Expert Discusses Adjuvant Ipilimumab Regimens in Melanoma

Jean Jacques Grob, MD, PhD

Patients with stage III melanoma who receive 10 mg/kg of adjuvant ipilimumab (Yervoy) see efficacious results, but at a much higher cost of toxicity compared to lower doses of the CTLA-4 inhibitor.

“There is a high proportion of grade 3 to 5 adverse events with 10 mg/kg of ipilimumab, especially in the adjuvant setting,” said Jean Jacques Grob, MD, PhD, who gave a presentation on ipilimumab at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany.

Due to these toxicities, Grob sees a 10 mg/kg dose of ipilimumab slowly leaving the treatment landscape for these patients. However, lower doses and combinations continue to be investigated and show promise.

OncLive: Can you provide an overview of your presentation on ipilimumab?

In an interview with OncLive, Grob, professor of Dermatology at the Hospital de la Timone, discussed the efficacy and tolerability of different doses of ipilimumab given in the adjuvant setting for patients with melanoma.Grob: I discussed the ratio between tolerability and efficacy of the different dosages of ipilimumab in the adjuvant setting. I covered different points of view, the first being that toxicity is proportional to the dose. We currently are using 3 different dosages: 10 mg/kg, 3 mg/kg, and 1mg/kg.

In the adjuvant setting, only 10 mg/kg has been studied so far, but studies are ongoing with all the dosages. The toxicity that has been observed in the adjuvant trial with 10 mg/kg was very high. Despite the very good impact on relapse-free survival and overall survival, there is a big debate, for many reasons, about whether it is reasonable to use the dosage in patients for adjuvant therapy.

Are there any ongoing studies investigating those challenges?

Can you discuss the safety profile of ipilimumab?

Ipilimumab is being looked at in combination with nivolumab (Opdivo). Are there any other combinations that are showing promise?

First, a lot of patients will be treated even if they do not need it because we are unable to select the right patient, individually. Secondly, we don’t know whether the fact that giving an adjuvant therapy with ipilimumab is preventing the future efficacy of immunotherapy, in general, when it might be needed in an advanced stage with the same patient. We don’t know whether it is good or bad to treat the patient early or to just wait for metastatic disease and then treat the metastatic disease. There is a panel of studies, but that is not covering all of the questions we continue to ask ourselves. However, the trials mainly focus on the dosage of ipilimumab and even consider the question of whether we should treat a patient early or late.There is a high proportion of grade 3 to 5 adverse events with 10 mg/kg, especially in the adjuvant setting. We have observed that the toxicity for a given dose is much higher when the drug is given in the adjuvant setting than when it's given in the metastatic setting. This is probably because the immune system is more active in patients with bigger tumor loads. There are other combinations. First of all, ipilimumab has also been tested with pembrolizumab (Keytruda), but this is much less advanced in terms of trials. Ipilimumab is tested at 1 mg/kg, which will be decreasing the toxicity profile and perhaps not decreasing the efficacy too much but this has to be tested. This is not yet in the adjuvant setting but ipilimumab is combined with different types of molecules.

What were the key points from this presentation that you hope the audience will take with them?

Is there anything else you would like to add?

Of course, ipilimumab can be replaced in the adjuvant setting by other molecules which are currently being studied, such as anti-ID1 antibodies, which might be better tolerated. However, for the moment, it is just a hypothesis. The main takeaway message is that high dosages of ipilimumab are probably losing their place very soon in the treatment landscape because of the other molecules in development in the adjuvant setting. Additionally, the ratio between the efficacy and the tolerability is promising. If there is a lower dose of ipilimumab of either 3 mg/kg, or even better 1 mg/kg, there is probably still a good place in the adjuvant setting. I would just like to mention that the patients we usually address with all the adjuvant treatments have a high risk of recurrence and metastatic disease, but they account for only a minority of future deaths for melanoma. Tumor stages which are accounting for the majority of these are tumors from stages IIa, IIb, and IIIa. This means that if we really want to do an adjuvant trial, we would have to study this subpopulation of stages IIIa, IIIb, and IIIc to achieve a very low toxicity since it is probably the only way to decrease the mortality of an adjuvant treatment.

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