Melanoma Systemic Therapy: Side Effects and Management … · 2019-02-10 · Melanoma Systemic...
Transcript of Melanoma Systemic Therapy: Side Effects and Management … · 2019-02-10 · Melanoma Systemic...
Melanoma Systemic Therapy: Side Effects and Management Strategies
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 novel
melanoma therapy– Targeted therapy – Immunotherapy
• CAEs as prognostic indicators
– T-cell mediated– Antibody-mediated– Neoplastic
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
Targeted therapies
Curry JL, Torres-cabala CA, Kim KB, et al. Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol. 2014;53(3):376-84.
Legend• BRAF inhibitors• Vemurafenib- FDA approved, metastatic melanoma• Dabrafenib- FDA approved, metastatic melanoma• Encorafenib- FDA approved, metastatic melanoma
• MEK inhibitors• Trametinib- FDA approved, metastatic melanoma• Cobimetinib- FDA approved, metastatic melanoma• Binimetinib- FDA approved, metastatic melanoma• Selumetinib- Phase III trials, NSCLC
Immune checkpoint inhibitors
Godwin JL, Zibelman M, Plimack ER, et al. Discov Med. 2014.
Immune checkpoint inhibitors
Godwin JL, Zibelman M, Plimack ER, et al. Discov Med. 2014.
Immune checkpoint inhibitorsCTLA4 inhibitors• Ipilimumab- Mar 2011, metastatic melanoma• Tremelimumab- failed Phase III trialsPD-1 inhibitors• Nivolumab- Dec 2014, metastatic melanoma• Pembrolizumab- Sep 2014, metastatic melanoma• Cemeplimab- cutaneous squamous cell carcinomaPD-L1 inhibitors• Atezolizumab- May 2016, urothelial carcinoma• Avelumab- March 2017, Merkel cell carcinoma• Durvalumab- May 2017, urothelial carcinoma
Combination therapy• Clinical trials,
metastatic melanoma
Significance• Quality of Life
– Pain– Pruritus– Emotional/social impact– Activities of daily living
• Cancer therapy– 30-50%, immune checkpoint inhibitors
• 20% (reduction or discontinuation)– Higher with combination therapy– Neoadjuvant, adjuvant,
Chan A, Cameron MC, Garden B, et al. Support Care Cancer. 2015.Welborn M, Kubicki S, Hashmi O, Zahirrudin S, Patel AB. Unpublished.
Repurposed rashes
Acneiform eruption• Treatment options:• Doxycycline 100 mg BID• Hydrocortisone 2.5%• Bland emollient• Clindamycin 1%• Silvadene
• Dose reduction/cessation
• MEK inhibitors• CTLA4 inhibitors
Acneiform eruption• Intralesional
triamcinolone• Oral prednisone• Topical or oral retinoid• Topical dapsone• Salicylic acid peels• Ivermectin
• MEK inhibitors• CTLA4 inhibitors
• Isotretinoin 40 mg daily• Acitretin 10 mg daily
Acneiform eruption• Folliculitis
– Yeast or bacteria
• Steroid acne– Prolonged systemic steroid use
• Acneiform eruption• Super-infected acneiform
eruption
• 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
Erythema nodosum• BRAF inhibitors• CTLA4 inhibitors
• Autoimmune disease• Infection• Idiopathic
• Treatment options:• None if asymptomatic• NSAIDs• Oral prednisone (5 mg)• SSKI
Phototoxicity• BRAF 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
Eczema• CTLA4 inhibitors• PD-1 inhibitors• PD-L1 inhibitors• Atopic dermatitis
– Flexural, FMH/PMH– Dry skin
• Allergic contact dermatitis– Geometric, pt history
• 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/PD-L1 inhibitors• Psoriasis
• 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
• Oral steroids• Oral retinoids• Methotrexate• Biologics
– TNF blockers– Anti IL23– Anti IL17
Lichenoid dermatitis• Treatment options:• Topical steroid• Oral steroid• Systemic retinoid• Methotrexate• Anti IL 17• Drug cessation
• PD-1/PD-L1 inhibitors• Lichen planus• Lichenoid drug
eruption
Granulomatous dermatitis• Treatment options:• Topical steroid• Oral steroid• Drug cessation
• BRAF inhibitors• CTLA4 inhibitors• PD-1/PD-L1 inhibitors• Primary granulomatous dermatitis
– Cutaneous sarcoidosis– Granuloma annulare
• Secondary granulomatous dermatitis– Infection (atypical)– Foreign Body
Vitiligo• CTLA4 inhibitors• PD-1/PD-L1 inhibitors
• Treatment options:• Nothing• Topical steroids or
topical tacrolimus+/- light therapy
• PD-1 inhibitors• PD-L1 inhibitors
• Treatment options:• Topical/oral/IV steroids• Anti CD20?• Anti IgE?• Drug cessation
• Long latency (3-16 weeks)
Bullous pemphigoid
• Systemic steroids and TNF inhibitors do not affect outcomes (that we know of)
Immunosuppression and Checkpoint inhibitors
Dermatomyositis• CTLA4 inhibitors• PD-1 inhibitors• Paraneoplastic• Autoimmune
• Treatment options:• Oral steroids• Methotrexate• Hydroxychloroquine• IVIG• Dose
reduction/cessation
Xerosis• CTLA4 inhibitors• PD-1 inhibitors
• Treatment options:• Bland emollient BID• Bath BID• Keratolytics
(ammonium lactate or salicylic acid)
• Topical steroid PRN
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
Keratinocytic neoplasms• BRAF inhibitors• PD-1/PD-L1
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
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
• Treatment options:• Skin exams
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.
Rashes as prognostic indicators
Who will get toxicities?
Do toxicities predict tumor response?
Who will respond to toxicity management?
Rashes as prognostic indicatorsWhat 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
Conclusion
• Could this be a therapy- related CAE?– Is it T- cell mediated?– Is it antibody-mediated?– Is it neoplastic?
• Diagnosis and management– Business as usual
YES!!
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