Panniculitis Associated with MEK Inhibitor Therapy: An Uncommon Adverse Effect

Abstract

The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors. We present here the first observation of panniculitis strictly induced by MEK inhibitors. Indeed, 10 days after the initiation of combined treatment with cobimetinib and vemurafenib for metastatic melanoma, our patient developed panniculitis predominantly on the upper and lower extremities. These cutaneous nodules disappeared during cobimetinib intermissions and recurred while the molecule was resumed. Recurrence of cutaneous nodules was observed after initiation of trametinib combined with dabrafenib, and resolved once again with trametinib discontinuation. We believe that clinicians should be aware of this cutaneous adverse event in patients treated with combined therapy, which can lead to unfounded BRAF inhibitor treatment discontinuation and compromise the antitumor response. Our case suggests a class effect linked with the MEK inhibition pharmacodynamic activity. Finally, laboratory investigation and histopathological examination are mandatory to exclude other panniculitis etiologies and subcutaneous metastasis of melanoma.

Panniculitis Under Successful Targeted Inhibition of the MAPK/ERK Signaling Pathway in a Patient With BRAF V600E-mutated Spindle Cell Oncocytoma of the Pituitary Gland

“…metastatic melanoma patients with BRAF V600E mutation, potential side effects are well known (6,7). Panniculitis has been reported as a rare adverse effect induced by BRAF inhibitors (15), MEK inhibitors (16) and the combined administration of both agents (17). In our patient, drug-induced panniculitis was observed, which typically affects predominantly upper and lower extremities (17).…”

Dabrafenib‐induced neutrophilic panniculitis in a child undergoing dual BRAF‐MEK inhibitor therapy for glioblastoma multiforme

“…3,4 Our patient was on dual BRAF-MEK inhibitor therapy with dabrafenib and trametinib when the eruption occurred. Although a single case of suspected MEK inhibitor-induced panniculitis has been reported in a patient undergoing dual BRAF-MEK inhibitor therapy, 5 this adverse event is generally thought to be caused by the BRAF inhibitor in such scenarios, as there have been no reported cases of panniculitis while on MEK inhibitor monotherapy. 1 Similar to other reported cases of vemurafenib-induced panniculitis, our patient's symptoms developed within several weeks of starting dabrafenib with a waxing and waning course.…”

Deciphering the Role of Combination Therapy of Cobimetinib, Vemurafenib, and Antidepressant Drugs in QTc Prolongation and Torsade De Pointes (TDP) in Malignant Melanoma

“…The common side-effects of BRAF inhibitors are cutaneous toxicity, nephrotoxicity, and cardiotoxicity. 1 In a previous clinical study, the combined administration of vemurafenib and cobimetinib has been associated with cardiotoxicity (heart failure) and QTc prolongation, that persisted after the discontinuation of therapy but returned to normal after six months. The patient was discharged with an implantable intracardiac defibrillator (ICD) for safety.…”