Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers

Abstract

Background Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed. Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also reported. Twice daily oral ulixertinib was administered at 10 to 900 mg in the dose escalation cohort (n = 27) and at 600 mg in 21-day cycles in the expansion cohort (n = 108). Results The incidence of ulixertinib-induced dAEs and combined rash were 79% (107/135) and 76% (102/135). The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. The presence of at least 1 dAE was associated with stable disease (SD) or partial response (PR) (OR = 3.64, 95% CI 1.52-8.72; P = .003). Acneiform rash was associated with a PR (OR = 10.19, 95% CI 2.67-38.91; P < .001). Conclusion The clinical spectrum of ulixertinib-induced dAEs was similar to EGFR and MEK inhibitors; dAEs may serve as a surrogate marker of tumor response. We propose treatment algorithms for common ERK inhibitor-induced dAEs to maintain patients' quality of life and dose intensity for maximal clinical benefit. Clinical Trial Registration: NCT01781429.

Keywords: Clinical trial; Dermatologic adverse events; ERK inhibitor; Ulixertinib.

Figures

Figure 1.. Clinical spectrum of dermatologic adverse events (dAEs) associated with ulixertinib.

(A) Acneiform rash: an eruption of acne-like erythematous papules and pustules on the seborrheic area of skin, including central face, chest, and upper back. (B) Acneiform rash with secondary bacterial infection: numerous yellowish pustules on the background of erythema, swelling, warmth, and tenderness of the arm. (C) Maculopapular rash: generalized erythematous macules and papules which may involve trunk, face, and extremities and can become confluent into large patches and plaques. (D) Dry skin with crackling and eczematous change on the dorsal hands. (E) Pruritus with scratch marks on the buttocks. (F) Trichomegaly of eyelashes.

Figure 2.. Histopathological features of dAEs associated with ulixertinib.

(A) The histopathology of acneiform rash showed typical presentation of suppurative superficial folliculitis with numerous neutrophils. (B)The histopathology of maculopapular rash showed interface dermatitis with perivascular and interstitial lymphoeosinophilic infiltrate. (C) The histopathology of photosensitivity showed spongiotic interface dermatitis with prominent exocytosis, focal acantholysis, sparse apoptotic bodies, and a perivascular lymphocytic infiltrate with eosinophils. (D) The skin biopsy of skin infection showed perivascular and interstitial dermal edema, predominantly neutrophilic infiltrate with eosinophils, compatible with cellulitis.

Figure 3.. Considerations for management of dAEs associated with ulixertinib

Examples of topical steroids include hydrocortisone 2.5% cream/ alclometasone 0.05% cream for the face and fluocinonide 0.05% cream/ mometasone 0.1% cream/ triamcinolone acetonate 0.1% cream/ clobetasol propionate 0.05% cream (ointment/ foam) for the body. BID, twice daily.