The recent FDA approval of the monoclonal antibody ipilimumab as an adjuvant treatment for melanoma has created an important opportunity for clinicians to weigh the benefits, risks, and limitations of this new treatment option.
The FDA’s decision was based on results from a 2015 randomized phase III study published in the Lancet Oncology (1). The results showed high-dose ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma, however those in the treatment arm were much more likely to suffer serious side effects than patients given placebo.
Naturally, people who present with surgically resectable melanoma that has a high risk of recurrence want to know what they can and should do to achieve the best possible outcome But based on the available data, the Melanoma Service at Memorial Sloan Kettering has so far been cautious in recommending adjuvant ipilimumab.
Adjuvant Therapy for Melanoma
Adjuvant therapy is a cancer treatment that is given after surgery to reduce the risk of recurrent or metastatic disease. For some cancer types, like breast cancer, adjuvant therapy can be very effective and a cornerstone of treatment. However, finding an adjuvant therapy with a meaningful benefit for melanoma has been more difficult. Interferon-alpha, for example, may delay disease recurrence in some melanoma patients, but its impact on overall survival is less clear and it carries a significant burden of side effects. (2), (3), (4) Local therapies such as adjuvant radiation may reduce the risk of disease recurrence at the primary site in select patients, but they do not decrease the risk of developing metastatic disease. (5)
Improved Recurrent-Free Survival at Three Years
The 2015 trial compared ipilimumab at 10 mg/kg with a placebo treatment in patients with high-risk stage III cutaneous melanoma who had their primary tumor surgically removed. All 951 patients had lymph node metastasis measuring 1 mm or greater and none had received previous systemic therapy. They were followed for approximately three years to measure side effects and recurrence-free survival. At three years, 46.5 percent of the patients that received ipilimumab were alive without evidence of recurrent disease compared with 34.8 percent of the patients that received the placebo. (1) The study has not yet reported whether patients who received ipilimumab lived longer or were less likely to develop metastatic disease than patients who did not.
Serious Side Effects
During the 36 month study period, patients who were randomized to ipilimumab were much more likely to have side effects than those who received the placebo. For more than half of the patients in the ipilimumab group, the side effects were serious enough that treatment was stopped early, and five patients died. (1) Based on these results, the FDA approved adjuvant ipilimumab at a dose of 10 mg/kg. This dose is higher than the 3 mg/kg used in the treatment of metastatic melanoma and may be a contributing factor to the high toxicity rate.
The MSK Position
The results of this clinical trial and the subsequent FDA decision, pose a dilemma on how to weigh the potential benefits against the risks of treatment. So far, the study analysis is incomplete because we do not know yet if patients who received ipilimumab will live longer. Patients with recurrent disease may go on to do very well on later treatments.
Therefore the decision as to whether to use high-dose iplimumab as an adjuvant treatment is difficult and requires excellent communication between physician and patient. Regardless of the choice, close follow-up with the clinical care team remains important. We eagerly await new information to better understand the benefits of ipilimumab, including the evaluation of lower 3 mg/kg dosing. In the meantime, research focusing on adjuvant treatment with agents that may have less toxicity than ipilimumab, such as PD-1 blocking antibodies, is ongoing.