Update on Cutaneous Reactions to and Therapy U031... · 1 U031‐Update on Cutaneous Reactions to Targeted and Immune Therapy Anisha B. Patel, M.D. Assistant Professor, Dermatology

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U031‐ Update on Cutaneous Reactions to Targeted and Immune Therapy

Anisha B. Patel, M.D.Assistant Professor, DermatologyUT MD Anderson Cancer Center

UT Health Science Center‐ Houston

Outline and Objectives

• Background• Cutaneous adverse events (CAEs) from immune checkpoint inhibitor therapy– Updates– Treatment pearls– Hair and nails

• CAEs as prognostic indicators

Significance• Quality of Life

– Pain– Pruritus– Emotional/social impact– Activities of daily living

• Cancer therapy– 76%, EGFR inhibitors

• 70% patients (reduction), 30% (discontinuation)

– 30‐50%, immune checkpoint inhibitors• 20% (reduction or discontinuation)

Chan A, Cameron MC, Garden B, et al. Support Care Cancer. 2015.Welborn M, Kubicki S, Hashmi O, Zahirrudin S, Patel AB. Unpublished.

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BackgroundCytotoxic chemotherapy

• Target rapidly replicating cells

• Emergence in early 1900s

• Increased systemic toxicities

• Hair: Anagen effluvium

• Skin: Toxic erythema

• Nails: Onycholysis, Beau’s lines, Pigmentation change

Targeted therapies

• Targeted inhibition of small molecules– Higher efficacy for cancer treatment

• Emergence in early 1990s

• Decreased systemic toxicities

• New hair, skin, nail toxicities

Immune checkpoint inhibitors

Godwin JL, ZibelmanM, Plimack ER, et al. Discov Med. 2014.



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Immune checkpoint inhibitorsCTLA4 inhibitors

• Ipilimumab‐ Mar 2011, metastatic melanoma

• Tremelimumab‐ failed Phase III trials for melanoma, Phase I‐III trials for various solid organ malignancies





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• Tremelimumab‐ failed Phase III trialsfor melanoma, Phase I‐III trials for various solid organ malignancies

PD‐1 inhibitors

• Nivolumab‐ Dec 2014, metastatic melanoma

• Pembrolizumab‐ Sep 2014, metastatic melanoma

PD‐L1 inhibitors

• Atezolizumab‐ May 2016, urothelial carcinoma

• Avelumab‐ March 2017, Merkel cell carcinoma

• Durvalumab‐ May 2017, urothelial carcinoma


Chen L, Flies DB. Nat Rev Immunol. 2013.



• Tremelimumab‐ failed Phase III trials

PD‐1 inhibitors

• Nivolumab‐ Dec 2014, metastatic melanoma

• Pembrolizumab‐ Sep 2014, metastatic melanoma

PD‐L1 inhibitors

• Atezolizumab‐ May 2016, urothelial carcinoma

• Avelumab‐ March 2017, Merkel cell carcinoma

• Durvalumab‐ May 2017, urothelial carcinoma

Combination therapy• Clinical trials,

metastatic melanoma

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Targeted therapies

Curry JL, Torres‐cabala CA, Kim KB, et al. Int J Dermatol. 2014.

Legend• Erlotinib, Gefitinib, Cetuximab, etc• Sorafenib, Sunitinib, Regorafenib• Trametinib, Cobimetinib, etc• Vemurafenib, Dabrafenib• Lapatinib, Trastuzumab, Pertuzumab• Sirolimus, Everolimus, Temsirolimus• Pazopanib• Vandetanib• Dasatanib, Nilotinib, Ponatinib

• EGFR inhibitors• Multikinase inhibitors• MEK inhibitors• BRAF inhibitors• HER2 inhibitors• mTOR inhibitors• VEGF inhibitors• RET inhibitors• Bcr‐Abl TKIs (2nd & 3rd gen)

irAEs in Immune checkpoint inhibitors

Villadolid J, Amin A. Transl Lung Cancer Res. 2015.

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• Combination therapy: 62% CAEs (increased efficacy and increased toxicity)

CAEs in Immune checkpoint inhibitors

Hassel JC, Heinzerling L, Aberle J, et al. Cancer Treat Rev. 2017.

Question

Erythema multiforme or Stevens Johnsons Syndrome has been reported with:

A. Immune checkpoint inhibitors

B. BRAF inhibitors

C. EGFR inhibitors

D. All of the above

Severe drug rashes• Erythema multiforme

• Stevens Johnsons Syndrome

• Toxic Epidermal Necrolysis

• EGFRi

• BRAFi

• Anti PD1

• Anti CTLA4

Doesch J, Debus D, Meyer C, et al. Lung Cancer. 2016.

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Question

Doxycyline can be preventative for:

A. Acneiform eruption

B. Paronychia

C. Photoxicity

D. A&B

E. All of the above

Acneiform eruption• Treatment options:• Doxycycline 100 mg BID• Hydrocortisone 2.5%• Bland emollient• Clindamycin 1%• Silvadene

• Dose reduction/cessation

• EGFR inhibitors

• Multikinase inhibitors

• MEK inhibitors

• HER2 inhibitors

• mTOR inhibitors

• VEGF inhibitors

• RET inhibitors

Acneiform eruption

• Intralesionaltriamcinolone

• Oral prednisone

• Topical or oral retinoid

• Topical dapsone

• Salicylic acid peels

• Ivermectin

• EGFR inhibitors


• MEK inhibitors

• HER2 inhibitors

• mTOR inhibitors

• VEGF inhibitors

• RET inhibitors

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• Mechanism– EGFR expressed in undifferentiated basal

keratinocytes

– Blockade causes • Early differentiation (increased KRT1, STAT3, p27)

• Decreased replication (downregulated Ki67, MAPK)

• Increased inflammatory cytokines ‐> apoptosis

– Thin stratum corneum, abnormally differentiated epidermis, dyskeratosis

– Follicular rupture ‐> Inflammation and Pustules

Lacouture ME. Nat Rev Cancer. 2006.

Acneiform eruption

• Quality of life is key component

• Eruption scoring scale

– Morphology and number of lesions

– Symptoms

– Blepharitis and paronychia

Acneiform eruption

Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Papules and/orpustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness

Papules and/or pustules covering 10‐30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL

Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self care ADL; associated with local superinfection with oral antibiotics indicated

Papules and/orpustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life threatening consequences

Death

Common Terminology Criteria for Adverse Events 4.0

De tursi M, Zilli M, Carella C, et al. Onco Targets Ther. 2017.

Question

Which can be aided by good foot care/podiatry?

A. Hand foot skin reaction

B. Keratoderma

C. Paronychia

D. All of the above

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Hand foot skin reaction (HFSR)Hand foot SYNDROME/Acral erythema:

– Doxorubicin, 5‐fluorouracil,

capecitabine

– Diffuse erythema and edema

Hand foot SKIN REACTION:

– Tender, erythematous focal plaques (weight‐bearing or friction)

– Hyperkeratosis or bullae

Maldonado cid P, Sendagorta cudós E, Nogueramorel L, et al.Dermatol Online J. 2013.

Hand foot skin reaction (HFSR)Hand foot SYNDROME Hand foot SKIN REACTION

Maldonado cid P, Sendagorta cudós E, Nogueramorel L, et al.Dermatol Online J. 2013.

Keratoderma BRAF inhibitor

Hand foot skin reaction


• VEGF inhibitors

• Treatment options:

• Preventative foot care (orthotics, shaving calluses/bunyons)

• Topical keratolytics (urea, lactic acid)

• Clobetasol 0.05%


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Hand‐foot skin reaction

• Mechanism

– VEGFR‐related• Worse with beclizumab

• Pressure and trauma with poor repair

– Fas/FasL mediated • Blocked with anti‐FasL antibody

• Same mediators as SJS/TEN

LabordeM. Podiatry Today. 2012

Paronychia• Treatment options:• Treat superinfections

– Oral antibiotics– Topical mupirocin and azole

• ½ water: ½ vinegar soaks• Betamethasone 0.05% lotion• Oral doxycycline• Nail avulsion• Phenol chemical matricectomy• Topical povidone‐iodine• Dose reduction/cessation

• EGFR inhibitors

• MEK inhibitors

• mTOR inhibitors

Question

Onycholysis is the most common nail side effect of immune checkpoint inhibitor therapy

A. True

B. False

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Onycholysis

• Taxanes– docetaxel and paclitaxel

• Tetracyclines and psoralen– Photo‐induced

• PD1 inhibitors

• Complications:– Subungual abscesses

Onychomadesis• Any cytotoxic chemotherapy• EGFR inhibitors

• Pathogenesis: Proximal nail matrix

• Clinical presentation: Shedding of the nail or a sulcus that splits the nail plate – Begins at the proximal nail fold– Extreme degree of Beau’s lines

Question

Which is NOT a potential hair side effect of targeted cancer therapy?

A. Darkening of hair

B. Curling of hair

C. Scarring alopecia

D. All of the above are possible

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Hair repigmentation

• PD‐1/PDL‐1 inhibitors

– Time to onset: 19.5 cycles

– Non small cell lung cancer

– Associated with tumor response

Rivera N, Boada A, Bielsa MI, et al. JAMA Dermatol. 2017.

Hair texture change

• BRAF inhibitors

– reversible

Scarring alopecia

• Bcr‐Abl TKIs (2nd and 3rd

gen)• Treatment options:

• Pruritus: antihistamines

• Topical/IL steroids


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Question

6. Name two drugs that can induce the tumor they are being used to treat.

A. MEK inhibitor and CTLA4 inhibitor

B. MEK inhibitor and PD1 inhibitor

C. BRAF inhibitor and CTLA4 inhibitor

D. BRAF inhibitor and PD1 inhibitor

Keratinocytic neoplasms• Multikinase inhibitors• BRAF inhibitors• PD‐1 inhibitors• Hedgehog pathway inhibitors• JAK inhibitors

• Treatment options:• Reactive:

– Cryotherapy– Electrodessication and

curettage– Excision/Mohs

• Preventative– Oral retinoid– MEK inhibitor– Photodynamic therapy– Topical 5‐FU

BRAF inhibitors

• Squamous papillomas– Hypertrophic actinic keratoses, irritated seborrheic

keratoses, verruca

Trinh VA, Davis JE, Anderson JE, Kim KB. Ann Pharmacother. 2014.

Lacouture ME, O'reilly K, Rosen N, Solit DB. J Clin Oncol. 2012.

• Cutaneous squamous cell carcinoma‐ Vemurafenib: 25%‐ Dabrafenib: 7% ‐ Mechanism: activates mutated HRAS

• 21.2% from BRAF inhibitor tumors versus 3.2% from control tumors

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PD1 inhibitors

Freites‐martinez A, Kwong BY, Rieger KE, et al. JAMA Dermatol. 2017.

Melanocytic neoplasms

• BRAF inhibitors

– New nevi

• PD1 inhibitors

• CTLA4 inhibitors

– Regression of nevi/tumoral melanosis


• BRAF inhibitors

• PD1 inhibitors



• Skin exams

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• Eruptive lentigines– Higher Cyclin D1 expression

– MAPK pathway upregulation

– Higher degree of atypia

• < 10% of patients required dose interruption

• New primary melanoma– 5/468 patients, Phase II/III

– Wild‐type BRAF, all < 0.5 mm

– Mechanism: activates MAPK

signaling pathway for wild‐type BRAF


• Regressing nevi– Time to onset: 2‐4 months

Mauzo SH, Tetzlaff MT, Nelson K, et al. Int J Dermatol. 2017.

Question

Which is not a typical BRAF inhibitor toxicity?

A. Sweet’s

B. EN‐like panniculitis

C. Phototoxicity

D. Acneiform eruption

E. Dysplastic nevi

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Erythema nodosum


• BRAF inhibitors


• mTOR inhibitors


• None if asymptomatic

• NSAIDs

• Oral prednisone (5 mg)

Phototoxicity

• EGFR inhibitors

• BRAF inhibitors

• RET inhibitors


• Photoprotection

– UPF clothing– Bemotrizinol (Tinosorb S)

– Bisoctrizole (Tinosorb M)

– Tris‐Biphenyl Triazine (Tinosorb A2B)

– Octyl methoxycinnamate (Tinosorb OMC)

• Oral or topical steroids

Pruritus• Treatment options:• Determine etiology

– Scabies– Drug reaction to beta blocker– Eczema– Lichen planus– Xerosis– Acneiform eruption

• Oral antihistamines• Emollients• Topical steroids• Antidepressants/antipsychotics• Phototherapy• Dose reduction/cessation

• EGFR inhibitors• Multikinase inhibitors• MEK inhibitors• BRAF inhibitors• HER2 inhibitors• CTLA4 inhibitors• PD‐1 inhibitors• mTOR inhibitors• Bcr‐Abl TKIs (2nd and 3rd gen)• RET inhibitors

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Question

7. Drug‐induced ________ is seen with immune checkpoint inhibitors.

A. Spongiotic dermatitis

B. Psoriasiform dermatitis

C. Lichenoid dermatitis

D. Granulomatous dermatitis

E. All of the above

Spongiotic dermatitis


• PD‐1 inhibitors

• mTOR inhibitors

• Treatment options:• Flare regimen:

– Triamcinolone 0.1% BID (body)– Hydrocortisone 2.5% BID x 5

days (face, genital area)– Oral or systemic steroids– RTC: 2 weeks

• Maintenance regimen:– Topical steroid BIW– Bland emollient daily

• Systemic therapy:– Anti IL4?

Psoriasiform dermatitis

• PD‐1 inhibitors • Systemic therapy:– Oral steroids

– Acitretin

– Methotrexate

– Anti IL17


• Flare regimen:

– Triamcinolone 0.1% BID (body)

– Hydrocortisone 2.5% BID x 5 days (face, genital area)

– RTC: 2 weeks

• Maintenance regimen:

– Topical steroid BIW

– Bland emollient daily

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Lichenoid dermatitis


• Topical steroid

• Oral steroid

• Systemic retinoid

• Methotrexate

• Anti IL 17

• Drug cessation


Granulomatous dermatitis

• BRAF inhibitors




• Topical steroid

• Oral steroid

• Drug cessation

• PD‐1 inhibitors • Treatment options:

• Topical/oral/IV steroids

• Anti CD20?

• Anti IgE?

• Drug cessation

• Long latency (3‐16 weeks)

Bullous pemphigoid

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Question

Using oral steroids will prevent the immune checkpoint inhibitor from working

A. True

B. False

• Systemic steroids and TNF inhibitors do not affect outcomes

Immunosuppression and Checkpoint inhibitors

Vitiligo




• Nothing

• Topical steroids or topical tacrolimus+/‐ light therapy

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Rashes as prognostic indicators

Who will get toxicities?

Do toxicities predict tumor response?

Who will respond to toxicity management?

Question

Prolonged response to immune checkpoint inhibitor therapy has been associated with?

A. Lung metastases

B. High functional status

C. Low‐grade Immune‐related adverse events

D. High‐grade immune‐related adverse events

Rashes as prognostic indicators

What we know• Acneiform eruption with EGFR inhibitors

– Non‐small cell lung cancer– Colorectal cancer

• Vitiligo with immune checkpoint inhibitors– Metastatic melanoma

Potential correlations• Acneiform eruption with MEK inhibitors• Granulomatous dermatitis with BRAF or immune checkpoint inhibitors• Psoriasiform dermatitis with anti PD‐1 therapy

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Acneiform eruption• EGFR inhibitors• Cancer types:

– Colorectal cancer– Non‐small cell lung

cancer– Head and neck SCC

• Rash characteristics:– Early appearance– Grade 2+

• Correlation to:– Progression‐free

survival– Overall survival– Tumor response

• Histo: – Decreased p‐EGFR

expression correlated to OS (normal skin)

MEK inhibitors? RET inhibitors?

Vitiligo

• Immune checkpoint inhibitors• UNDER REPORTED

– Retrospective– Clinical trials run by oncologists

• Cancer types:– Melanoma

• Correlation to:– Progression‐free survival – Tumor response

• 67 patients• Prospective

• Incidence of vitiligo: 25%

• Time to onset: – 52 to 453 days– median, 126 days

• Tumor response:– Higher occurrence of vitiligo – 71% vs. 28%

– 3/17 (18%) had a complete response

– 9/17 (53%) had a partial response– 3/17 (18%) had stable disease– 2/17 (12%) had progressive disease

Hua C, Boussemart L, Mateus C, et al. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol. 2016;152(1):45‐51.

(Anti‐PD1)

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Granulomatous reactions

• Indicate immune response– Hodgkin’s disease – Gastric adenocarcinoma

• BRAF inhibitors• Anti CTLA4• Anti PD‐L1

Granulomatous dermatitis• BRAF inhibitors

– 3 patients– Time to onset: 2‐10 months– Erythematous, and violaceous papules– Tumor response (2), progression of disease (1)

Garrido MC, Gutierrez C, Riveiro-falkenbach E, et al. Am J Dermatopathol. 2015.

Sarcoidosis• Ipilimumab (11), Anti‐PD‐L1 (1)• Cancer type:

– Melanoma– Prostate CA– Lung adenoCA

• Sarcoidosis presentation: – Lung, kidney, spleen, skin– Skin: 2 in combination with lung, 1 primary– 4/8: Partial or complete response– 1/8: Stable disease– 3/8: Progression of disease

Suozzi KC, Stahl M, Ko CJ, et al. JAAD Case Rep. 2016.

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Psoriasiform dermatitis• Anti PD‐1

– PD‐L1 expression is increased in melanoma tumor cells– PD‐1 expression is increased in Th17 cells in psoriatic lesions

Kim JH, Choi YJ, Lee BH, et al. J Allergy Clin Immunol. 2016.

Summary

• Cutaneous toxicities from targeted cancer therapy are significant

• Old rashes in a new context

• CAEs can be a window into drug mechanisms and tumor response

Thank you

• Shelby Kubicki, MS2

• Macartney Welborn, MS2

• Osama Hashmi, MS4

• Amanda Cersonek Herrmann, PhD, MS4

• Sana Zahirrudin, MD

• Saira George, MD

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Update on Cutaneous Reactions to and Therapy U031... · 1 U031‐Update on Cutaneous Reactions to Targeted and Immune Therapy Anisha B. Patel, M.D. Assistant Professor, Dermatology