17/01/2017. ckit NRAS BRAF MEK ERK. ANTITUMOR IMMUNE RESPONSE PROLIFERATION
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1 BRAF inhibitors: vemurafenib (Zelboraf ) dabrafenib (Tafinlar ) Universitair Ziekenhuis Gent MEK inhibitors: cobimetinib trametinib(mekinist ) selumetinib CUTANEOUS SIDE EFFECTS OF BRAF-INHIBITORS Lieve Brochez Hoogleraar Dermatologie Bestuurslid Immuno-oncologisch NetwerkGent (ION-Gent) BestuurslidCancer Research Institute Ghent (CRIG) Voorzitter Belgian Association of Dermato-Oncology (BADO) c-kit inhibitors: imatinib(glivec ) nilotinib(tasigna ) Dasatinib(Sprycel ) ckit NRAS BRAF MEK ERK Lieve.Brochez@ugent.be ANTITUMOR IMMUNE RESPONSE PROLIFERATION Anti CTLA4: ipilimumab (Yervoy ) Anti-PD1: nivolumab (Opdivo ) pembrolizumab (Keytruda ) Photosensitivity Facial erythema Cheilitis Xerosis Hyperkeratoses Keratosis follicularis Hand Foot Skin Reaction Other: mucosal (oral, vulvar), nipple Milia- Cystic lesions VerrucousPapilloma Keratoacanthoma SpinocellularCA Eruptive nevi second primary melanoma Radiodermitis Panniculitis Hair changes - alopecia * BoussemartL et al. Prospective study of cutaneousside-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol Feb 13. [Epubahead of print] **darocha Dias S. EurJ Cancer 2013 Adapted from BoussemartL. Ann Oncol
2 Photosensitivity mainly to UVA UVA penetrates clouds and glass UVA only slightly fluctuates during the day and with seasons DummerR. NEJM 2012 BoussemartL et al. Prospective study of cutaneousside-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol Feb 13. [Epubahead of print] ±1/3 pruritus R/: lower washing frequency, tepid water oily soaps nutritive cream 2
3 comparable to HFSR in multikinase inhibitors e.g. sorafenib and sunitinib mainly soles / palms esp. pressure points e.g. heel, MTP hyperkeratosis, erythema may be painful PREVENTION - cotton socks - adapted footwear - protect pressure points TREATMENT - preparations with ureum10-50% or salicylic acid 5-10% - topical corticoids in erythema - pedicure / podiatrist PREVENTIVE TREATMENT - emollient creams - ureum5-10% preparations mucosal: vulvar, oral nipple ±1/3 from 7-15w after start of R/ 70% 10% 20% nodular lesions with verrucous, hyperkeratotic aspect multiple > face, trunk 3
4 17/01/2017 Treatment: Verrucous papilloma: - cryo - curettage Kerato-acanthoma / SCC: - excision ; no interruption BRAFi Vemurafenib-related cutaneous side effects ameliorated by acitretin. J Drugs Dermatol. 2014; 13(5): 586 RISK FACTORS: Age 65j Increased prior sun exposure geographical variations PROGNOSIS: Low metastatic potential Spontaneous regression possible (after R/ stop) 4
5 MECHANISM: - Role HPV? Koilocyt-like cells in some lesions - Paradoxical stimulation MAPK pathway during BRAFi in case of BRAFwt and RAS mutation MEKi COMBI treatment : BRAFi + MEKi syngergistic antitumor activity decrease of proliferative skin lesions eruptive nevi in 10% darkening of the nevi changes of nevi BRIM 3: Phase 3 trial comparing RO in comparison with dacarbazine in previously untreated patients with metastastic melanoma vemurafenib(n=5) dacarbazine(n=6) Total body examination + dermoscopy 6 atypical lesions excised (n=4) No lesions excised 5 melanomas (BRAF wt) 5
6 Stop BRAFi5 half lives before and after RT Imke Satzger et al. JCO 2013;31:e220-e222 Hair loss(8-36%) / thinning Changes in structure (curly hair) Changes in color (greying) Friable nails Colorchanges of the nails R/ NSAID systemic corticoids 6
7 CUTANEOUS SIDE EFFECTS OF BRAF-INHIBITORS CONCLUSIONS CUTANEOUS SIDE EFFECTS: -FREQUENT -PREDOMINANT -AFFECTING QUALITY OF LIFE PATIENT EDUCATION e.g. photosensitivity e.g. prevention of HFSR BRAF inhibitors: vemurafenib (Zelboraf ) dabrafenib (Tafinlar ) DERMATOLOGICAL FOLLOW-UP - before start - after 6-10w - photographic documentation Induction of: KA, SCC Melanoma (?) Other malignancies?? Repercussions for use in the adjuvant setting at least in monotherapy BRAF inhibitors: vemurafenib (Zelboraf ) dabrafenib (Tafinlar ) 7
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