Adverse Cutaneous Reactions to Targeted Anti‐Cancer Therapies

Jonathan Cotliar, MDClinical Associate Professor & Chief

Division of DermatologyCity of Hope National Medical Center

DisclosuresDisclosures

• Consultant for Xcovery

ObjectivesObjectives

• Discuss the role of the dermatologist in the care of cancer patientsp

• Recognize the diverse clinical presentation of adverseRecognize the diverse clinical presentation of adverse cutaneous reactions to traditional chemotherapeutic agents

• Recognize and treat cutaneous toxicities to targeted anti‐cancer drugs

What is Oncodermatology?What is Oncodermatology?

OncodermatologyOncodermatology• Expanding dermatology 

b i ltsubspecialty

• Partnership with oncologists

• Availability Afatinib (Gilotrif)

EGFR Inhibitors• Supportive care to facilitate cancer treatment

F ili i i h f

EGFR Inhibitors

• Familiarity with spectrum of chemotherapeutics & targeted anti‐cancer drugs and their associated cutaneous toxicities

Challenges in OncodermatologyChallenges in Oncodermatology

• Keeping patients on therapy

• Toxicities worse than cancer

• Inability to improve cutaneous toxicities

• Lack of dermatologists/ access

ChemotherapeuticsChemotherapeutics

• Alkylating agentsClassic: cyclophosphamide, ifosmamide, thiotepaPlatinum agents: cisplatin, carboplatin, oxaliplatin • Mitotic inhibitors

Taxanes: docetaxel, paclitaxel

• AntimetabolitesAnalogs: cytarabine, fludarabine, cladribine, gemcitabine,  

pemetrexedFluorouracil: 5FU, capecitabine, tegafur

Vinca alkaloids: vincristine, vinblastine, vinorelbineMacrocyclic analogue: eribulin

• Topoisomerase inhibitorsFluorouracil: 5FU, capecitabine, tegafur

• Antitumor antibioticsAnthracyclines: doxorubicin, daunorubicin

• Topoisomerase inhibitorsTopoisomerase I: topotecan, irinotecanTopoisomerase II: etoposide, teniposide, amsacrine

Bleomycin

Targeted anti‐cancer agentsTargeted anti cancer agentsMonoclonal Antibodies• Rituximab• Trastuzumab

Immunomodulatory Drugs• Thalidomide• Lenalidomide• Trastuzumab

• Alemtuzumab• Cetuximab• Bevacizumab• Panitumumab• Ofatumumab• Pertuzumab• Obinutuzumab

• Lenalidomide• Ipilimumab• Pomalidomide• Binatumomab• Pembrolizumab• Nivolumab

Signal Transduction InhibitorsObinutuzumab• Ramucirumab• Siltuximab• Dinutuximab• Darzalex/daratumumab• Elotuzumab• Ibritumomab tiuxetan• Tositumumab

Signal Transduction Inhibitors• Imatinib regorafinib• Gefitinib cabozantinib• Trametinib ponatinib• Erlotinib dabrafenib• Sorafenib afatinib• Dasatinib ibrutinib• Sunitinib ceritinibTositumumab

• Brentuximab• Ado‐trastuzumab

Transcription/ Translational Inhibitors• Decitabine• Vorinostat• Romidepsin

Sunitinib ceritinib• Lapatinib zydelig• Temsirolimus levatinib• Nilotinib palbociclib• Everolimus alectinib• Pazopanib bosutinib• Vandetanib Ziv‐affibercept• Vemurafenib Vismodegibp

• Omacetaxine• Belinostat• Panobinostat• Trabectedin

DNA Repair Inhibitors• Olaparib

g• Crizotinib Axitinib• Ruxolitinib

Proteosome Inhibitors• Bortezomib• Carfilzomab• Ixazomib

Toxic Erythema of Chemotherapy (TEC)Toxic Erythema of Chemotherapy (TEC)

Toxic Erythema of Chemotherapy (TEC)B l i l JAAD 2008Bolognia et al. JAAD 2008

•• Overlap of reactions to chemotherapy Overlap of reactions to chemotherapy 

•• Toxic effect on eccrine ducts, acrosyringium, epidermisToxic effect on eccrine ducts, acrosyringium, epidermis

•• Areas of involvement reflect high density of eccrine glandsAreas of involvement reflect high density of eccrine glandsAreas of involvement reflect high density of eccrine glandsAreas of involvement reflect high density of eccrine glands

•• Shared histologic featuresShared histologic features

•• CytarabineCytarabine, Cyclophosphamide, Anthracyclines, 5, Cyclophosphamide, Anthracyclines, 5‐‐FU, FU, Capecitabine, Taxanes, MethotrexateCapecitabine, Taxanes, Methotrexate

Toxic Erythema of Chemotherapy (TEC)

TECTEC

• Hands, feet,• Flexural, intertriginous• Painful or asymptomatic• Desquamation• Recurrent/ progressive

Hi t l i f t• Histologic features:– Keratinocyte dysmaturation, 

apoptosis, necrosisl d i– Vacuolar degeneration

– Eccrine squamous syringometaplasia

Parker TL, Cooper DL, Seropian SE, Bolognia JL. Toxic erythema of chemotherapy followingi.v. BU plus fludarabine for allogeneic PBSC transplant. Bone marrow transplantation. 2012. 

Toxic Erythema of ChemotherapyB l i l 2008Bolognia et al. 2008

•• AraC earsAraC ears • Acral erythema•• Burgdorf’s reactionBurgdorf’s reaction

•• Eccrine squamous syringometaplasiaEccrine squamous syringometaplasia

Acral erythema

–– Acral erythrodysesthesiaAcral erythrodysesthesiaChemotherapyChemotherapy induced acralinduced acral•• Intertriginous eruption associated Intertriginous eruption associated 

with chemotherapywith chemotherapy

•• Flexural erythematous eruptionFlexural erythematous eruption

–– ChemotherapyChemotherapy‐‐induced acral induced acral erythemaerythema

–– HandHand‐‐foot syndromefoot syndromePalmarPalmar plantar erythemaplantar erythema

•• Intertrigo dermatitisIntertrigo dermatitis

•• Neutrophilic eccrine hidradenitisNeutrophilic eccrine hidradenitis

h hh h hh

–– PalmarPalmar‐‐plantar erythemaplantar erythema–– PalmarPalmar‐‐plantar erythrodysesthesiaplantar erythrodysesthesia–– Toxic acral erythemaToxic acral erythema–– Toxic erythema of the palms andToxic erythema of the palms and•• ChemotherapyChemotherapy‐‐induced hidradenitisinduced hidradenitis

•• Epidermal dysmaturationEpidermal dysmaturation

•• ChemotherapyChemotherapy‐‐induced epidermalinduced epidermal

–– Toxic erythema of the palms and Toxic erythema of the palms and solessoles

ChemotherapyChemotherapy induced epidermal induced epidermal dystrophydystrophy

TEC PearlsTEC Pearls

• Tender rather than pruritic

• Can develop late and last 2‐3 weeks beyond tx

• Mistaken for acute GVHD

• Sometimes anatomic site trumps morphology

• Check dressingsg

• Pyridoxine (Vitamin B6)?

Pyridoxine (B6) for TEC?Pyridoxine (B6) for TEC?

• Ota et al. 2014‐ 60mg QD ineffective for HFS in CRC pts on capecitabine

• Braik et al 2014‐ 100mg QD ineffective for HFSBraik et al. 2014 100mg QD ineffective for HFS

• Myung et al. 2015‐ effective for tx HFS but not prophylaxis

• Chen et al. 2013‐ 400mg pyridoxine may be effective to prevent HFS

• Macedo et al. 2014‐ celecoxib efficacious for prophylaxis of HFS

Hand Foot Syndrome

• Subtype of TEC

• Prodrome of dysesthesia

• Painful, symmetric erythema, edema

• Blisters, erosions

Hand Foot SyndromeHand Foot Syndrome

Acral erythrodysesthesiaAcral erythrodysesthesiaChemotherapyChemotherapy‐‐induced acral erythemainduced acral erythemaAcral erythemaAcral erythemaP lP l l t thl t thPalmarPalmar‐‐plantar erythemaplantar erythemaPalmarPalmar‐‐plantar erythrodysesthesiaplantar erythrodysesthesiaToxic acral erythemaToxic acral erythemaToxic acral erythemaToxic acral erythemaToxic erythema of the palms and solesToxic erythema of the palms and soles

Toxic Erythema of Chemotherapy:Hand Foot Syndrome subtypeHand Foot Syndrome subtype

(HFS)

How to grade HFSHow to grade HFS

Nail ToxicitiesNail Toxicities

Nail ToxicitiesNail Toxicities

• Taxanes, Anthracyclines, Capecitabine

• Docetaxel 35%• Paclitaxel  44%

Capriotti K, Capriotti JA, Lessin S, et al. The risk of nail changes with taxane chemotherapy: a systematic review of the literatureand meta‐analysis. The British journal of dermatology. Feb 21 2015. 

Nail ToxicitiesNail Toxicities

• Treatment strategies:Treatment strategies:

‐ Minimizing wet work, hand work‐ Refraining from 

manicures/pedicures‐ Vinegar soaksVinegar soaks‐ Cold gloves?‐ Culture!!!

Secondary Nail InfectionsSecondary Nail Infections

Prevention/ Treatment of nail infectionsPrevention/ Treatment of nail infections

• Suspect gram negative, fungal organisms• Culture!!!• Ciprofloxacin• Examine prior to treatment• Avoid manicures/pedicures• Mupirocin, Cephalexin for Gram+

Vi k QD BID• Vinegar soaks QD‐BID (1/2 cup warm H2O, 1/2 cup white vinegar)

Toxicities to targeted anti‐cancer agentsToxicities to targeted anti cancer agents

Hand Foot Skin Reaction(HFSR)

Zuo et al. JAMA Derm Feb 2015 

Multikinase inhibitors (MKIs) that cause HFSRMultikinase inhibitors (MKIs) that cause HFSR

• Sorafenib‐ VEGFR, PDGFR, C‐raf, B‐raf‐ Renal Cell Ca, Hepatocellular CaHFSR 34%

• Sunitinib‐ VEGFR, PDGFR, c‐KIT, FLT3, RET, G‐CSF1R‐ Renal Cell Ca, GISTHFSR 19%

• Pazopanib‐ VEGFR‐1, VEGFR‐2, VEGFR‐3, PDGFR, c‐KIT‐ Renal Cell Ca, soft tissue sarcomaHFSR 4.5%

• Regorafenib‐ VEGFR,TIE‐2, KIT, REF, RAF‐1, BRAF, PDGFR – Colorectal Ca, Hepatocellular Ca, GISTHFSR 61%

• Axitinib‐ VEGFR‐1, VEGFR‐2, VEGFR‐3‐ Renal Cell CaHFSR 29%

Cabozantinib‐VEGFR‐2, c‐MET, RET‐Medullary Thyroid CaHFSR 54%HFSR 54%

Vemurafenib, Dabrafenib‐BRAF‐melanomaHFSR 10‐20%

Lapatinib‐ dual TKI (HER2/neu, EGFR)‐ Metastatic Breast ca

SunitinibSunitinib

SorafenibSorafenib

CabozantinibCabozantinib

RegorafenibRegorafenib

AxitinibAxitinib

SorafenibSorafenib

What’s the difference?What s the difference?

Hand Foot Syndrome Hand Foot Skin ReactionHand Foot Syndrome Hand Foot Skin Reaction

What’s the difference?

HFSR HFS HFSR

What s the difference?

HFSR HFS HFSR

What’s the difference?What s the difference?

How to treat HFS/HFSRHow to treat HFS/HFSR• Minimizing hand/foot use

O th ti tt k id ti ht• Orthotics, cotton socks, avoid tight‐fitting shoes, running

• Emollients• Keratolytics‐ urea• High‐potency topical steroids• Topical anesthetics• NSAIDs, GABA agonists, opioids• Pyridoxine (B6)Pyridoxine (B6)• Cold gloves• Celecoxib• Vit E

• Stop anti‐cancer drug/ dose reduction

Targeted agents for melanomaTargeted agents for melanoma

BRAF InhibitorsBRAF Inhibitors

• Metastatic or unresectable melanomamelanoma

• Vemurafenib, Dabrafenib

• Fatigue, arthralgias, nausea, g , g , ,diarrhea, AKI

BRAF InhibitorsBRAF Inhibitors• 74% develop skin toxicity• Rash in nearly 18‐27% (dose‐dependent)Rash in nearly 18 27%  (dose dependent)• Erythema, morbilliform, papulopustular, KP‐like

• Verruca• Eruptive KA, SCC‐ 20%• Warty dyskeratoma• Grover’s disease• Wild‐type melanoma• Nevi

H d f t ki ti• Hand‐foot‐skin reaction• Photosensitivity‐ 42%• Keratosis pilaris‐like• Pruritus• Acneiform eruptionAcneiform eruption• Alopecia• Panniculitis

VemurafenibVemurafenib

VemurafenibVemurafenib

Belum VR, Fischer A, Choi JN, Lacouture ME. Dermatological adverse events from BRAFDermatological adverse events from BRAF inhibitors: a growing problem. Current oncologyreports. Jun 2013;15(3):249‐259. 

Lacouture ME, Duvic M, Hauschild A, etal. Analysis of dermatologic events in vemurafenib‐treated patients with melanoma. The oncologist. 2013;18(3):314‐322. 

MEK InhibitorsMEK Inhibitors

MEK InhibitorsMEK Inhibitors• Trametinib‐ inhibits MEK1/MEK2‐

alone or w/ dabrafenibalone or w/ dabrafenib• Cobimetinib (w/ vemurafenib)• Selumetinib, Binimetinib

• Morbilliform eruption (dose‐dependent) 46‐74%

• Papulopustular eruption‐ decreased incidence in BRAF/MEK combo

• Xerosis• Alopecia• Paronychia• Mitigate eruptive SCC from BRAF 

inhibitors

Jae Jung, MD, PhD

Checkpoint InhibitorsCheckpoint Inhibitors

http://www.nzmu.co.nz/anti‐pd‐1‐inhibitors

IpilimumabIpilimumab• Fully human monoclonal antibody 

to  cytotoxic T‐lymphocyte antigen (CTLA)‐4

• Approved for unresectable or metastatic melanoma

• Most common toxicities:RashPruritusDiarrhea/ colitis http://www.nzmu.co.nz/anti‐ctla‐4‐inhibitors

earliest onset

IpilimumabIpilimumab• Incidence of Derm AEs 44% • High‐grade 2.4%

• Pruritus

• Morbilliform, reticulated, erythematous, papular, sarcoidal

• Vitiligo (favorable prognosis)

• Perivascular lymphocytes, i hileosinophils

• Reactive treatment with topical/ systemic steroids antihistaminessystemic steroids, antihistamines

Lacouture ME, Wolchok JD, Yosipovitch G, Kahler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. Journal of the American Academy of Dermatology. Jul 2014;71(1):161‐169. 

IpilimumabIpilimumab

M billif P lMorbilliform Papular

Lacouture ME, Wolchok JD, Yosipovitch G, Kahler KC, Busam KJ, Hauschild A.Ipilimumab in patients with cancer and the management of dermatologicand the management of dermatologic adverse events. Journal of the AmericanAcademy of Dermatology. Jul 2014;71(1):161‐169. 

PD‐1, PD‐L1 InhibitorsPD 1, PD L1 Inhibitors

PD‐1 InhibitorsPD 1 Inhibitors• Nivolumab‐melanoma, NSCLC, RCC, HL• Pembroli mab melanoma NSCLC• Pembrolizumab‐melanoma, NSCLC, 

H&N SCC

• FatigueP i hill i f i ti• Pyrexia, chills, infusion reactions

• Diarrhea/ colitis• Hypophysitis• Hypo/hyperthyroidism• Adrenal insufficiency• Hepatitis• Pneumonitis• Myasthenia gravisy g• Uveitis• Interstitial nephritis• Pancreatitis 

Naidoo J, Page DB, Li BT, et al. Toxicities of the anti‐PD‐1 and anti‐PD‐L1 immune checkpoint antibodies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Dec 2015;26(12):2375‐2391.

PD‐1 Inhibitors and Skin ToxicityPD 1 Inhibitors and Skin Toxicity

42% P b li b t / ki AE 42% Pembrolizumab pts w/ skin AEsMorbilliformPapulopustularPruritusHypopigmentationAlopecia

Lipson EJ Forde PM Hammers HJ Emens LA Taube JM Topalian SL Antagonists ofLipson EJ, Forde PM, Hammers HJ, Emens LA, Taube JM, Topalian SL. Antagonists of PD‐1 and PD‐L1 in Cancer Treatment. Seminars in oncology. Aug 2015;42(4):587‐600. 

Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab CutaneousAdverse Events and Their Association With Disease Progression.JAMA dermatology. Jul 29 2015. 

JAAD March 2016

82 patients

40/82 (49%) developed adverse skin events

Unclear if adverse events surrogate markersof efficacy

PD‐1 Inhibitors and PsoriasisPD 1 Inhibitors and Psoriasis

PD‐1 Inhibitors and PsoriasisPD 1 Inhibitors and Psoriasis

PD‐1 Inhibitors and PsoriasisPD 1 Inhibitors and Psoriasis

Pembrolizumab

Nivolumab

Sahuquillo‐Torralba A, Ballester‐Sanchez R, Pujol‐Marco C, Botella‐Estrada R. Pembrolizumab: a new Drug That Can Induce Exacerbations of Psoriasis.Actas dermo‐sifiliograficas. Nov 3 2015. 

Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of Psoriasiform Eruption During Nivolumab Therapy for Primary Oral Mucosal Melanoma. JAMA dermatology. Jul 2015;151(7):797‐799. 

Pembrolizumab and Hypertrophic Lichen Planus

Pembrolizumab and SarcoidosisPembrolizumab and Sarcoidosis

Hedgehog pathway InhibitorsHedgehog pathway Inhibitors

Hedgehog pathway InhibitorsHedgehog pathway Inhibitors• Vismodegib, Sonidegib

M i BCC l ll d d• Metastatic BCC or locally advanced that can’t be tx with surgery/XRT

• 25% serious adverse events• Leg cramps/muscle spasms (68%)‐

amlodipine, Gatorade, Mg• Alopecia (10‐63%)‐minoxidil• Dysgeusia (23 57%) zinc• Dysgeusia (23‐57%)‐ zinc, 

Synsepalum dulcificum (“miracle fruit”)

F ti• Fatigue• Nausea• Diarrhea• KA/SCC?KA/SCC?

VismodegibVismodegib

ConclusionsConclusions

•• Oncodermatology will continue to growOncodermatology will continue to grow

•• Universal nomenclature is importantUniversal nomenclature is important

•• Dermatology participation in pilot studies, grading Dermatology participation in pilot studies, grading schema management of cancer pts is vitalschema management of cancer pts is vitalschema, management of cancer pts is vitalschema, management of cancer pts is vital

•• Be aware of autoimmune dermatoses from PDBe aware of autoimmune dermatoses from PD‐‐11Be aware of autoimmune dermatoses from PDBe aware of autoimmune dermatoses from PD 1 1 inhibitorsinhibitors

Dermatology at City of HopeDermatology at City of Hope

• Oncodermatology clinic• Primary care dermatology• Inpatient consult service

• Multidisciplinary GVHD clinic• Multidisciplinary CutaneousMultidisciplinary Cutaneous 

lymphoma clinic• Cutaneous Immunotherapy 

clinicclinic• Dermatopathology• Oncodermatology fellowship

jcotliar@coh.org