Fresh Insight on Ipilimumab's Potential in the Adjuvant Melanoma Setting

Ahmad A. Tarhini, MD, PhD

Approved adjuvant therapy options for melanoma are currently limited, with the standard of care being interferon-alpha. However, new options are on the horizon, including ipilimumab (Yervoy), which is being studied for melanoma in the adjuvant setting as part of several trials.

In an interview with OncLive at the 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies, Ahmad A. Tarhini, MD, PhD, associate professor of Medicine, Clinical and Translational Science, Division of Hematology/Oncology, University of Pittsburgh, discussed the benefits and challenges of ipilimumab and other immunotherapies and how they could change the adjuvant treatment paradigm for melanoma.

What is the current landscape for adjuvant therapy in melanoma?

Adjuvant therapy in melanoma is indicated for patients that can be rendered disease-free surgically, but continue to carry a high-risk for melanoma relapse that may lead to death. This includes patients with an estimated 5-year risk of about 40% or more.

Currently, interferon-alpha is the only FDA approved adjuvant agent in the United States. Overall, randomized controlled trials of adjuvant interferon-alpha, and analysis of these trials, have shown a consistent impact in improving relapse-free survival (RFS). Improvement in overall survival (OS) was seen only with the high dose regimen as tested in the E1684 study versus observation, and in the E1694 study versus the ganglioside GMK vaccine.

Recently, the EORTC 18071 trial that is testing ipilimumab at the dose level of 10 mg/kg versus placebo was reported. This study met its primary endpoint of RFS with an HR of 0.75. This study, however, continues to be blinded in relation to the OS endpoint. Other major studies are ongoing, including the US intergroup E1609 study that is testing ipilimumab.

The field is moving at a rapid pace, and new studies testing anti—PD-1 antibodies pembrolizumab and nivolumab are expected to be activated in the near future.

What are the pros and cons of the 3-milligram dose of ipilimumab, as approved now, versus the 10-milligram dose as used in adjuvant trials?

The current standard of care in the treatment of metastatic melanoma is the 3-milligram per kilogram regimen. This regimen is given intravenously once every 3 weeks. It consists of only four doses and does not include a maintenance phase. This is based on the MDX010-20 study, which tested ipilimumab in this regiment with or without the gp100 vaccine versus gp100 vaccine alone. The 10-milligram dose is higher, and consists of an induction phase and a maintenance phase.

One thing we know about ipilimumab, based on a phase II study, a dose ranging study which tested the 0.3 mg/kg milligram per kilogram, 3 mg/kg milligram per kilogram, and 10 mg/kg milligram per kilogram, is that the toxicity is also dose dependent. We expect to see higher toxicity with a higher dose of ipilimumab, but the activity was also superior with the higher dose. It is not known at this time if the 10 milligrams dose is actually superior to the 3 milligrams definitely, but this data will be available in the near future. We have the results of the BMS-CA184-169 study, that which hopefully will have an answer to this question.

What has been learned about better managing the side effects of ipilimumab?

The blockade of CTLA-4 signaling with ipilimumab prolongs T cell activation and restores T cell proliferation. Thus, this amplifies T-cell—mediated immunity and the patient’s capacity to mount an effective anti-tumor response. While this immune stimulation has unprecedented OS overall survival benefits, it can also result in immune-mediated effects on various organ systems, including what we call immune-related adverse events. These immune-related adverse events are typically low grade and manageable, but can also be serious and sometimes be life threatening. The skin and gastrointestinal track are most frequently affected effected, while hepatic endocrine and neurological events are less common.

With proper management, most immune-related adverse events resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these immune-related adverse events is essential, and treatment guidelines have been developed to assist oncologists and their teams. The implementation of these management algorithms will help ensure that the patients are able to benefit from ipilimumab therapy with adequate control of the toxicities.

What clinical trials will help define the best use of immunotherapy in the adjuvant setting? When do you expect to hear data?

I think the most important clinical trials in the adjuvant setting currently include the EORTC 18071 study, which was reported in ASCO 2014 that it met its primary endpoint of relapsed-free survival. This study continues to be blinded for the OS overall survival endpoint. We know that, recently, Bristol-Myers Squibb has actually filed with the FDA in regards to this regimen.

The next study is The US Intergroup E1609 study, which is testing ipilimumab at two different dose levels, 3 mg and 10 mg versus the standard of care, which is interferon-alpha. This study is a key study because it is not only looking at ipilimumab versus interferon-alpha, but is also examining looking at two different dose levels. We can evaluate both the toxicity and efficacy of these regimens versus the standard of care. The studies that will to be implemented in the near future will be testing the anti—PD-1 monoclonal antibodies pembrolizumab and nivolumab. These will also be key and most likely change the fate of treating melanoma in an adjuvant setting.