Some patients respond more rapidly to immune therapies like ipilimumab, and clinicians have observed delayed toxicities with prolonged use of checkpoint inhibitors; effective treatments for subtypes of melanoma, such as uveal melanoma, have not yet emerged.
Studying rapid responders to immunotherapy and researching therapeutic targets for melanoma subtypes like uveal melanoma are some focal points for clinicians who treat melanoma, according to doctors who spoke at the 9th annual Canadian melanoma conference, Whistler, British Columbia, Canada.
"The response that you typically see with ipilimumab is slow and ongoing," said David Hogg M.D., F.R.C.P.C., attending physician, Princess Margaret Hospital in Toronto, Site Leader, Melanoma Medical Oncology, division of medical oncology and hematology. "Four doses are given every three weeks for up to 12 weeks. You hope to see a slight response in the tumor at the end of that period, and then a slow decrease thereafter."
There are a group of patients, however, who experience shrinkage of disease after one infusion of ipilimumab, a monoclonal antibody to CTLA-4. "We do see these patients," Dr. Hogg says. "They occur about once in 30 individuals. There are no biomarkers that allow us to select them beforehand (as rapid responders)."
When clinicians do encounter rapid responders to ipilimumab, they should not modify the standard protocol to the therapy.
"The question is if you handle these patients any differently, particularly if they have toxicity," Dr. Hogg says. "You actually do handle them the same way. You still give these patients four cycles of therapy, and you do not stop the drug."
The rapid responders to ipilimumab should be examined closely, for they may provide clues to how to optimize treatments, according to Dr. Hogg. "They should probably be studied to give us insight into patients who develop a rapid immune response," Dr. Hogg says.
While there is no current genetic information that suggests why a subset of patients are rapid responders to ipilimumab, the presence of another skin condition is predictive of a favorable response to ipilimumab, Dr. Hogg explains.
"The majority of the patients that I saw had vitiligo," he says. "The presence of vitiligo is a favorable marker of positive response to immune therapy."
A systematic review found a correlation between less risk of disease progression and mortality in patients with stage III-IV melanoma who experienced vitiligo-like depigmentation, but the overall cumulative incidence of vitiligo was low at 3.4 per cent. Still, vitiligo induction signalled improved survival.1
Clinicians should not possess an automatic sense of comfort with extended use of the newer checkpoint inhibitor therapies. While they are generally safe and easy to administer, a group of patients have been observed to develop delayed toxicities with extended use, Dr. Hogg says.
"The adverse events are not as frequent as with ipilimumab," Dr. Hogg says. "My point is that you can get lulled into a sense of security. A number of patients that we see now are treated on maintenance therapy with anti-PD-1 monoclonal antibodies for more than a year and up to two years. They develop an adverse event, and it's not clear what triggers this adverse event. It might be an infection or reactivity to a human antigen."
The fact that patients are developing delayed reactions to checkpoint inhibitors has raised questions about the appropriate duration of treatment with anti-PD-1 monoclonal antibodies, Dr. Hogg says.
"The big question is if we should treat them for a year or more," he says. "Perhaps there should be a stop date. They may have had enough treatment, and we opt to observe these patients instead. It's an important clinical question that will have to be addressed in clinical trials."
Xinni Song M.D., F.R.C.P.C., a medical oncologist at the Ottawa Hospital Cancer Centre and an assistant professor at the University of Ottawa, explained that optimal sequencing of therapies for patients with melanoma who are positive for BRAF mutations, is in evolution.
"For patients with BRAF-mutation positive melanoma, the optimal sequencing or combination of targeted therapy and immunotherapy is still to be determined. There are no biomarkers available to help clinicians in selection of therapy," Dr. Song says.
Melanoma treatments are sometimes associated with significant toxicities, and they are not inexpensive; further research and development of predictive markers would be useful in helping with treatment selections for optimal patient care, according to Dr. Song.
For less common subtypes of melanoma, such as uveal melanoma, there is little that can be offered in the way of therapy, Dr. Song says. "There is no effective targeted therapy (for uveal melanoma), and the benefit of immunotherapy is limited, with some patients achieving stable disease with anti CTLA-4 monoclonal antibodies," Dr. Song says.
"There is no standard therapy for uveal melanoma, and we do encourage our patients to consider clinical trial options," Dr. Song says. "We look forward to learning more about the benefit of combination therapies , i.e. combining targeted therapy and different types of immunotherapies, and using these therapies in the appropriate sequence. Upcoming trials are looking at how to sequence therapy and different ways of potentiating the immune system.
"We want to offer patients what will help them the most and choose therapy that has the least toxicity," Dr. Song says. "With more options available, we want to know what is the best therapy for each individual patient."
Dr. Song echoed Dr. Hogg's comments about the development of delayed side effects being an unknown in the treatment of patients and added that the development of these side effects can result in the cessation of therapy.
Dr. Song sits on advisory boards for BMS, Merck, and Roche. Dr. Hogg sits on advisory boards for BMS, Merck, Roche, and GSK.
1. Journal of Clinical Oncology. 2015 Mar 1;33(7):773-781