Prospective Case Series of Cutaneous Adverse Effects Associated With Dabrafenib and Trametinib

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1 670368CMSXXX / Journal of Cutaneous Medicine and SurgeryLacroix and Wang research-article2016 Original Article Prospective Case Series of Cutaneous Adverse Effects Associated With Dabrafenib and Trametinib Journal of Cutaneous Medicine and Surgery 2017, Vol. 21(1) The Author(s) 2016 Reprints and permissions: sagepub.com/journalspermissions.nav DOI: / jcms.sagepub.com Jean-Philip Lacroix 1 and Beatrice Wang 1 Abstract Background: Dabrafenib, a novel selective small-molecule inhibitor of BRAF, has been shown to increase overall survival in patients with unresectable metastatic melanoma harboring the BRAF V600E mutation. The development of resistance has led to combination therapy with selective MEK inhibitor trametinib. Compared with vemurafenib, dabrafenib is a more recent BRAF inhibitor approved by the Food and Drug Administration in May 2013 for metastatic melanoma; fewer data are available in the current literature regarding cutaneous toxicity. Objectives: We sought to present additional cutaneous side effects of dabrafenib and trametinib and follow their evolution and management. Methods: We carried out a prospective study of 14 patients treated with dabrafenib alone or with trametinib. Patients were followed every 4 weeks, and we collected detailed cutaneous symptoms, photos, and biopsy specimens. Results: All patients presented with at least 1 adverse skin reaction. The mean duration of treatment was 24 weeks. The most common adverse effect was papillomas (7/14), followed by palmoplantar hyperkeratosis (5/14), alopecia (5/14), and seborrheic dermatitis-like eruption (2/14). Three patients who received trametinib developed an acneiform eruption (3/5). One patient developed a keratoacanthoma-like squamous cell carcinoma. Side effects presented as early as 2 weeks after starting therapy, with a mean time of onset of 9 weeks. Conclusion: Selective BRAF inhibitor dabrafenib and MEK inhibitor trametinib are associated with multiple skin adverse effects. Given their recent approval and the potential for malignant lesions to develop on treatment, awareness of potential adverse effects and their management is necessary. Keywords cancer, pathology, melanoma, drug reaction Metastatic melanoma has a poor prognosis, with the median survival for patients with stage IV melanoma ranging from 8 to 18 months after diagnosis. 1 The incidence of melanoma has been increasing over the past years, and it is estimated that the lifetime risk of developing an invasive melanoma for an American is 1 in 50 in Genetic mutations in the mitogen-activated protein kinase pathway (MAPK; RAS- RAF-MEK-ERK mitogen-activated protein kinase pathway) are present in 40% to 60% of cutaneous melanomas, with the most common mutation in BRAF V600E in 90%. 3,4 Dabrafenib is an oral, small-molecule kinase inhibitor that targets selectively activated BRAF V600E oncoprotein, thereby inhibiting this pathway that is important in melanoma tumorigenesis. 5 Dabrafenib was approved by the Food and Drug Administration (FDA) in May 2013 for unresectable metastatic melanoma with BRAF V600E mutation. Dabrafenib has been shown to improve response rates progression-free survival and overall survival in patients harboring a V600E mutation. 6 Inhibition of the MAPK pathway in keratinocytes can result in inflammation, decreased keratinocyte cell migration, and keratinocyte cell death, causing dermatologic side effects. 7 Noncutaneous adverse reactions to BRAF inhibitors include fatigue, nausea, arthralgias, and diarrhea. Cutaneous adverse effects are the most common toxicity to BRAF inhibitors, affecting 74% of patients. Several clinical trials and clinical studies documented cutaneous adverse effects of BRAF inhibitor agents such as photosensitivity, palmarplantar hyperkeratosis, keratosis-pilaris like eruptions, keratoacanthomas (KA), and squamous cell carcinomas (SCC) Most studies describe cutaneous adverse effects of vemurafenib, another selective BRAF V600E inhibitor that was approved by the FDA in 2011 for treatment of metastatic melanoma harboring the BRAF V600E mutation. However, 1 McGill University, Division Dermatology, Montréal, QC, Canada Corresponding Author: Jean-Philip Lacroix, McGill University, Division Dermatology, 377 des seigneurs street, app 610, Montréal, QC H3J 0A9, Canada. jeanphilip.lacroix@gmail.com

2 Lacroix and Wang 55 Table 1. Clinical characteristics of each patient. Patient No. Characteristic Targeted therapy D D D D D D D + T D D D + T D D + T D + T D + T Age, y Sex M F M M F M M M M F F F M F Duration of treatment, wk Abbreviations: D, Dabrafenib; F, female; M, male; T, Trametinib. there are limited data available in the current literature regarding cutaneous toxicity of the more recent BRAF inhibitor dabrafenib, mainly because of its more recent use. No head-to-head trials have been conducted to compare the clinical efficacy of vemurafenib and dabrafenib. Both are selective BRAF inhibitors with proven efficacy in BRAF V600E metastatic melanoma, but differences exist with regard to toxicity profile and prospective evidence for activity against brain metastases. Trials of dabrafenib and vemurafenib suggest less frequent cutaneous toxicities related to dabrafenib compared with vemurafenib. Photosensitivty seems to be a vemurafenib-specific side effect. 6 There is stronger prospective evidence that dabrafenib has proven intracranial activity compared with vemurafenib. 12 Trametinib is a potent selective inhibitor of MEK in the MAPK pathway and has been approved as an oral daily treatment of metastatic or unresectable melanoma with BRAF B600E or B600K gene mutation. Multiple trials combining BRAF inhibitor with trametinib in phase 1/2 trials showed reduction in potential for resistance and decreased cutaneous adverse effects. 7,13 In a study of 109 patients, Flaherty et al 9 reported SCC in less than 1% of patients. Combining BRAF inhibitors and MEK inhibitors was associated with an increased risk of developing acneiform eruption. 14 A recent phase 3 trial of 423 patients comparing the use of dabrafenib alone or combination therapy with trametinib showed that combination therapy improved the rate of progression-free survival and reported decreased cutaneous side effects. 15 Methods Between November 2014 and November 2015, 14 patients (8 men and 6 women) with a mean age of 59 years (range, 46-47) who were treated with dabrafenib (9 patients) or dabrafenib combination with trametinib (5 patients) underwent a dermatologic evaluation and photography every 4 weeks. Patients were followed in the multidisciplinary oncology-dermatology melanoma clinic of the Royal-Victoria Hospital. Detailed descriptions of clinical and pathological features as well as characterization of the severity and evolution of these cutaneous adverse effects were undertaken. Data were collected at each clinic visit during this study. Patients were questioned about skin symptoms and skin events. Cutaneous lesions occurring during therapy were photographed and biopsied for histologic examination if necessary. Four patients received a 4-mm skin biopsy to classify the cutaneous adverse effect. Our cohort was not part of a randomized controlled trial. The study was approved by the full board ethics review of the McGill University Health Center Research Institute. Results All patients experienced at least 1 cutaneous adverse effect, with a mean time of onset of 9 weeks. The diverse cutaneous adverse effects that occurred in each patient under dabrafenib or in combination with trametinib are reported in Tables 1, 2, and 3. Both benign and malignant skin tumors occurred during therapy, but the most common adverse effect was the appearance of benign papillomas (7/14), with a mean time to onset of 7 weeks (Figure 1). Five patients developed hand-foot skin reactions predominantly of the soles (5/14). Patients developed diffuse yellowish hyperkeratosis localized on the pressure points of the foot (Figure 2). The mean time of onset was 7 weeks, and it occurred as early as 4 weeks. Patients were treated with a keratolytic cream such as urea-based cream (20%), which improved the discomfort of patients. No mucosal hyperkeratosis or paronychia was observed. Alopecia was also common and occurred in 5 of 14 patients. The hair change consists of diffuse hair thinning over the scalp, and severity increased with prolonged duration of treatment (Figure 3). Minoxidil 5% showed mild improvement in 1 patient. One patient also developed alopecia of bilateral lateral eyebrows. Mean time of onset was 10 weeks, and it occurred as early as 6 weeks. Three patients receiving combination therapy of dabrafenib and trametinib developed acneiform eruption (Figure 2). Monomorphic papules and pustule developed predominantly over the trunk and face. Patients significantly improved with clindamycin lotion or a short course of oral antibiotics in the tetracycline family. Two patients on dabrafenib developed seborrheic dermatitis-like eruption of the face at a mean time of onset of 16 weeks (Figure 2). Patients were successfully treated with topical hydrocortisone 1% cream in combination with topical ciclopirox. One patient in our cohort developed a KA over the shoulder (Figure 4) that was excised. The lesion occurred at 8 weeks of treatment with dabrafenib only and grew rapidly over weeks, showing an erythematous plaque with a keratin-filled crater in

3 56 Journal of Cutaneous Medicine and Surgery 21(1) Table 2. Timeline of cutaneous adverse effects of each patient. Week Patient Papilloma, PPHK Alopecia Seborrheic dermatitis 2 Alopecia 3 Papilloma, PPHK Seborrheic dermatitis 4 PPHK Papilloma 5 6 PPHK, darkening nevi Alopecia 7 Acneiform 8 Papilloma 9 PPHK Papilloma, SCC-KA 10 Acneiform 11 Papilloma, milia-cyst 12 Alopecia 13 Acneiform 14 Papilloma, alopecia, lipomas Abbreviations: PPHK, palmar-plantar hyperkeratosis; SCC-KA, squamous cell carcinoma, keratoacanthoma. Table 3. Cutaneous adverse effects reported among the 14 patients, classified in the order of decreasing frequency. Cutaneous Side Effects the center. One patient developed multiple milia cysts on the face and forehead. One patient developed darkening of existing nevi but no new development of nevi and not associated with atypical clinical features. One patient developed multiple subcutaneous nodules mainly over the trunk and upper extremities. Those lesions started to appear at 8 weeks of treatment, and additional nodules appeared over weeks. In total, 7 subcutaneous nodules were noted, and histology was consistent with cutaneous lipoma (Figure 5). Discussion Total Patients Affected (%) Mean Time of Onset, wk Papillomas 7 (50) 8 Palmar-plantar 5 (36) 7 hyperkeratosis Alopecia 5 (36) 10 Acneiform eruption 3 (21) 4 Seborrheic dermatitis 2 (14) 16 Squamous cell carcinoma, 1 (7) 8 keratoacanthoma Milia-cyst 1 (7) 8 Darkening melanocytic nevi 1 (7) 8 Multiple lipomas 1 (7) 8 All 9 In our study, we notice that different cutaneous adverse effects occurred at different times. Acneiform eruptions and palmoplantar hyperkeratosis occurred earlier than other cutaneous adverse effects, whereas seborrheic dermatitis was a late complication occurring at 16 weeks of treatment (Table 2). Papillomas clinically appear as small (3-5 mm) hyperkeratotic skin-colored to brown polypoid papules mainly over the trunk but also occurred on the face, neck, and extremities (Figure 1A). Histology shows features of verruca vulgaris such as hyperkeratosis, hypergranulosis, and acanthosis with absence of squamous dysplasia. They are also referred in the past literature as verrucous keratosis or warty dyskeratoma. The mechanism underlying development of KA and SCCs in patients with BRAF inhibitor is related to wild-type BRAF keratinocyte undergoing paradoxical increased MAPK signalling under pharmacologic RAF blockade. 16 Heidorn et al 17 showed that paradoxical activation of the MAPK pathway in normal wild-type keratinocytes leads to increased keratinocyte proliferation and may also be responsible for the clinical findings of papillomas. Activation of MAPK signalling by itself is not sufficient to induce SCCs and KAs. Oberholzer et al 18 showed that RAS-activating mutations are found more frequently in SCCs and KAs from patients treated with the BRAF inhibitor vemurafenib (30%) and sorafenib (11%) compared with those from control patients (3.2%). Heidorn et al showed that BRAF inhibitor binds to wild-type in KRASmutant cells and promotes the formation of CRAF complexes, resulting in activation of the MEK-ERK pathway. 17,19 To our knowledge, this is the first case description of the occurrence of multiple lipomas during dabrafenib and trametinib therapy. Porras et al 20 showed that the Raf kinase mutation part of the MAPK pathway in adipocytes is implicated in inducing adipocytes differentiation. Whether

4 Lacroix and Wang 57 Figure 1. (A) Hyperkeratotic skin-colored papule on neck. (B) Biopsy specimen demonstrating hyperkeratosis, acnanthosis, and papillomatosis in the absence of squamous dysplasia, consistent with papillomas (hematoxylin-eosin stain; original magnification: 20 ). (C) Hyperkeratotic skin-colored plaque on arm. (D) Biopsy specimen demonstrating changes consistent with papillomas (hematoxylin-eosin stain; original magnification: 40 ). Figure 2. (A) Palmoplantar hyperkeratosis: painful, yellow, hyperkeratotic plaques of feet. (B) Seborrheic dermatitis-like eruption of face. (C) Multiple milia-like cysts of the face. (D) Acneiform eruption of forehead.

5 58 Journal of Cutaneous Medicine and Surgery 21(1) Figure 3. (A-C) Progressive diffuse hair thinning at 12, 16, and 20 weeks of treatment with dabrafenib. (D, E) Progressive diffuse hair thinning at 12 and 20 weeks of treatment with dabrafenib. (F) Lateral eyebrow alopecia. Figure 4. (A) Volcano-like plaque with keratin-filled center. (B) Biopsy showing keratin-filled crater with pale eosinophilic epithelial proliferation with mild cytologic atypia (hematoxylin-eosin stain; original magnification: 40 ). a RAS-activating mutation leads to paradoxical adipocyte proliferation when using a BRAF inhibitor, as was shown in keratinocytes and keratinocytic proliferation, remains to be proven. Several studies combining trametinib with BRAF inhibitors in phase 1/2 trials for melanoma showed potential reduction in BRAF inhibitor resistance and decreased incidence of SCC side effects. 7 No patient developed SCC or KA in our cohort receiving combination therapy. In a phase 1/2 expansion cohort of BRAF inhibitor and MEK inhibitor, 6% had exanthems and none reported SCCs in a total of 43 melanoma patients. 20 The rate of acneiform eruption on combination therapy was estimated to be 8% in a recent phase 3 trial of 423 patients. 15 Photosensitivity has been shown to occur in 12% of patients taking vemurafenib and is rarely reported with dabrafenib. 6,8 We report no photosensitivity in our cohort in both patients treated with monotherapy and patients treated with combination therapy with trametinib. We also report no morbilliform eruption in our cohort. In conclusion, selective BRAF inhibitor dabrafenib and MEK inhibitor trametinib are associated with multiple cutaneous adverse effects. Given their recent approval and the potential for malignant lesions to develop on treatment,

6 Lacroix and Wang 59 Figure 5. (A) Subcutaneous nodule of anterior shoulder. (B) Proliferation of normal-appearing adipocytes consistent with lipoma (hematoxylin-eosin stain; original magnification: 40 ). awareness of potential adverse effects and their management is necessary. Acknowledgments We acknowledge the McGill University Health Center and the Canadian Dermatology Foundation for the supporting this project. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the Canadian Dermatology Foundation. References 1. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36): Rigel DS, Russak J, Friedman R. The evolution of melanoma diagnosis: 25 years beyond the ABCDs. CA Cancer J Clin. 2010;60(5): Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892): Dong J, Phelps RG, Qiao R, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003;63(14): Lemech C, Arkenau HT. Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clin Med Insights Oncol. 2012;6: Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAFmutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839): Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013;27(1): Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26): Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9): Chu EY, Wanat KA, Miller CJ, et al. Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study. J Am Acad Dermatol. 2012;67(6): Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sensitivity skin reaction after ipilimumab. N Engl J Med. 2012;366(9): Menzies AM, Long GV, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther. 2012;6: Lavoie H, Therrien M. Cancer: a drug-resistant duo. Nature. 2011;480(7377): Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20): Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20): Hatzivassiliou G, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287): Heidorn SJ, Song K, Yen I, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell, (2): p Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30(3): Cichowski K, Janne PA. Drug discovery: inhibitors that activate. Nature. 2010;464(7287): Porras A, Muszynski K, Rapp UR, Santos E. Dissociation between activation of Raf-1 kinase and the 42-kDa mitogenactivated protein kinase/90-kda S6 kinase (MAPK/RSK) cascade in the insulin/ras pathway of adipocytic differentiation of 3T3 L1 cells. J Biol Chem. 1994;269(17):