Post on 07-Mar-2019
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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 Unpublished.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.
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
Immune checkpoint inhibitors
Godwin JL, ZibelmanM, Plimack ER, et al. Discov Med. 2014.
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 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
Immune checkpoint inhibitors
Chen L, Flies DB. Nat Rev Immunol. 2013.
Immune checkpoint inhibitorsCTLA4 inhibitors
• Ipilimumab‐ Mar 2011, metastatic melanoma
• 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
• Multikinase 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
• Multikinase inhibitors
• VEGF inhibitors
• Treatment options:
• Preventative foot care (orthotics, shaving calluses/bunyons)
• Topical keratolytics (urea, lactic acid)
• Clobetasol 0.05%
• Dose reduction/cessation
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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
• Dose reduction/cessation
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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
Melanocytic neoplasms
• BRAF inhibitors
• PD1 inhibitors
• CTLA4 inhibitors
• Treatment options:
• Skin exams
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Melanocytic neoplasms
• 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
Melanocytic neoplasms
• 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
• Multikinase inhibitors
• BRAF inhibitors
• CTLA4 inhibitors
• mTOR inhibitors
• Treatment options:
• None if asymptomatic
• NSAIDs
• Oral prednisone (5 mg)
Phototoxicity
• EGFR inhibitors
• BRAF inhibitors
• RET inhibitors
• Treatment options:
• 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
• CTLA4 inhibitors
• 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
• Treatment options:
• 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
• Treatment options:
• Topical steroid
• Oral steroid
• Systemic retinoid
• Methotrexate
• Anti IL 17
• Drug cessation
• PD‐1 inhibitors
Granulomatous dermatitis
• BRAF inhibitors
• CTLA4 inhibitors
• PD‐1 inhibitors
• Treatment options:
• 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
• CTLA4 inhibitors
• PD‐1 inhibitors
• Treatment options:
• 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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