Cutaneous Toxicities of Anti-Cancer Therapies

Matthew R. Hall, M.D. Assistant Professor of Dermatology Mayo Clinic Florida Mayo Clinic Cutaneous Oncology Symposium Jacksonville, FL Saturday, September 24, 2016

DISCLOSURES

None

Overview

SCC Therapies EGFR Inhibitors (cetuximab, panitumumab, gefitinib, erlotinib)

Melanoma Therapies BRAF Inhibitors (Vemurafenib and Dabrafenib)

MEK/ERK Inhibitors (Trametinib, Cobimetinib)

CTLA4 Inhibitor (Ipilimumab)

PD-1 Inhibitors (Nivolumab, pembrolizumab)

Sorafenib

EGFR Inhibitors

Head and Neck SCC Monoclonal antibodies to EGFR

Cetuximab and Panitumumab

Small molecule tyrosine kinase inhibitors (specific for EGFR) Erlotinib and gefitinib

Macdonald et al., 2015

Cutaneous Toxicities of EGFR Inhibitors EGFR is expressed in epidermis and appendages

Important in epidermal and pilosebaceous function

Cutaneous toxicities are common (50-90%)

Tell patients to expect a rash, it is not a drug allergy and not reason to stop Rx

Cetuximab, panitumumab>erlotinib>gefitinib

Median onset 7-10d after drug initiation Papulopustular eruption (up to 75%)

Xerosis (30%)

Hair changes (slower growth, brittle, trichomegaly)

Mucositis

Nail changes

Photosensitivity

Papulopustular Eruption

Macdonald et al., 2015

Reyes-Habito and Roh 2014

Papulopustular Eruption

Reyes-Habito and Roh 2014

Papulopustular Eruption

Unlike acne No comedones or cystic papules

Pruritic

Severity of the eruption correlates with tumor response to EGFR inhibition and survival

Etiology EGFR downregulates IL-1 dependent inflammation in the hair follicle

Thus, EGFR blockade leads to increased follicular inflammation

Paronychia & Pyogenic Granuloma

Reyes-Habito and Roh 2014

Trichomegaly

Macdonald et al., 2015

Treatment of EGFR Inhibitor Toxicities

Papulopustular eruption

Grade 1 eruptions (<10% BSA)

Topical antibiotics (clindamycin)

Topical steroids

Topical calcineurin inhibitors (off-label)

Avoid retinoids (irritation, lack of comedones)

Grade 2 and 3 eruptions (10-30% BSA)

Tetracyclines

Low dose isotretinoin

Culture to rule out superinfection

Pruritusantihistamines (doxepin if severe)

Paronychia

Antibacterial soaks

Dilute vinegar

Dilute bleach

4% thymol in 70% EtOH

Culture

Topical steroids

Vermurafenib and Dabrafenib

Inhibitors of mutated BRAF Raf/MEK/Erk MAP kinase pathway BRAF is an activator in the Map Kinase pathway

Mutated in ~50% of melanomas

Macdonald et al., 2015

Vemurafenib

Cutaneous reactions are common and polymorphous Diffuse rash

Epidermal tumors

Keratosis pilaris-like eruption

Seborrheic dermatitis-like eruption

Hyperkeratotic hand-foot reaction

Photosensitivity

Panniculitis

Melanocytic proliferations

Vemurafenib

Rash Most commonly folliculocentric papules Morbilliform (measles-like) distribution

“Maculopapular”

Involves trunk and extremities Histology shows features of classic drug reaction

Treatment of rash Emollients Antihistamines Topical steroids

Prednisone if severe Don’t necessarily need to stop medication but can try dose reduction

Morbilliform Drug Eruption

Fitzpatrick’s Dermatology in General Medicine, 8th ed.

Keratosis Pilaris-like Eruption

Macdonald et al., 2015

Seborrheic Dermatitis-like Eruption

Macdonald et al., 2015

Hyperkeratotic Hand-Foot Eruption

Desquamation at sites of friction on palms and soles Can be painful May require dose reduction Management

Avoid friction and pressure

Topical steroids

Hyperkeratotic Hand-Foot Eruption

Macdonald et al., 2015

Vemurafenib

Epidermal tumors SCC and verrucal keratoses

Verrucal keratoses are not caused by HPV

SCCs can appear rapidly (within 1st week) Occur in up to 30% of patients

Most occur within the first 6 months (peak within 1st 18 weeks)

Generally show low grade histology

Widespread benign verrucal keratoses can occur in up to 80% Peaks within 6-12 weeks

Vemurafenib

Mechanism of SCC induction RAF blockade can lead to paradoxical MAPK activation, especially in

the presence of RAS mutations (sun damaged skin)

This unmasks pre-existing mutationstumor formation

Accounts for rapid SCC development after starting medication

Downstream concurrent inhibition of MEK leads to decreased SCC development

Verrucal Keratoses

Macdonald et al., 2015

Squamous Cell Carcinomas

Macdonald et al., 2015

Management of Epidermal Neoplasms on BRAF Inhibitors

Verrucal Keratoses Benign

May be premalignant

Monitor closely for evolution into SCC

Consider cryotherapy

SCC Excision, electrodessication and curettage, or cryotherapy if early

Consider intralesional 5-fluorouracil

Typically does not require dose reduction

Unclear whether these have increased risk of metastasis

Can be eruptive and resolve after treatment ends

Intralesional 5-FU for SCC

Intralesional 5-FU 50mg/ml Inject 0.1-0.3 ml per quadrant of the tumor

No more than 1-1.5cc at a time Tumor involutes Closely monitor patient for resolution

MEK/ERK Inhibitors

Raf/MEK/Erk MAP kinase pathway Selumetinib, Trametinib

Macdonald et al., 2015

MEK/ERK inhibitors

Similar cutaneous side effect to EGFRs rather than RAF blockade Combination of MEK and BRAF inhibitors can decrease risk of

cutaneous adverse effects Morbilliform eruption Papulopustular eruption Xerosis Alopecia Hyperpigmentation Paronychia Trichomegaly

Papulopustular Eruption

Macdonald et al., 2015

Paronychia

Macdonald et al., 2015

CTLA4 and PD-1 inhibitors

Immune checkpoint inhibitors that augment the normal immune response and produce proinflammatory skin reactions

CTLA4 inhibitor: Ipilimumab PD-1 inhibitors: Nivolumab, pembrolizumab

Ipilimumab Due to augmented immune response, autoimmune skin reactions are

common (40%) Pruritus (up to 30%) Morbilliform eruption (10-50%) Vitiligo-like hypopigmentation

Portends favorable prognosis

Less common Prurigo nodularis

Lichenoid eruption

Papulopustular eruption

Ulcerations

Photosensitivity

Toxic epidermal necrolysis (TEN) reported

Nivolumab and Pembrolizumab

Autoimmune skin eruptions Vitiligo

Pruritus

Lichenoid eruptions Do not necessitate discontinuation of the medication

Lichenoid Eruptions

Joseph et al., 2015

Pathology

Joseph et al., 2015

Sorafenib

Multikinase inhibitor to treat melanoma Small molecule inhibitors of tyrosine kinase inhibitors Inhibit VEGF, PDGF, KIT, RAF, and others

Macdonald et al., 2015

Sorafenib Many cutaneous adverse effects

Hyperkeratotic hand-foot skin reactions

Stomatitis (25%)

Alopecia (44%)

Hair color and texture changes

Morbilliform eruption

Genital eruption

New SCCs and inflammation of AKs (10%)

Subungual splinter hemorrhages (70%)

Seborrheic dermatitis-like eruption with facial edema (60%)

Hand-Foot Skin Reaction

Reyes-Habito and Roh 2014 Macdonald et al., 2015

Hyperkeratotic Hand-Foot Skin Reaction Different from hand-foot syndrome due to conventional chemotherapy

Erythema that can blister and ulcerate

Painful, hyperkeratotic plaques at sites of pressure and friction Dose-dependent reaction Treatment

Moisturizing creams and ointments Keratolyic creams (40% Urea) Gel or foam shoe inserts Potent topical steroids (clobetasol) Topical lidocaine Consider dose reduction for severe, debilitating pain Antiseptic baths of blisters or erosions

Dilute vinegar or bleach

Psoriasiform Genital Eruption

Macdonald et al., 2015