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 Unpublished.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!!

References• Berthod G, Lazor R, Letovanec I, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30(17):e156-9.• Coutinho I, Pereira N, Gouveia M, Cardoso JC, Tellechea O. Interstitial Granulomatous Dermatitis: A Clinicopathological Study. Am J Dermatopathol.

2015;37(8):614-9.• Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient.

Dermatology (Basel). 2009;218(1):69-70.• Garrido MC, Gutierrez C, Riveiro-falkenbach E, Ortiz P, Rodriguez-peralto JL. BRAF Inhibitor-Induced Antitumoral Granulomatous Dermatitis Eruption in

Advanced Melanoma. Am J Dermatopathol. 2015;37(10):795-8.• Jansen YJ, Janssens P, Hoorens A, et al. Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated

with dabrafenib and trametinib. Melanoma Res. 2015;25(6):550-4.• Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic

adverse events. J Am Acad Dermatol. 2014;71(1):161-9.• Luke JJ, Lezcano C, Hodi FS, Murphy GF. Antitumor granuloma formation by CD4+ T cells in a patient with rapidly progressive melanoma experiencing

spiking fevers, neuropathy, and other immune-related toxicity after treatment with ipilimumab. J Clin Oncol. 2015;33(6):e32-5.• Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients

undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol. 2014;150(3):307-11.• Suozzi KC, Stahl M, Ko CJ, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep.

2016;2(3):264-8.• Toumeh A, Sakhi R, Shah S, Arudra SK, De las casas LE, Skeel RT. Ipilimumab-Induced Granulomatous Disease Occurring Simultaneously With Disease

Progression in a Patient With Metastatic Melanoma. Am J Ther. 2016;23(4):e1068-71.• Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma

undergoing complete remission. J Clin Oncol. 2012;30(2):e7-e10.

References• Parma J, Pavlick A, Schiff R, et al. Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer.

Pharmacotherapy. 2013;33(10):1126-9.• Lee Y, Shim HS, Park MS, et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with

advanced squamous cell lung carcinoma. Clin Cancer Res. 2012;18(6):1760-8.• Jonker DJ, O'callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040-8.• Klinghammer K, Knödler M, Schmittel A, Budach V, Keilholz U, Tinhofer I. Association of epidermal growth factor receptor polymorphism, skin toxicity,

and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res. 2010;16(1):304-10.

• Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2009;45(10):e155-60.

• Huang CL, Yang CH, Yeh KH, et al. EGFR intron 1 dinucleotide repeat polymorphism is associated with the occurrence of skin rash with gefitinib treatment. Lung Cancer. 2009;64(3):346-51.

• Parmar S, Schumann C, Rüdiger S, et al. Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. Pharmacogenomics J. 2013;13(2):181-8.• Peréz-soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?. J Clin Oncol. 2005;23(22):5235-46.• Zaborowska-szmit M, Kowalski DM, Piórek A, Krzakowski M, Szmit S. A decrease in D-dimer concentration and an occurrence of skin rash as iatrogenic

events and complementary predictors of survival in lung cancer patients treated with EGFR tyrosine kinase inhibitors. Pharmacol Rep. 2016;68(6):1140-1148.

• Kudo K, Hotta K, Bessho A, et al. Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. Cancer Chemother Pharmacol. 2016;77(5):1005-9.

References• Sugiura Y, Nemoto E, Kawai O, Ohkubo Y, Fusegawa H, Kaseda S. Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung

adenocarcinoma in Japanese patients. Springerplus. 2013;2(1):22.• Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with

anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer. 2012;78(1):8-15.• Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the

epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13):3913-21.• Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung

cancer: a systematic review and meta-analysis. PLoS ONE. 2013;8(1):e55128.• Agulnik M, Da cunha santos G, Hedley D, et al. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with

recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol. 2007;25(16):2184-90.• Kim JH, Choi YJ, Lee BH, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell

death 1-high T cells. J Allergy Clin Immunol. 2016;137(5):1466-1476.e3.