ABSTRACT: Metastatic melanoma is a challenging disease to treat, with few effective therapies available. The survival rate for patients with metastatic melanoma has historically been grim, with few patients achieving complete or durable responses to therapy. Recently, however, there has been a great deal of excitement within the melanoma community, particularly regarding a new therapy that has demonstrated a survival advantage. This interview with Dr. Stephen Hodi, Director, Melanoma Disease Center, Dana Farber Cancer Institute, describes this new agent, an anti-CTLA-4 antibody known as ipilimumab. Dr. Hodi was the lead investigator of the Phase 3 clinical trial involving ipilimumab discussed in this interview and has been instrumental in advancing research into melanoma and its treatment.
Metastatic melanoma is a challenging disease to treat, with few effective therapies available for this devastating disease. The survival rate for patients with metastatic melanoma has historically been grim, with few patients achieving complete or durable responses to therapy. Recently, however, there has been a great deal of excitement within the melanoma community, particularly regarding a new therapy that has demonstrated a survival advantage. This interview with Dr. Stephen Hodi describes this new agent, an anti-CTLA-4 antibody known as ipilimumab.
Krista M. Rubin (KMR): Could you provide me with a background on the current landscape for metastatic melanoma and its treatment?
Dr. Hodi: The treatment for metastatic disease includes a couple of FDA-approved drugs. One is a chemotherapy drug, Dacarbazine (DTIC), a drug given intravenously, with varied response rates; somewhere between 10% and 25% of people will have some sort of response to the treatment. The problem with the chemotherapy is, and why it is not working in many people, is that even for those that respond, the response does not last very long. It is rather unsatisfactory.
The other Food and Drug Administration-approved drug that is frequently discussed as an option for treatment is interleukin-2, an agent that boosts the immune system in its own special way, by activating T cells. This treatment is labor intensive; it involves two 1-week long inpatient stays and is associated with many side effects, including lowering of blood pressure and leaking of fluids into the lungs, among others. And with all that, only approximately 15% of patients respond, and a smaller percentage, approximately 5%, have a durable (prolonged) response. Although this therapy can be highly effective in some patients, it is a very small percentage, and it can be very toxic.
These are the basic approved treatments for advanced melanoma right now.
KMR: There is a new drug, called ipilimumab, that has received a lot of attention. Could you talk a bit about what this drug is, and what it does, and if there are any side effects that would involve dermatology?
Dr. Hodi: Ipilimumab is an antibody that essentially takes the brakes off the immune system. This agent blocks these brakes, the natural brakes the immune system uses, causing the patient's own immune system to attack and kill melanoma cells. By removing these natural brakes on immune cells, you allow the immune system to react to normal parts of the body [that it otherwise would not react to]. As such, some of the potential side effects associated with ipilimumab include inflammation in normal parts of the body, with the one that is most serious being inflammation in the gut, or colon. While it has its own unique side effect profile, it can treat melanoma in an effective way, and some of these responses can be very durable [prolonged].
In terms of skin findings, rashes are actually the most common skin finding and can occur in more than 70% of patients. Skin findings may be subtle. A vast majority of these rashes are very mild, with kind of an erythematous lacey appearance. Sometimes you get small papules and such. And only in a minority of patients are these rashes of significance, where they may require topical steroids or even systemic steroids; this is very rare. And very, very rare is toxic epidermal necrolysis (TN). TN can occur as the most serious possible side effect of the drug, but is a very, very rare occurrence, but is something to be aware of.
Something that could also occur is general itchiness, a feeling that can come and go throughout the day. This typically can be treated with low doses of antihistamines, even if patients do not have a rash. It can be effectively treated. So the pruritis is something that is very common but treatable.
KMR: Would we expect patients receiving this drug to be photosensitive, or have any other skin effects that dermatology nurses should be educating them about, or at least be aware of?
Dr. Hodi: Photosensitivity has not been a primary issue. In terms of skin issues besides the rashes and rare TN, I think one that may be found, not very commonly, in perhaps just a couple of percent of patients, is uveitis (inflammation of the eye). Patients may be complaining of eye problems. They may seek out help in a dermatology practice, but that is the only other side effect I would envision being noted in a dermatology office.
KMR: Who would be eligible to get this drug?
Dr. Hodi: Right now, the availability of this drug is for patients with advanced melanoma. It is for patients whose disease has gone beyond the local region and is not surgically amenable, and who have already had prior treatment. At this time, the drug is currently available in that setting, and is only available within a clinical trial for compassionate use. That is the only indication and availability of the drug at this point but depending upon how the drug is developed in terms of potential FDA approval and the results of other trials that are coming out, the availability and indication of the drug may change in the very near future.
KMR: How is this drug given?
Dr. Hodi: It is given by an intravenous infusion usually over 90 minutes, typically at least for the first few doses it is given every 3 weeks X 4. Typically, these patients are being seen and managed by their medical oncology team.
KMR: Because this drug manipulates the immune system, does this make patients receiving it at greater risk of infection?
Dr. Hodi: There is no evidence supporting that, and in actuality you are boosting the immune system here. We do have patients receiving ipilimumab who have had colds and other common infections such as urinary tract infections, but they report the natural course of these is somewhat different than what you would expect from the normal course of those types of infections [in someone who had never received ipilimumab].
KMR: Could you please simplify the recent data that was presented this past June at the meeting of the American Society of Clinical Oncology (ASCO)?
Dr. Hodi: The recent trial [see Sidebar 1; Hodi et al., 2010] that was presented was a trial in which patients either received ipilimumab (ipi) alone or with a peptide vaccine, or the peptide vaccine by itself. What the trial showed is that the ipi improved survival with or without the vaccine, compared to the vaccine alone, and the median survival was improved by 4 months. But one of the more dramatic parts was the so called "tail of the curve": for a subset of the patients receiving a benefit, this benefit lasted a long time.
This is the first trial that has showed that any treatment offers a survival advantage in patients with metastatic melanoma.
KMR: What can we expect in the future with this agent?
Dr. Hodi: I think that the future is working out the best dose schedule for the drug, possible combinations with chemotherapy or with cytokines or other agents, and fine-tuning-hopefully determining those patients earlier on who may receive a benefit from it or not, with the development of predictive biomarkers. That would be one of the goals for future studies.
KMR: Do you feel this is going to be an effective drug for patients who have involvement of melanoma in the brain?
Dr. Hodi: There is some evidence in some trials that were also presented at ASCO (Lawrence et al., 2010) that this drug can be effective in some patients who had disease in the brain. The trial that was mentioned earlier (Hodi et al., 2010), with the combination of vaccine that was presented at ASCO, allowed patients with previously treated brain metastases onto the trial. So both of those trials that were presented suggest the drug may have activity in patients who have either previously treated brain disease, by radiation for example, or brain disease that has not been treated. We are waiting for some of those studies to be more mature so that we can better define the effectiveness of this drug in patients with brain metastases, but at least early and anecdotally, at least this potential exists, and we are looking forward to seeing how the data mature on patients with brain metastases.
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363(8), 711-723. [Context Link]
Lawrence, D. P., Hamid, O., McDermott, D. F., Puzanov, I., Sznol, M., Clark, J., Margolin, K. A. (2010). Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastases. Journal of Clinical Oncology, 28(15s), (suppl; abstr 8523). [Context Link]