Une nouvelle Dermatologie

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Toxicité cutanée des thérapies ciblées
Vincent SIBAUD, Dermatologue Unités de Recherche Clinique et de Phase I Centre Régional de Lutte contre le Cancer – Toulouse
sibaud.vincent@claudiusregaud.fr
Vendredi 11 avril 2014
thérapies ciblées
‐Mab = monoclonal antibodies
BEVACIZUMAB
RITUXIMAB
TRASTUZUMAB
PANITUMUMAB
CETUXIMAB
PERTUZUMAB
thérapies ciblées
ximab = anticorps chimérique anticorps chimérique
‐ximab
‐zumab = anticorps humanisé
‐mumab = anticorps humain
‐Momab = anticorps murin
BEVACIZUMAB
RITUXIMAB
TRASTUZUMAB
PANITUMUMAB
CETUXIMAB
PERTUZUMAB
thérapies ciblées
‐ximab = anticorps chimérique ‐zumab = anticorps humanisé
‐mumab = anticorps humain
‐Momab = anticorps murin
tu = tumoral (ou ti)
‐tuximab = anticorps chimerique p
q
‐tuzumab = anticorps humanisé
‐tumumab
tumumab = anticorps humain
= anticorps humain
RITUXIMAB (MabThera®)
TRASTUZUMAB (Herceptin®)
PANITUMUMAB (Vectibix®)
PANITUMUMAB (Vectibix®)
CETUXIMAB (Erbitux®)
PERTUZUMAB
IPILIMUMAB (Y
IPILIMUMAB (Yervoy®)
®)
BEVACIZUMAB (Avastin®)
thérapies ciblées
‐nib = inhibiteur (tyrosine) kinase
IMATINIB
AFATINIB
AXITINIB
ERLOTINIB
SUNITINIB
DASATINIB
NILOTINIB
TRAMETINIB
LAPATINIB
VANDETANIB
PAZOPANIB
SORAFENIB
GEFITINIB
REGORAFENIB REGORAFENIB
TRAMETINIB
VEMURAFENIB
DABRAFENIB
Inhibiteurs récepteurs EGF
Cetuximab (Erbitux®): cancer du colon, ORL
Erlotinib (Tarceva®): cancer du poumon, pancréas
Panitinumab (Vectibix®): cancer du colon
(Vectibix®): cancer du colon
Lapatinib (Tyverb®): cancer du sein (HER1+HER2)
Maubec E. Phase II study of cetuximab as first‐line single‐drug therapy in patients with unresectable squamous cell carcinoma of
the skin. J Clin Oncol 2011; 29: 3419‐26.
Caron J. Metastatic basal cell carcinoma: report of two cases treated with cetuximab. Br J Dermatol 2009; 161: 702‐3.
Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer, 2006.
Inhibiteurs récepteurs EGF - anti MEK
Papulopustules and/or paronychia,
paronychia regulatory
abnormalities of hair growth, itching, and
dryness due to epidermal growth factor
receptor inhibitors
Lacouture ME The PRIDE syndrome Br J Dermatol 2006
Lacouture ME. The PRIDE syndrome. Br J Dermatol, 2006. Nb: Trastuzumab (Herceptine®), inhibiteur HER2 – pas de tox cutanée
Éruptions « acnéiformes » (80% des cas)
Robert C. cutaneous side effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005; 6: 491‐500.
É
Éruptions
« acnéiformes » (80% des cas)
Robert C, Sibaud V, Mateus C, Cherpelis BS. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 2012; 39: 227‐240.
Éruptions « acnéiformes » (80% des cas)
Segaert S. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005; 16: 1425‐1433.
Inhibiteurs MEK
Éruption folliculaire papulo-pustuleuse (77-80%)
Infante JR. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose‐
escalation
l i trial.
i l Lancet Oncol
O l 2012;
2012 13:
13 773‐81.
3 81
Querfeld C. Disseminated follicular eruption during therapy with the MEK inhibitor AZD6244. J Am Acad Dermatol, 2011.
Desar IME. Case studies showing clinical signs and management of cutaneous toxicity of the MEK1/2 inhibitor (ARRY‐142886) in patients with solid tumors. Acta Oncol 2010; 110‐3.
Lacouture ME. Skin toxicity evaluation protocol with panitunumab (STEPP), a phase II, open‐label, randomized trial evaluating the impact of a pre‐emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol, 2010.
Que « nous apporte » cette dermatotoxicité?
Marqueur de réponse thérapeutique
Petrelli F. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta‐analysis of published trials. Targ Oncol, 2013.
Pettrelli F. Relationship between skin rash and outcome in non‐small –cell lung cancer patients treated with anti EGFR tyrosine kinase inhibitors: a literature‐based meta‐analysis of 24 trials. Lung Cancer 2012; 78: 8‐15.
y
g
;
Xérose cutanée (40%)
(
)
Heidary N. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol, 2008. Appareil peri‐unguéal
Fissures
Fissures Lacouture ME Clinical practice guidelines for the prevention and treatment of EGFR inhibitor associated dermatologic toxicities Support Care Cancer 2011; 19:
Lacouture ME. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor‐associated dermatologic toxicities. Support Care Cancer 2011; 19: 1079‐1095.
Thomas M, Robert C. Dermatologic manifestations of MEK inhibitors. In : Sibaud V, Robert C, eds. Skin side effects induced by targeted anticancer therapies : a new dermatology. Toulouse : Privat, 2010 ; 89‐ 94.
Appareil peri‐unguéal
Paronychies Inhibiteurs EGFR – MEK – mTOR
(afatinib, erlotinib, cetuximab, gefetinib, trametinib, selumetinib, everolimus, temsirolimus….)
Sibaud V and Robert C, Mateus C and Baran R. Nail toxicities induced by systemic anticancer treatments. Lancet Oncol, 2014 (submitted). Appareil peri‐unguéal
granulomes pyogeniques (20%)
Inhibiteurs EGFR – MEK – mTOR
Sibaud V, Chevreau C, Mourey L et al. Pyogenic granuloma induced by m TOR inhibitors. Acta Dermatol Venereol 2011; 91: 584‐5.
Granulomes pyogéniques ‐ prise en charge
Baran R. Nail toxicity of targeted anticancer therapies. In: Cutaneous side effects induced by targeted anticancer therapies: a new dermatology. Sibaud V, Robert C. Editions Privat.
Kiyohara Y. Erlotinb‐related skin toxicities : treatment strategies in patients with metastatic non small cell lung cancer. J Am Acad Dermatol, 2013.
Granulomes pyogéniques ‐
Granulomes
pyogéniques ‐ prise en charge prise en charge
podologique
Inhibiteurs EGFR – MEK – mTOR
Sibaud V and Robert C, Mateus C and Baran R. Nail toxicities induced by systemic anticancer treatments. Lancet Oncol, 2014 (submitted). Chimiothérapie et tablette unguéale (taxanes, capecitabine, doxorubicine, cisplatine, 5FU…)
Sibaud V and Robert C, Mateus C and Baran R. Nail toxicities induced by systemic anticancer treatments. Lancet Oncol, 2014 (submitted). Chimiothérapie et tablette unguéale
chimiothérapie
hyperpigmentation
Sibaud V, Fricain JC, Baran R, Robert C. Pigmentary disorders induced by anticancer agents. Part I: chemotherapy. Ann Dermatol Venereol 2013; 140: 183‐96.
Inhibiteurs récepteurs EGF et MEK
Trichomegalie - hypertrichose
Schad K. Mitogen‐activated protein/extracellular signal‐regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders Clin Cancer Res 2010; 16: 1058‐64
homeostasis with keratinocytic apoptosis and pigmentation disorders. Clin Cancer Res 2010; 16: 1058‐64.
Robert C, Sibaud V, Mateus C, Cherpelis BS. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 2012; 39: 227‐240.
Modifications des cheveux
Lynch TJ. Epidermal growth factor receptor inhibitor associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist, 2007. Agero R. Dermatologic side effects associated with the epidermal growth factor receptors inhibitors. J Am Acad Dermatol, 2006.
ge o
e a o og c s de e ec s assoc a ed
e ep de a g o
ac o ecep o s
b os
cad e a o , 006
Osio A. Cutaneous side effects in patients on long term treatment with epidermal growth factor receptor inhibitors. Br J Dermatol, 2009.
Alopecie chimiothérapie
Paus R, Haslam I, Sharov AA, Botcharev. Pathobiology of chemotherapy‐induced hair loss. Lancet Oncol 2013; 14:e50‐59.
Tallon B, Blanchard E, Goldberg LJ. Permanent chemotherapy‐induced alopecia: histopathologic criteria still to be defined. J Am Acad Dermatol 2013;68:e151‐2.
Alopecie chimiothérapie
Paus R, Haslam I, Sharov AA, Botcharev. Pathobiology of chemotherapy‐induced hair loss. Lancet Oncol 2013; 14:e50‐59.
Tallon B Blanchard E Goldberg LJ Permanent chemotherapy induced alopecia: histopathologic criteria still to be defined J Am Acad Dermatol 2013;68:e151 2
Tallon B, Blanchard E, Goldberg LJ. Permanent chemotherapy‐induced alopecia: histopathologic criteria still to be defined. J Am Acad Dermatol 2013;68:e151‐2.
Inhibiteurs (B)RAF
sorafenib (Nexavar®)
(
)
regorafenib (Stivarga®)
Vemurafenib (Zelboraf®)
(
)
dabrafenib (Tafinlar®)
Inhibiteur BRAF – Vemurafenib
Keratoacanthomes – carcinomes épidermoides (18-31%)
8 à 12 semaines- zones photo-exposées ou non – (H)RAS mutations
Sosman JA. Survival in BRAF V600‐mutant advanced melanoma treated with vemurafenib. N Eng J Med 2012; 366: 707‐714.
Chapman PB. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507‐2515.
Flaherty KT. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809‐19.
Inhibiteur BRAF – Vemurafenib
Lésions hyperkératosiques induites
•hyperkératose du mamelon
• Dyskératose
y
acantholytique
y q ((Grover-like))
•Lésions kystiques (épidermiques, miliaires…)
Anforth RM. Cutaneous Manifestations of Dabrafenib (GSK2118436): A Selective Inhibitor of Mutant BRAF in patients with Metastatic Melanoma. Br J Dermatol 2012; 167: 1153‐60.
Boyd KP. Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. J Am Acad Dermatol 2012; 67: 1375‐9.
Inhibiteurs BRAF
Lésions kystiques
Chu EY et al. Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study. J Am Acad Dermatol 2012; 67: 1265‐72.
Huang V. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol 2012; 148: 628‐33.
Inhibiteur BRAF
Keratose pilaire-like
pilaire like
Lacouture ME. Analysis of dermatologic events in vemurafenib‐treated patients with melanoma. The Oncologist 2013; 18: 314‐22.
inhibiteur BRAF
Syndrome main-pied
Sibaud V, Lamant L, Delord JP. Skin adverse events induced by BRAF inhibitors: a systematic review. Ann Dermatol Venereol 2013; 140: 510‐20.
Sibaud V et al. HFS 14: a specific quality of life scale for patients suffering from hand‐foot syndrome. The Oncologist 2011; 16: 1469‐78.
Syndrome main‐pied et thérapies ciblées (‐nib)
Incidence all grades (%)
all grades (%)
Incidence High grades (%)
High grades (%)
Regorafenib (Stivarga ®)
60,5
20,4
Sorafenib (Nexavar ®)
33,8
Sunitinib (Sutent®)
Cibles
indications
VEGFR 1‐3; PDGFR α‐β; c‐KIT; RAF;TIE‐2; RET; P38 MAPK, FGFR‐ 1
K colorectal
8,9
VEGFR 1‐3; PDGFR β; c‐KIT, RET, RAF
K hépato‐cellulaires et rénaux
18,9
5,5
VEGFR 1‐3; PDGFR β; c‐KIT, RET; Flt3; CSF‐1R K rein et GIST
Axitinib (Inlyta ®)
29,2
9,6
VEGFR 1‐3; PDGFR α‐β; c‐KIT K rein
Vemurafenib (Zelboraf®)
7‐23
2
BRAF
Mélanome métastatique et localement avancé 4,5
1,8
VEGFR 1‐3; PDGFR α‐β; c‐KIT; RAF
K rein
Pazopanib (Votrient®)
Balagula Y. The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta‐analysis. Invest New Drugs, 2011.
Belum VR The risk of hand foot skin reaction with the novel multikinase inhibitor regorafenib: a meta analysis Invest New Drugs 2013
Belum VR. The risk of hand foot skin reaction with the novel multikinase inhibitor regorafenib: a meta‐analysis. Invest New Drugs, 2013.
Fischer A. The risk of hand foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta‐analysis. Invest New Drugs, 2013.
Syndrome main-pied et chimiothérapie
(d
(doxorubicine,
bi i
capecitabine,
it bi
taxanes,
t
FU)
chimiothérapie
hyperpigmentation
Sibaud V, Robert C. pigmentary disorders induced by anticancer agents. Part II: targeted therapies. Ann Dermatol Venereol 2013; 140:266‐
73.
Syndrome main-pied et chimiothérapie
(d
(doxorubicine
bi i liposomale
li
l pegylée,
lé capecitabine…..)
it bi
)
Lassere Y. Management of hand‐foot syndrome in patients treated with capecitabine. Eur J oncol Nurs, 2004.
Abushullaih S. Incidence and severity of hand‐foot syndrome in colorectal cancer patients treated with capecitabine: a single‐institution experience. Cancer Invest, 2002.
Wasif Saif M. Capecitabine and hand‐foot syndrome. Exp Opin Drug Saf 2011; 10: 159‐69.
inhibiteur BRAF – Vemurafenib
naevi éruptifs
Sibaud V, Fricain JC, Baran R, Robert C. Pigmentary disorders induced by anticancer agents. Part I: chemotherapy. Ann Dermatol Venereol 2013; 140: 183‐96.
Sorafenib – vemurafenib -dabrafenib
naevi éruptifs
RAF inhibition
Kong HH, Sibaud V, Chevreau C. Sorafenib‐induced eruptive melanocytic lesions. Arch Dermatol 2008; 144: 820‐2. Munsch C, Lamant L, Sibaud V. Eruptive nevi with regorafenib: the first report of an ancient adverse event !. Clin Colorectal Cancer (submitted).
Capecitabine
Naevi induits
Sibaud V, Robert C. pigmentary disorders induced by anticancer agents. Part II: targeted therapies. Ann Dermatol Venereol 2013; 140:266‐
73.
inhibiteur BRAF – Vemurafenib
naevi éruptifs (10%) – Mélanomes de novo
Haenssle HA et al. Dynamic Changes in Nevi of a Patient With Melanoma Treated With Vemurafenib: Importance of Sequential Dermoscopy. Arch Dermatol 2012; 20:1‐3. Zimmer L et al Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing
Zimmer L et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012;30:2375‐83.
inhibiteur BRAF
Alopécie
p
Sibaud V, Lamant L, Delord JP. Skin adverse events induced by BRAF inhibitors: a systematic review. Ann Dermatol Venereol 2013; 140: 510‐20.
Toxicité buccale –ulcérations aphtoides
cetuximab
trametinib
everolimus
temsirolimus
sunitinib
everolimus
Sibaud V, Fricain JC. Oral manifestations induced by new targeted anticancer therapies. Ann Dermatol Venereol, 2013 (submitted).
Langue géographique et antiangiogéniques (sorafenib, sunitinib, bevacizumab)
Hubiche T, Valenza B, Chevreau C, Fricain JC, Del Giudice P, Sibaud V. Geographic tongue induced by angiogenesis inhibitors. Oncologist 2013; 18: e16‐7.
Hyperkétatose et inhibiteurs BRAF (vemurafenib)
BRAF (vemurafenib)
Boussemart L,et al. Prospective study of cutaneous side‐effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013;24:1691‐7. E synthèse
En
thè
• Peu
P d’
d’effets
ff t indésirables
i dé i bl « graves »; qualité
lité de
d vie
i souventt ttrès
è
altérée
•Approche multidisciplinaire
•Rôle fondamental du dermatologue
• Nouveaux effets indésirables à « découvrir » +++
• « Rôle de la peau » comme marqueur tumoral?
Balagula Y. The emergence of supportive oncodermatology: the study of dermatologic adverse events to cancer therapies. J Am Acad Dermatol 2011; 65: 624‐35. Balagula Y. The emergence of supportive oncodermatology: the study of dermatologic adverse events to cancer therapies. J Am Acad Dermatol 2011; 65: 624‐35
Dermatol 2011; 65: 624‐35.

Une nouvelle Dermatologie

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