Multikinase inhibitors: Multikinase inhibitors: Regorafenib skin toxicity. Cutaneous side effects of multikinase-inhibitors and their management

Transcription

1 TARGETED THERAPIES AND THEIR CUTANEOUS TOXICITIES Brussels, 14/1/2017 Cutaneous side effects of multikinase-inhibitors and their management Siegfried Segaert Dermatology Dept. Uinversity Hospital Leuven 4 th BADO meeting Brussels, January 14 th 2017 Multikinase inhibitors: - Regorafenib (Stivarga ; VEGFR1-3, (B)RAF, PDGFRβ, c-kit) - Sorafenib (Nexavar ; RAF, VEGFR2-3, PDGFRβ, FLT3) - Sunitinib (Sutent ; c-kit, VEGFR2, PDGFRβ, FLT3) - Imatinib (Gleevec, c-kit, BCR-ABL, PDGFRβ) - Axitinib, linifanib, pazopanib Multikinase inhibitors: - Sorafenib (Nexavar ) - Sunitinib (Sutent ) - Imatinib (Gleevec ) - Regorafenib (Stivarga ) Regorafenib: AEs in previously-treated mcrc The most common ( 10%) drug-related, treatment-emergent AEs of any grade experienced by patients enrolled in CORRECT 1 Regorafenib skin toxicity Regorafenib + BSC (n=500) Placebo + BSC (n=253) Treatment-related adverse event, % All grades Grade 3 Grade All 4 grades Grade Grade 3 4 Hand foot skin 47% 17% 0 8% <1% 0 reaction Fatigue 47% 9% <1% 28% 5% <1% Diarrhea 34% 7% <1% 8% 1% 0 Anorexia 30% 3% 0 15% 3% 0 Voice changes 29% <1% 0 6% 0 0 Hypertension 28% 7% 0 6% 1% 0 Oral mucositis 27% 3% 0 4% 0 0 Rash or desquamation 26% 6% 0 4% 0 0 Nausea 14% <1% 0 11% 0 0 Weight loss 14% 0 0 2% 0 0 Thrombocytopenia 13% 3% <1% 2% <1% 0 Fever 10% 1% 0 3% 0 0 Grothey A, et al. Lancet. 2013;381:

2 Hand-Foot Skin Reaction (HFSR) HFSR over time HFSR is distinct from the more widely known hand foot syndrome (HFS also known as PPE, palmar-plantar erythrodysesthesia) which occurs with older therapies such as capecitabine 1 Cutaneous areas typically affected by HFSR are those under the most pressure or friction, such as the palms of the hand, soles of the feet, fingers or toes 1,2 HFSR typically develops soon (2 4 weeks) after a patient starts treatment 2 HFSR is not life-threatening and usually resolves with appropriate management and/or dose modification 2 Frequency of HFSR (%) # Patients at risk Treatment Cycle CORRECT (n=500) Grade 1 Grade 3 1. Wood LS, et al. Commun Oncol. 2010;7: Lacouture ME, et al. Oncologist. 2008;13: AE, adverse events; CORRECT, COloRectal cancer treated with REgorafenib or Grothey A, et al. ASCO GI, Abstract 467. placebo after failure of standard Therapy; mcrc, metastatic colorectal cancer. HFSR: clinical presentation Grade 1 HFSR is characterized by lesions localized to frictional and weight bearing areas of the skin (heels, metatarsal heads, ) 1,2 Initially, affected areas become tender and erythematous 1 Lesions become edematous and evolve into painful blisters 1 Blisters transform into painful calluses (thickening of the epidermis) affecting the patient s ability to perform daily activities 1,2 Photographs courtesy of Kathleen Polson, N.P. 1. Lacouture ME, et al. Oncologist. 2008;13: Wood LS, et al. Commun Oncol 2010;7:23-9. Grade 1 2

3 Grade 3 Grade 3 3

4 HFSR: symptoms : clinical picture HFSR symptoms may include: 1,2 Tenderness Dysesthesia and paresthesia (numbness feeling of pins and needles) Pain Intolerance to contact with hot objects often precedes or accompanies HFSR 3 Hand-foot syndrome Lesions on friction/pressure points Entire palms/soles Onset after days to weeks Onset after weeks to months Painful blister callus Erythema, edema, scaling Dysesthesia, pain Dysesthesia, pain Regorafenib, sorafenib, sunitinib, 5-FU, capecitabine vemurafenib, dabrafenib, axitinib, doxorubicine, cytarabine pazopanib Insufficient repair of frictional skin trauma due to inhibition VEGFR + PDGFR Concentration of cytostatic in skin via eccrine sweat ducts 1. Wood LS, et al. Commun Oncol. 2010;7: Lacouture ME, et al. Oncologist 2008;13: Robert C, et al. J Am Acad Dermatol. 2009;60: McLellan et al. Ann Oncol 2015; 26: , : histopathology : pathophysiology Repetitive frictional trauma on thick epidermis of palms and soles Repair mechanisms fail due to inhibition of VEGFR and PDGFR Keratinocyte necrosis spongiosis (intraepidermal edema) blister formation Intensive inflammation Hyperproliferation of epidermal keratinocytes Hyperkeratosis and callus formation Faivre et al. J Clin Oncol 2006; 24: Yang et al. Br J Dermatol 2008; 158: McLellan et al. Ann Oncol 2015; 26: , 4

5 : treatment : treatment - Preventive measures: - remove calluses before starting treatment - avoid friction, pressure, irritation - nicely fitting shoes (no sandals or slippers) / cotton socks - wear gloves for washing, cleaning, working - don t wash hands too often and avoid very hot water use wash oil e.g. Eucerin wash oil - use hand- or foot cream hand cream: Neutrogena, Huizinga Fagron, Eucerin hand cream foot cream: Xerial feet, Eucerin foot cream - pressure absorbing silicone shoe sole - Ultrapotent topical steroids for inflammation (redness, blisters) e.g. Dermovate, preparation with salicylic acid + clobetasolpropionate - Urea or salicylic acid ointment for hyperkeratosis (callus) e.g. Xerial 10 (feet), Xerial 30, Xerial 50 salicylic acid in preparation by dermatologist - Topical anaesthetics for pain e.g. Xylocain gel - Oral analgetics for pain if insufficient - When the lesions are wet, take a swab and use oral antibiotics (adjust according to antibiogram) e.g. fluxloxacillin, cefuroxim HFSR management: dose modifications Maculopapular rash GRADE 1 GRADE 2 GRADE 3 First Occurrence Maintain dose level Consider decreasing dose by 1 dose level and institute Institute immediate support measures. Interrupt and institute immediate immediate supportive measures. therapy for a minimum of 7 days until toxicity supportive measures If no improvement, interrupt therapy for a minimum of 7 resolves to Grade 0-1. for symptomatic relief days, until toxicity resolves to grade 0 1. When resuming treatment, decrease dose by 1 A dose reescalation is permitted at the discretion of the dose level. A dose reescalation is permitted at treating physician the discretion of the treating physician Second Occurrence *Interrupt therapy until toxicity resolves to Grade 0-1. Institute immediate supportive measures. When resuming treatment, treat at reduced dose level. Interrupt therapy for a minimum of 7 days until A dose reescalation is permitted at the discretion of the toxicity resolves to grade 0 1. When resuming treating physician treatment, decrease dose by 1 additional dose level Third Occurrence Skin rash may occur in patients treated with kinase inhibitors, including regorafenib 26% of patients enrolled in CORRECT who were treated with regorafenib experienced skin rash or desquamation (all grades), compared with 4% of patients treated with placebo 1 Symptoms associated with skin rash may include: 2-4 Erythematous macules or papules, suddenly appearing in a symmetrical way Itch Rarely pain, blisters, mucosal involvement in severe cases Interrupt therapy until toxicity resolves to Grade 0-1. When resuming treatment, treat at reduced dose level (minimum 80 mg daily). A dose reescalation is permitted at the discretion of the treating physician Discontinue treatment permanently Fourth Occurrence Discontinue therapy permanently Lacouture ME, et al. Oncologist. 2008;13: Grothey A, et al. Lancet. 2013;381(9863): Porta C. Clin Exp Med. 2007;7: Bellmunt J, et al. Crit Rev Onc. 2010;78: Wood LS. Commun Oncol. 2006;3: Rash over time Grade 1 Grade 3 Grade 4 Frequency of AE (%) RASH Treatment Cycle n Grothey A, et al. ASCO GI Abstract

6 -3-3 Grade 3 Grade 3 6

7 Maculopapular rash Stomatitis Oral antihistamine for itch e.g. loratadine daytime, hydroxyzine evening Anti-itch cream e.g. menthol cream Potent topical steroid for moderate to severe rashes e.g. clobetasolpropionate cream (Dermovate ) Oral steroids - Common (27%) days after start - Risk factors: old age, poor dental hygiene, poor nutritional status - Preventive measures: * dental care * mouth wash * avoid hot or spicy food - Treatment * mouthwash containing saline ± antiseptic ± antifungal ± anaesthetic Dose modification / interruption may be required for severe rash Retreatment is possible except for Stevens-Johnson syndrome, TEN or DRESS Alarm symptoms: pain, blisters, facial swelling, mucosal erosions De Wit et al. Support Care Cancer 2014; 22: Hair changes Eruptive naevi Mild alopecia Depigmentation Curly hair Sibaud et al. Eur J Dermatol 2015; 25:85-6. Sibaud et al. Eur J Dermatol 2015; 25:85-6. Regorafenib skin toxicity (50%) Alopecia (30%), depigmentation of hair, curly hair Maculopapular rash (25%) Stomatitis (25%) Seborrheic dermatitis-like rash face and scalp Eruptive naevi Keratoacanthoma Skin toxicity of other MKIs: - Sorafenib - Sunitinib - Imatinib 7

8 Sorafenib skin toxicity Sorafenib skin toxicity (35% - 70%) Seborrheic dermatitis-like rash face and scalp (65%) Maculopapular rash (20-35%) Alopecia, curly hair Stomatitis (20%) Xerosis, itch (esp. scalp), eczema Subungual splinter haemorrhages (30%) Keratosis pilaris-like follicular hyperkeratosis (20%) Inflamed seborrheic keratosis (10%) Keratinocyte neoplasia (keratosis, keratoacanthoma, SCC) (5%) Eruptive naevi (1%) Radiation recall dermatitis Sorafenib: subungual splinter haemorrhages Sorafenib: keratinocyte neoplasia Splinter haemorrhages: reflection of anti-vegfr or anti-angiogenesis effects? Robert et al. Ann Intern Med 2005; 143: Sorafenib: keratosis pilaris-like follicular hyperkeratosis Sunitinib skin toxicity Stomatitis Facial / periorbital edema Yellow discolouration of the (facial) skin Hair depigmentation Subungual splinter haemorrhages Seborrheic dermatitis-like rash face and scalp (acneiform eruption?) Xerosis, itch (esp. scalp), eczema Genital and scrotal irritation Lee et al. Br J Dermatol 2009; 161:

9 Sunitinib: hair depigmentation Sunitinib: hair depigmentation caused by inhibition c-kit (sunitinib) (anti-kit Ab) Faivre et al. J Clin Oncol 2006; 24: Moss et al. J Pharmacol Exp Ther 2003; 307: Imatinib skin toxicity Imatinib-induced edema Edema (eyelid, facial to generalized) Pigmentary changes - localized or general depigmentation (esp. dark skin) - hyperpigmentation (4%) - repigmentation of grey hair (7%) Rash (including AGEP, erythroderma, pityriasis rosea-like) Pruritus Xerosis Arora et al. Ann Oncol 2004; 15: Valeyrie et al. J Am Acad Dermatol 2003; 48: Legros et al. Br J Dermatol 2005; 153: Thank you for your kind attention! 9