SKIN TOXICITIES WITH BRAF INHIBITORS

Skin reactions to targeted drugs used for melanoma tend to be lumped together as "rash," but differentiating the specific cutaneous toxicities could improve treatment, dermatology researchers say.

The cutaneous toxicity seen with BRAF and MEK inhibitors used in the treatment of metastatic melanoma is described in detail in a report published online July 22 in JAMA Dermatology.

"Cutaneous toxicities are poorly described and understood," said senior author Pablo Fernandez-Peñas, MD, PhD, professor of dermatology at the University of Sydney and head of dermatology at Westmead Hospital in Sydney, Australia.

"Most trials don't involve dermatologists, and anything on the skin is classified as a rash," Dr Fernandez-Peñas told Medscape Medical News. "Unless we make proper dermatological diagnoses, we won't be able to manage the different conditions hidden in the word rash, and treatments are going to be inadequate."

For the most part, oncologists treat these so-called rashes with sunscreens, hydrocortisone, and moisturizers "because this is the standard treatment for rash in most clinical trial protocols," he explained. But careful description of these cutaneous toxicities could lead to a better understanding of the mechanisms that underlie their manifestations.

A classic example is the segregation of Stevens Johnson syndrome – toxic epidermal necrolysis from erythema multiforme on the basis of clinical presentation, Dr Fernandez-Peñas said. "In dermatology, we can differentiate between multiple conditions that require very different approaches, and most of the time, we are very effective at treating them. If cutaneous toxicities are properly managed, oncologists won't need to reduce doses or cease medications, and this impacts the survival of patients."

In their study, Dr Fernandez-Peñas and his colleagues assessed cutaneous toxic effects in patients with unresectable stage IIIC and IV melanoma from September 2009 to November 2013. They compared BRAF inhibitor monotherapy — vemurafenib (Zelboraf) or dabrafenib (Tafinlar) — with the CombiDTcombination of dabrafenib plus the MEK inhibitor trametinib (Mekinist).

Of the 185 patients, 119 received dabrafenib, 36 received vemurafenib, and 30 received the combination therapy.

Skin Toxicities With BRAF Inhibitor Monotherapy

Table. Common Cutaneous Toxic Effects Related to BRAF Inhibitor Monotherapy

Toxic Effect	Dabrafenib Monotherapy, %	Vemurafenib Monotherapy, %
Verrucous keratosis	66.4	72.2
Grover disease	42.9	38.9
Cutaneous squamous cell carcinoma	26.1	36.1
Photosensitivity	0.8	38.9
Plantar hyperkeratosis	39.5	38.9

With BRAF inhibitor monotherapy, verrucous keratosis lesions appeared as early as 7 days after the start of treatment and continued throughout the treatment period. With Grover disease, patients developed scattered hyperkeratotic papules with variable degrees of itch and inflammation on the trunk.

Cutaneous squamous cell carcinoma (SCC) is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy.

Skin Toxicities With Combination Therapy

The adverse-effect profile with the combination therapy was different than that with dabrafenib, and patients treated with the combination had fewer events.

None of the patients treated with the combination experienced verrucous keratosis, Grover disease, or cutaneous SCC (P< .001 for all).

Folliculitis was more common with the combination than with dabrafenib monotherapy (40.0% vs 6.7%; P < .001).

The rate of plantar hyperkeratosis and acneiform reaction was the same with the combination and dabrafenib monotherapy (16.7% vs 16.7%).

One patient (3.3%) in the combination group developed facial and trunk erythema after minimal sun exposure.

Three patients (10.0%) in the combination group developed localized or whole-body maculopapular eruptions or drug reactions with the concomitant use of penicillin, methotrexate, and anticonvulsants.

In addition, seven patients in the combination group had been previously treated with dabrafenib, and one had been treated with vemurafenib. After switching to the combination therapy, two of these patients experienced a reduction in the frequency of cutaneous SCC, verrucous keratosis, Grover disease, and plantar hyperkeratosis, and six experienced a resolution.

Dr Fernandez-Peñas said he could only speculate why there are fewer cutaneous toxicities with the combination than with BRAF monotherapy. "We know that MEK inhibitors block the RAS-RAF-MEK-ERK pathway one step down from RAF. We know that inhibitors of mutant BRAF stimulate wild-type BRAF. Keratinocytes do not usually harbor mutant BRAF, and the pathway is stimulated in patients on BRAF inhibitors, creating hyperproliferative lesions, such as verrucous keratosis, squamous cell carcinoma, palmoplantar hyperkeratosis, and probably Grover disease. When the pathway is blocked by the addition of MEK inhibitors, these abnormal hyperproliferations are also blocked," he explained.

"Our group has shown that single-agent MEK produces frequent acneiform reactions and folliculitis. This side effect is still present in CombiDT, but is not as frequent or severe. We do not have a plausible explanation at this stage," he added.

Close Monitoring Still Needed

Because the combination of BRAF and MEK inhibitors has been shown to have a survival advantage over BRAF inhibitor monotherapy, the monotherapy is not used as frequently as it was in the past. However, for patients treated with BRAF inhibitor monotherapy, close monitoring is needed because of the frequent development of cutaneous SCC, Dr Fernandez-Peñas said.

"These patients can develop many other skin toxicities, and probably should be managed by dermatologists," he said.

For patients on vemurafenib, sunscreen is a must, whether they are indoors or outdoors, he advised.

In addition, patients being treated with the combination "need to be aware that folliculitis and acneiform reactions are going to be common, and measures similar to those used in patients on EGFR inhibitors should be implemented. Eczema and maculopapular exanthems could appear in 10% to 20% of patients, but these are usually mild reactions that can be managed with moisturizers and topical corticosteroids," Dr Fernandez-Peñas noted.

"For plantar hyperkeratosis, well-fitting shoes, to avoid friction, are required, and moisturizers with at least 10% urea should be used frequently," he said.

Dr Fernandez-Peñas reports that was on Roche's advisory board in the past.

JAMA Dermatol. Published online July 22, 2015. Abstract