WAIKOLOA, HAWAII – The spectacular developments in the treatment of advanced melanoma that began with approval of ipilimumab in 2011 continue to accelerate, and these advances promise to keep dermatologists quite busy for the foreseeable future in treating the cutaneous side effects of these targeted therapies.
Cutaneous toxicities requiring medical attention are extremely common with the new therapeutic agents. The key to minimizing their effects is proactive management, Dr. James E. Sligh emphasized at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
"This is a plea to dermatologists," he continued. "If you have a patient who’s going on a BRAF inhibitor, they need to be seen in your office regularly. And if your next available appointment isn’t until 4 months down the road, you absolutely need to make room for these patients, because after 4 months they may have very large squamous cell carcinomas.""The message is that people are living longer with advanced melanoma, but you really need to work with your oncologists to get the absolute benefit patients deserve out of these advanced drugs," he said. "All patients on any of the BRAF inhibitors should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and for 6 months following treatment discontinuation. And while I use this as a guide, there are definitely patients I see for whom 2 months is way too long between visits," he added. "If they’re growing squamous cell carcinomas or verrucous keratoses at a good clip, they need to be seen more often. I’ll see them every other week if need be," said Dr. Sligh, chief of the dermatology division at the University of Arizona, Tucson.
One in four advanced melanoma patients on a BRAF inhibitor – vemurafenib and dabrenafib are the two available thus far – will develop squamous cell carcinomas, Dr. Sligh said. If it’s going to happen, it typically begins in the first month or two of therapy. Caught early, the treatment is simple removal. The same goes for verrucous keratoses, which occur in close to half of treated patients.
"I use cryotherapy in the office, and I give patients 5-FU [5-fluorouracil] so they can start treating a lesion the day they see it, rather than waiting to show it to me a couple of months later," explained Dr. Sligh.
Other common cutaneous adverse events seen as a class effect with the BRAF inhibitors include photosensitivity reactions, seen in approximately one-third of patients in the phase III clinical trials; pruritus, seen in 23%; plantar hyperkeratosis in 10%-20%; and maculopapular rash in 9%.
The pretreatment dermatologic visit is an ideal time for patient education regarding sunscreen use, protective clothing, and the necessity to stay indoors in the event a photosensitivity rash emerges, Dr. Sligh noted. These are issues medical oncologists typically won’t counsel patients about, he said.
"The real advantage to doing this is you want these patients to maintain their optimal dose. For vemurafenib, it’s 960 mg b.i.d. There are very few things that will cause a dose reduction with these drugs, so if cutaneous toxicity is something patients are having a difficult time with, it’s our job as dermatologists to ensure that they have the best chance to make those side effects tolerable. Remaining on the drug is absolutely their best chance for survival," Dr. Sligh continued.
Serious hypersensitivity reactions, including anaphylaxis, as well as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients on a BRAF inhibitor. Such events do require permanent discontinuation of therapy. But that’s not necessarily the end of the road. "There are fantastic new options coming on board each year as alternatives for these people," according to Dr. Sligh.
New primary melanomas can arise while a patient is on BRAF inhibitor therapy. If they are detected early through those bimonthly office visits, the treatment is excision with no dosage adjustment.
Ipilimumab, which targets cytotoxic T-lymphocyte antigen 4, differs from the BRAF inhibitors in that its cutaneous adverse effects can emerge long after the drug is stopped.
"If you see a rash that’s not typical in a patient even 1 or 2 years after they were on ipilimumab, you should still consider that drug to be a likely culprit," Dr. Sligh said.
Trametinib, a MEK inhibitor, was approved last year for the treatment of melanomas with BRAF V600E or V600K mutations. Cutaneous toxicity occurs in close to 90% of patients on the drug, including a 12% rate of severe, grade 3 skin reactions. When trametinib is given in combination with vemurafenib or dabrafenib in an effort to delay emergence of tumor resistance, the result is longer progression-free survival than with either agent alone, and with a lower rate of squamous cell carcinomas and other cutaneous adverse events than with either agent as monotherapy. However, the question of whether or not combination therapy improves overall survival remains unclear, and is the subject of ongoing trials.