Melanoma

Jeffrey S. Weber, MD, PhD

In the EORTC 18071 study, patients with melanoma who received ipilimumab (Yervoy; n = 475) had an average recurrence-free survival of 26.1 months versus 17.1 months in placebo-treated patients (n = 476). Additionally, 46.5% of ipilimumab-treated patients survived 3 years without experiencing recurrence compared to 34.8% of patients in the control arm.

The significance of the results has been debated, as the dosage used in the trial was 10 mg/kg, while the FDA-recommended dosage for ipilimumab in the advanced setting is 3 mg/kg. The treatment was also associated with significantly higher toxicity than placebo treatment, including higher rates of gastrointestinal disorders, alterations in kidney function, and inflammation of the pituitary gland. These adverse events resulted in 52% of patients on ipilimumab discontinuing treatment.

The FDA has accepted a supplemental application for ipilimumab for use as an adjuvant treatment in patients with stage III melanoma at high-risk of recurrence following complete resection. The deadline for a final approval decision is October 28, 2015.

To better understand the impact of the EORTC 18071 trial, the chances of approval in the adjuvant setting, and the challenges concerning the dosage and toxicity with ipilimumab, OncLive spoke with the study’s lead author Jeffrey S. Weber, MD, PhD, senior member, Moffitt Cancer Center.

OncLive: What was the goal of the EORTC 18071 trial?

Dr Weber: The goal of the study was to evaluate the use of ipilimumab as an adjuvant therapy after resection in patients with stage III melanoma. The primary endpoint to this large randomized trial, which I think accrued around 950 patients, was relapse-free survival (RFS). However, overall survival (OS) will ultimately be collected in the study.

In melanoma, there was always a controversy over whether the endpoint should be OS or RFS. RFS is an endpoint that will be reached relatively quickly. For example, this study began in 2008 and it ended in 2010, so we had to wait 5 years to see the data published. To get the data on OS, we would have to wait even longer to see a difference, because the event we are monitoring would be death. For RFS, the event is a relapse. It is too long of a wait to have to depend on survival, so RFS is a surrogate for OS. Most of us would agree that RFS probably reflects benefit in patients with melanoma who are resected and rendered free of disease, so it is a good endpoint. However, the ultimate endpoint is always survival.

What findings were the most significant from the trial?

There is clear evidence of benefit with the use of ipilimumab in adjuvant therapy after resection in patients compared to placebo. There is benefit with prolongation of RFS. My prediction is that there will be a survival advantage once all the data comes in.

What is the standard adjuvant treatment for patients with stage III resected melanoma?

This is a European study, although it was done at a few centers in the United States, including Moffitt Cancer Center. The standard of care for stage III resected melanoma in Europe, at that time, was no therapy. Therefore, that was the appropriate control arm. In the United States, stage III resected melanoma patients often get high-dose interferon.

The question is, “How relevant is a placebo-controlled trial when, in the United States, interferon is FDA approved for this use?” The answer is that in the stage III patients with a moderate risk, the benefit of interferon is modest. I felt perfectly fine putting patients with stage IIIa disease on this trial, as well as the stage IIIb patients and even a few stage IIIc patients. In the United States, a lot of patients will not receive interferon if they have stage IIIa disease because the relative benefit is fairly low. We saw a good benefit in patients that received ipilimumab in this trial. The hazard ratio was respectable, ranging from .6 up to .85. Across the board, almost all patients benefited from getting ipilimumab versus placebo.

An interesting question would be to compare the ipilimumab survival to interferon at 3 years in the most recent studies to determine if ipilimumab is better than receiving interferon. If I had a choice of ipilimumab versus interferon, I would probably take ipilimumab. This is because interferon, while it does not have horrible side effects, does have side effects associated with it that almost everyone gets. With ipilimumab, about half of the patients did not finish treatment due to side effects. However, a lot of it is easily reversible with steroids and other treatments.

Why was this higher dose used, and what are the advantages and disadvantages of this dose?

When this trial started in 2008, ipilimumab was not an approved drug and there was data suggesting that 10 mg/kg was better than 3 mg/kg. Data suggested that the response rate and the progression-free survival were clearly better in metastatic disease when you use 10 mg over 3 mg. In those days, everyone agreed that 10 mg was a better option than 3 mg, which is why it was used. However, it is more toxic across the board.

The question is, “Is the increased benefit worth the increased toxic side effects?” In my view, probably yes. However, that is not an easy question to answer and, ultimately, a quality of life analysis needs to be made. We will find out that answer.

There is another trial, ECOG 1609, which is looking at the two doses compared to high-dose interferon. However, the results from that study will not be released for approximately 2 to 3 years.

Now that the FDA has accepted a supplemental application for ipilimumab in this setting, do you envision an approval around the corner?

That is going to be interesting. I predict it comes down to an Oncologic Drugs Advisory Committee (ODAC) meeting. Anytime there is any controversy surrounding something, there is an ODAC meeting and the toxicity of the dosing is controversial. I think it may happen, but we will find out when the ODAC meets. They will probably have information on a number of deaths on either arm because there won’t be enough data to make a formal analysis of survival. That is dependent on the number of events. They will have the raw data on a number of deaths in either arm and if that is favorable for ipilimumab, it will likely be approved. If the number of deaths is no different between the two arms that will probably be to its determinant.

What role will ipilimumab continue to play in the frontline setting for advanced melanoma?

For patients with metastatic disease, most of my colleagues and I will use nivolumab or pembrolizumab (Keytruda) upfront in an off-protocol patient that we cannot put on a trial. Interestingly, a lot of academic centers use pembrolizumab because it is administered every 3 weeks and a lot of patients travel a fair distance. Whereas, many practicing doctors prefer nivolumab because their patients live closer to the office and they prefer for them to come in more regularly to keep a close watch on their treatment.

Ipilimumab will now be a second-line drug. The big question in the field is, “Whom do you administer a PD-1 antibody to upfront, and whom do you give concurrent [this year’s] ASCO, but there will be some information provided on this topic.