Adverse Cutaneous Reactions to Targeted Anti‐Cancer Therapies

Jonathan Cotliar, MD Clinical Associate Professor & Chief Division of Dermatology City of Hope National Medical Center

Disclosures • Consultant for Xcovery

Objectives • Discuss the role of the dermatologist in the care of cancer  p patients • Recognize Recognize the diverse clinical presentation of adverse  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?

Oncodermatology • Expanding dermatology  subspecialty b i lt • Partnership with oncologists Afatinib (Gilotrif)

• Availability • Supportive care to facilitate  cancer treatment • FFamiliarity with spectrum of  ili i ih f chemotherapeutics & targeted  anti‐cancer drugs and their  associated cutaneous toxicities

EGFR Inhibitors EGFR Inhibitors

Challenges in Oncodermatology Challenges in Oncodermatology • Keeping patients on therapy • Toxicities worse than cancer • Inability to improve cutaneous toxicities • Lack of dermatologists/ access

Chemotherapeutics •

Alkylating agents

Classic: cyclophosphamide, ifosmamide, thiotepa Platinum agents: cisplatin, carboplatin, oxaliplatin

•

Antimetabolites

Analogs: cytarabine, fludarabine, cladribine, gemcitabine,   pemetrexed Fluorouracil: 5FU, capecitabine, tegafur Fluorouracil: 5FU, capecitabine, tegafur

•

Antitumor antibiotics

Anthracyclines: doxorubicin, daunorubicin Bleomycin

•

Mitotic inhibitors

Taxanes: docetaxel, paclitaxel Vinca alkaloids: vincristine, vinblastine, vinorelbine Macrocyclic analogue: eribulin

•

Topoisomerase inhibitors Topoisomerase inhibitors

Topoisomerase I: topotecan, irinotecan Topoisomerase II: etoposide, teniposide, amsacrine

Targeted anti‐cancer Targeted anti cancer agents agents Monoclonal Antibodies • Rituximab • Trastuzumab • Alemtuzumab • Cetuximab • Bevacizumab • Panitumumab • Ofatumumab • Pertuzumab Obinutuzumab • • Ramucirumab • Siltuximab • Dinutuximab • Darzalex/daratumumab • Elotuzumab • Ibritumomab tiuxetan • Tositumumab • Brentuximab • Ado‐trastuzumab Transcription/ Translational Inhibitors • Decitabine • Vorinostat p • Romidepsin • Omacetaxine • Belinostat • Panobinostat • Trabectedin DNA Repair Inhibitors • Olaparib

Immunomodulatory Drugs • Thalidomide • Lenalidomide • Ipilimumab • Pomalidomide • Binatumomab • Pembrolizumab • Nivolumab Signal Transduction Inhibitors Signal Transduction Inhibitors • Imatinib • Gefitinib • Trametinib • Erlotinib • Sorafenib • Dasatinib • Sunitinib • Lapatinib • Temsirolimus • Nilotinib • Everolimus • Pazopanib • Vandetanib • Vemurafenib • Crizotinib • Ruxolitinib Proteosome Inhibitors • Bortezomib • Carfilzomab • Ixazomib

regorafinib cabozantinib ponatinib dabrafenib afatinib ibrutinib ceritinib zydelig levatinib palbociclib alectinib bosutinib Ziv‐affibercept g Vismodegib Axitinib

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

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

• Overlap of reactions to chemotherapy  • Toxic effect on eccrine ducts, acrosyringium, epidermis • Areas Areas of involvement reflect high density of eccrine glands of involvement reflect high density of eccrine glands • Shared histologic features • Cytarabine, Cyclophosphamide, Anthracyclines, 5 Cytarabine, Cyclophosphamide, Anthracyclines, 5‐‐FU,  Capecitabine, Taxanes, Methotrexate

Toxic Erythema of Chemotherapy (TEC)

TEC • • • • • •

Hands, feet , Flexural, intertriginous Painful or asymptomatic Desquamation Recurrent/ progressive Hi t l i f t Histologic features: – Keratinocyte dysmaturation,  apoptosis, necrosis – Vacuolar degeneration l d i – Eccrine squamous  syringometaplasia

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

Toxic Erythema of Chemotherapy B l Bolognia et al. 2008 i l 2008

•

AraC ears

•

Burgdorf’s reaction

•

Eccrine squamous syringometaplasia

•

Intertriginous eruption associated  with chemotherapy

•

Flexural erythematous eruption

– –

Acral erythrodysesthesia Chemotherapy‐‐induced acral  Chemotherapy induced acral erythema Hand‐‐foot syndrome Hand Palmar‐‐plantar erythema Palmar plantar erythema

•

Intertrigo dermatitis

–

Palmar‐‐plantar erythrodysesthesia Palmar

•

Neutrophilic eccrine hidradenitis

•

Chemotherapy‐ Chemotherapy h h ‐induced hidradenitis h

– –

•

Epidermal dysmaturation

Toxic acral erythema Toxic erythema of the palms and Toxic erythema of the palms and  soles

•

Chemotherapy‐‐induced epidermal  Chemotherapy induced epidermal dystrophy

• Acral erythema Acral erythema – –

TEC Pearls TEC 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 dressings g • 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 HFS Braik 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 Syndrome Hand Foot Syndrome Acral erythrodysesthesia Chemotherapy‐‐induced acral erythema Chemotherapy Acral erythema P l Palmar‐ Palmar ‐plantar erythema l t th Palmar‐‐plantar erythrodysesthesia Palmar Toxic acral erythema Toxic acral erythema Toxic erythema of the palms and soles

Toxic Erythema of Chemotherapy: Hand Foot Syndrome subtype Hand Foot Syndrome subtype (HFS)

How to grade HFS How to grade HFS

Nail Toxicities Nail Toxicities

Nail Toxicities Nail 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 literature and meta‐analysis. The British journal of dermatology. Feb 21 2015. 

Nail Toxicities Nail Toxicities • Treatment strategies: Treatment strategies: ‐ ‐ ‐ ‐ ‐

Minimizing wet work, hand work Refraining from  manicures/pedicures Vinegar soaks Vinegar soaks Cold gloves? Culture!!!

Secondary Nail Infections Secondary Nail Infections

Prevention/ Treatment of nail infections Prevention/ Treatment of nail infections • • • • • • •

Suspect gram negative, fungal organisms Culture!!! Ciprofloxacin Examine prior to treatment Avoid manicures/pedicures Mupirocin, Cephalexin for Gram+ Vi Vinegar soaks QD‐BID  k QD BID (1/2 cup warm H2O, 1/2 cup white vinegar)

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

Hand Foot Skin Reaction (HFSR)

Zuo et al. JAMA Derm Feb 2015 

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

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

•

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

•

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

•

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

•

Axitinib‐ VEGFR‐1, VEGFR‐2, VEGFR‐3‐ Renal Cell Ca HFSR 29%



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



Vemurafenib, Dabrafenib‐BRAF‐ melanoma HFSR 10‐20%



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

Sunitinib

Sorafenib

Cabozantinib

Regorafenib

Axitinib

Sorafenib

What’ss the difference? What the difference? Hand Foot Syndrome Hand Foot Syndrome

Hand Foot Skin Reaction Hand Foot Skin Reaction

What’ss the difference? What the difference? HFSR

HFS

HFSR

What’ss the difference? What the difference?

How to treat HFS/HFSR How to treat HFS/HFSR • • • • • • • • • • •

•

Minimizing hand/foot use O th ti Orthotics, cotton socks, avoid tight‐ tt k id ti ht 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 melanoma Targeted agents for melanoma

BRAF Inhibitors BRAF Inhibitors •

Metastatic or unresectable  melanoma

•

Vemurafenib, Dabrafenib

•

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

BRAF Inhibitors BRAF Inhibitors •

74% develop skin toxicity

•

Rash in nearly 18‐27% Rash in nearly 18 27%  (dose (dose‐dependent) 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 Hand‐foot‐skin reaction ti Photosensitivity‐ 42% Keratosis pilaris‐like Pruritus Acneiform eruption Acneiform eruption Alopecia Panniculitis

Vemurafenib

Vemurafenib

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

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

MEK Inhibitors MEK Inhibitors

MEK Inhibitors MEK Inhibitors • •

Trametinib‐ inhibits MEK1/MEK2‐ alone or w/ dabrafenib alone 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 Inhibitors Checkpoint Inhibitors

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

Ipilimumab •

•

•

Fully human monoclonal antibody  to  cytotoxic T‐lymphocyte  antigen (CTLA)‐4 Approved for unresectable or  metastatic melanoma Most common toxicities: Rash Pruritus Diarrhea/ colitis

earliest onset http://www.nzmu.co.nz/anti‐ctla‐4‐inhibitors

Ipilimumab • •

Incidence of Derm AEs 44%  High‐grade 2.4%

•

Pruritus

•

Morbilliform, reticulated,  erythematous, papular, sarcoidal

•

Vitiligo (favorable prognosis)

•

Perivascular lymphocytes,  eosinophils i hil

•

Reactive treatment with topical/  systemic steroids antihistamines systemic 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. 

Ipilimumab M billif Morbilliform

P Papular l

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

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

PD‐1 PD 1 Inhibitors Inhibitors • •

Nivolumab‐ melanoma, NSCLC, RCC, HL Pembroli mab melanoma, NSCLC,  Pembrolizumab‐ melanoma NSCLC H&N SCC

• • • • • • • • • • • •

Fatigue P Pyrexia, chills, infusion reactions i hill i f i ti Diarrhea/ colitis Hypophysitis Hypo/hyperthyroidism Adrenal insufficiency Hepatitis Pneumonitis Myasthenia gravis y 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 PD 1 Inhibitors and Skin Toxicity Inhibitors and Skin Toxicity  42% Pembrolizumab pts w/ skin AEs 42% P b li b t / ki AE Morbilliform Papulopustular Pruritus Hypopigmentation Alopecia Lipson EJ, Forde PM, Hammers HJ, Emens Lipson EJ Forde PM Hammers HJ Emens LA, Taube JM, Topalian LA Taube JM Topalian SL. Antagonists of  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 Cutaneous Adverse 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 markers of efficacy

PD‐1 PD 1 Inhibitors and Psoriasis Inhibitors and Psoriasis

PD‐1 PD 1 Inhibitors and Psoriasis Inhibitors and Psoriasis

PD‐1 PD 1 Inhibitors and Psoriasis 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 Mucosa l Melanoma. JAMA dermatology. Jul 2015;151(7):797‐799. 

Pembrolizumab and Hypertrophic Lichen Planus

Pembrolizumab and Sarcoidosis Pembrolizumab and Sarcoidosis

Hedgehog pathway Inhibitors Hedgehog pathway Inhibitors

Hedgehog pathway Inhibitors Hedgehog pathway Inhibitors • •

Vismodegib, Sonidegib M Metastatic BCC or locally advanced  i BCC l ll d d 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”)

• • • •

FFatigue ti Nausea Diarrhea KA/SCC?

Vismodegib

Conclusions • Oncodermatology will continue to grow • Universal nomenclature is important • Dermatology participation in pilot studies, grading  schema management of cancer pts is vital schema, management of cancer pts is vital • Be Be aware of autoimmune dermatoses from PD aware of autoimmune dermatoses from PD‐ PD‐1  1 inhibitors

Dermatology at City of Hope Dermatology at City of Hope • Oncodermatology clinic • Primary care dermatology • Inpatient consult service • Multidisciplinary GVHD clinic Multidisciplinary Cutaneous • Multidisciplinary Cutaneous  lymphoma clinic • Cutaneous Immunotherapy  clinic • Dermatopathology • Oncodermatology fellowship [email protected]