EXPERT ANALYSIS FROM PMO LIVE
SEATTLE (FRONTLINE MEDICAL NEWS) – As targeted agents become a cornerstone of melanoma therapy, oncologists who treat the disease must be prepared to identify and manage the various associated skin toxicities, according to Dr. Mario E. Lacouture, director of the oncodermatology program and an associate attending in dermatology at the Memorial Sloan Kettering Cancer Center in New York.
These toxicities often result from hitting the target in normal skin. Managing them is critical because of their negative impact on psychosocial well-being, finances, physical health, and – likely most important – dose intensity of antimelanoma therapies, he told attendees at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.
“An early and proactive approach towards these events is advisable,” he maintained. “And dermatologic conditions will increase in importance as these drugs enter the adjuvant setting and with dose escalation and combination studies.”
Acneiform rash with MEK inhibitors
One of the most common skin toxicities in this setting is the acneiform rash seen with use of MEK inhibitors. “This rash is not really acne but it does look like acne because it affects areas such as the face, the chest, and upper back, and it is characterized by papules and pustules,” Dr. Lacouture explained.
The rash occurs in more than half of patients treated with trametinib (Mekinist), but its incidence drops sharply when that agent is combined with the BRAF inhibitor dabrafenib (Tafinlar). “So, in addition to the clinical benefit from the use of these agents in combination, you can see that there is a lower incidence of the acneiform rash,” he noted.
Data from the thoracic oncology field and experience with the indistinguishable acneiform rash caused by the targeted agent erlotinib (Tarceva) support a proactive approach to management, according to Dr. Lacouture. A trial in that setting found that incidence of grade 3 rash was reduced from 34% with observation alone to 14% with prophylactic oral minocyline and to 10% with reactive treatment with topical clindamycin plus hydrocortisone, with or without minocycline, at the time of rash occurrence. Moreover, patients in the prophylactic arm were on therapy 50% longer than counterparts in the other two arms.
Nonspecific rash with RAF inhibitors
The RAF inhibitors are associated with a nonspecific rash consisting of maculopapules and features similar to those of keratosis pilaris, giving the skin a sandpaper-like appearance. It occurs most commonly with vemurafenib (Zelboraf), but also is seen with dabrafenib. “This rash appears to be explosive in nature, usually occurring within the first 2-4 weeks,” Dr. Lacouture noted.
Management here consists of antihistamines, as well as corticosteroids (topically for grade 1 rash and orally for grade 2 or 3 rash) and dose interruption of the targeted agent with rechallenge at a lower dose.
Recent data show increased levels of cytokines and chemokines in patients who develop this rash on vemurafenib, suggesting that it is an inflammatory reaction, and lack of drug-specific T cells associated with type 1 hypersensitivity (Hautarzt. 2015;66[4]:221-3). Subsequent experience by these investigators showed that all patients with a grade 3 rash were able to start the drug again without recurrence of the rash, “dispelling the notion that any patient with a grade 3 maculopapular rash hypersensitivity-type reaction cannot be rechallenged with the drug,” he commented.
Hyperkeratosis
The BRAF inhibitors, especially vemurafenib, also can produce a hyperkeratosis of the palms and soles called hand-foot syndrome. Adding a MEK inhibitor to therapy appears to reduce the incidence of this adverse effect.
“The way to prevent this is not well known,” Dr. Lacouture said, but some approaches have been borrowed from the liver cancer clinicians and their experience in managing a similar hyperkeratosis associated with sorafenib (Nexavar).
“In the clinic, we treat these patients prophylactically with moisturizers that contain exfoliants or keratolytics, or agents that disrupt the barrier between the stratum corneum keratinocytes, such as salicylic acid and urea,” he explained. “When these lesions become symptomatic, we use topical anesthetics such as lidocaine or topical corticosteroids [that work] likely due to their anti-inflammatory activity and their inhibitory activity on the proliferation of keratinocytes.”
“Not infrequently, we refer these patients to podiatrists, who perform frequent peeling of the feet, removing the calluses with these special devices,” Dr. Lacouture added. “I have found myself performing pedicures on patients – something that I didn’t know was going to be part of my career, but this is something that is very helpful for these patients.”
New skin cancers
About one in five patients treated with vemurafenib or dabrafenib will develop squamous cell carcinoma. The incidence of this adverse effect is likewise reduced by addition of a MEK inhibitor.
“It is noteworthy that these lesions will occur usually within the first 2-3 months of therapy, and they do not have a very atypical phenotype,” Dr. Lacouture noted. “Most of them can be managed by simple curettage or saucerization, and there have been no reports of metastases of these lesions.”
A handheld device called a dermatoscope, which uses magnification and polarized light, permits visualization of cutaneous lesions with greater sensitivity and can help sort cancers from benign lesions. “I know that there are many oncologists who now have a dermatoscope in their practices,” he said.
Dermoscopic and clinical analysis of 112 BRAF inhibitor–induced proliferative skin lesions identified a set of features associated with malignancy: large size, nodular appearance, a central keratin plug, adherent scale, ulceration, a red halo, and a scaly ring (Cancer. 2015;121[1]:60-8).
Another recent study using dermoscopy suggests that 56% of patients with melanoma treated with vemurafenib who have additional pigmented lesions experience a change in those lesions over time (J Invest Dermatol. 2014;134[5]:1351-8). Changes in color or globules predominate. In all, 21% of patients were determined to have a second primary melanoma.
Photosensitivity and radiosensitivity
Forty-two percent of patients receiving vemurafenib become photosensitive, with some developing sunburn after just minutes of sun exposure (N Engl J Med. 2012;366:480-1).
“This photosensitivity is caused by ultraviolet radiation A, not ultraviolet radiation B, which means that, if your patients do not have a broad-spectrum sunscreen on, they can get burned by going through your office, or they can get burned inside their own homes, because UVA will penetrate window glass,” Dr. Lacouture noted.
Radiosensitivity also can occur with vemurafenib, manifesting in a variety of forms from a painful, pruritic dermatitis to extensive hyperproliferation. “The only positive studies to show prevention of radiation dermatitis are with the use of high-potency topical steroids or topical antibiotics,” he said.
Immunotherapy-related rash and pruritus
The immune checkpoint inhibitors used to treat melanoma – ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) – also can produce skin toxicity, including a maculopapular rash and, separately, a severe pruritus.
The pruritus may manifest as scratches or excoriations. “The important thing about this pruritus is that it can be associated with pain and infections, as well as decreasing quality of life in these patients,” Dr. Lacouture said. “Interestingly, this [condition] appears to respond very well to oral antihistamines or topical or oral steroids, depending on the severity.” Data also suggest that the antinausea and antiemetic agent aprepitant (Emend) also may be efficacious in severe cases (Lancet Oncol. 2012;13[10]:1020-4).
Dr. Lacouture disclosed that he performs contracted research with Berg, Bristol-Myers Squibb, and Genentech, and that he receives consulting fees from AstraZeneca, Bayer, Genentech, Novocure, and RP Pharmaceuticals.
