Melanoma Systemic Therapy: Side Effects and Management Strategies

Transcription

1 Melanoma Systemic Therapy: Side Effects and Management Strategies Anisha B. Patel, M.D. Assistant Professor, Dermatology UT MD Anderson Cancer Center UT Health Science Center- Houston

2 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

3 Background Cytotoxic 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

4 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):

5 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

6 Immune checkpoint inhibitors Godwin JL, Zibelman M, Plimack ER, et al. Discov Med

7 Immune checkpoint inhibitors Godwin JL, Zibelman M, Plimack ER, et al. Discov Med

8 Immune checkpoint inhibitors CTLA4 inhibitors Ipilimumab- Mar 2011, metastatic melanoma Tremelimumab- failed Phase III trials PD-1 inhibitors Nivolumab- Dec 2014, metastatic melanoma Pembrolizumab- Sep 2014, metastatic melanoma Cemeplimab- cutaneous squamous cell carcinoma 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

9 Quality of Life Pain Pruritus Emotional/social impact Activities of daily living Significance 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 Welborn M, Kubicki S, Hashmi O, Zahirrudin S, Patel AB. Unpublished.

10 Repurposed rashes

11 Acneiform eruption MEK inhibitors CTLA4 inhibitors Treatment options: Doxycycline 100 mg BID Hydrocortisone 2.5% Bland emollient Clindamycin 1% Silvadene Dose reduction/cessation

12 Acneiform eruption MEK inhibitors CTLA4 inhibitors Isotretinoin 40 mg daily Acitretin 10 mg daily Intralesional triamcinolone Oral prednisone Topical or oral retinoid Topical dapsone Salicylic acid peels Ivermectin

13 Acneiform eruption Folliculitis Yeast or bacteria Steroid acne Prolonged systemic steroid use Acneiform eruption Super-infected acneiform eruption

14 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

15 Erythema nodosum BRAF inhibitors CTLA4 inhibitors Autoimmune disease Infection Idiopathic Treatment options: None if asymptomatic NSAIDs Oral prednisone (5 mg) SSKI

16 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

17 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?

18 Psoriasiform dermatitis PD-1/PD-L1 inhibitors Psoriasis Oral steroids Oral retinoids Methotrexate Biologics TNF blockers Anti IL23 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

19 Lichenoid dermatitis PD-1/PD-L1 inhibitors Lichen planus Lichenoid drug eruption Treatment options: Topical steroid Oral steroid Systemic retinoid Methotrexate Anti IL 17 Drug cessation

20 Granulomatous dermatitis BRAF inhibitors CTLA4 inhibitors PD-1/PD-L1 inhibitors Primary granulomatous dermatitis Cutaneous sarcoidosis Granuloma annulare Secondary granulomatous dermatitis Infection (atypical) Foreign Body Treatment options: Topical steroid Oral steroid Drug cessation

21 Vitiligo CTLA4 inhibitors PD-1/PD-L1 inhibitors Treatment options: Nothing Topical steroids or topical tacrolimus +/- light therapy

22 Bullous pemphigoid PD-1 inhibitors PD-L1 inhibitors Treatment options: Topical/oral/IV steroids Anti CD20? Anti IgE? Drug cessation Long latency (3-16 weeks)

23 Immunosuppression and Checkpoint inhibitors Systemic steroids and TNF inhibitors do not affect outcomes (that we know of)

24 Dermatomyositis CTLA4 inhibitors PD-1 inhibitors Paraneoplastic Autoimmune Treatment options: Oral steroids Methotrexate Hydroxychloroquine IVIG Dose reduction/cessation

25 Xerosis CTLA4 inhibitors PD-1 inhibitors Treatment options: Bland emollient BID Bath BID Keratolytics (ammonium lactate or salicylic acid) Topical steroid PRN

26 Pruritus EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors Bcr-Abl TKIs (2 nd and 3 rd gen) RET inhibitors 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

27 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

28 BRAF inhibitors Squamous papillomas Hypertrophic actinic keratoses, irritated seborrheic keratoses, verruca Cutaneous squamous cell carcinoma - Vemurafenib: 25% - Dabrafenib: 7% - Mechanism: activates mutated HRAS 21.2% from BRAF inhibitor tumors versus 3.2% from control tumors Lacouture ME, O'reilly K, Rosen N, Solit DB. J Clin Oncol Trinh VA, Davis JE, Anderson JE, Kim KB. Ann Pharmacother

29 PD1 inhibitors Freites-martinez A, Kwong BY, Rieger KE, et al. JAMA Dermatol

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31 Melanocytic neoplasms BRAF inhibitors New nevi PD1 inhibitors & CTLA4 inhibitors Regression of nevi/tumoral melanosis Treatment options: Skin exams

32 Melanocytic neoplasms Eruptive lentigines Higher Cyclin D1 expression MAPK pathway upregulation Higher degree of atypia 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 < 10% of patients required dose interruption

33 Melanocytic neoplasms Regressing nevi Time to onset: 2-4 months Mauzo SH, Tetzlaff MT, Nelson K, et al. Int J Dermatol

34 Rashes as prognostic indicators Do toxicities predict tumor response? Who will get toxicities? Who will respond to toxicity management?

35 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

36 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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