Cutaneous side effects of EGFR-

inhibitors and their management

TARGETED THERAPIES
Siegfried Segaert
AND
Dermatology Dept
THEIR CUTANEOUS TOXICITIES
University Hospital Leuven
Brussels, 14/1/2017 Belgium

4th BADO meeting

Brussels, January 14th 2017

EGFR inhibitors
Monoclonal antibodies EGFR inhibitors
- Cetuximab (Erbitux)
- Panitumumab (Vectibix) - Cetuximab (Erbitux)
- Panitumumab (Vectibix)
Oral tyrosine kinase inhibitors - Erlotinib (Tarceva)
- Erlotinib (Tarceva) - Gefitinib (Iressa)
- Gefitinib (Iressa) - Lapatinib (Tyverb)
- Lapatinib (Tyverb) - Afatinib (Giotrif)
- Afatinib (Giotrif)

EGFR is abundantly expressed in the skin EGFR inhibitor skin toxicity

Acneiform eruption

Xerosis, eczema, fissures

Nail changes

Hair changes

Hyperpigmentation

Telangiectasia

Mucosal changes
Epidermis Hair follicle

Albanell et al. J Clin Oncol 2001; 20:110-124 Segaert & Van Cutsem Ann Oncol 2005; 16:1425-33

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Acneiform eruption: grade 1 Acneiform eruption: grade 2

Acneiform eruption: grade 3 Acneiform eruption: grade 3

Xerosis, eczema, fissures

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 Nail changes Hair changes

Hyperpigmentation Telangiectasia

Mucosal changes
Radiation and cetuximab combination therapy

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 Sparing of previously irradiated skin
Acneiform eruption by MEK-inhibitor

EGF

EGFR

Transgenic mice mimic EGFRi skin toxicity Overall survival depends on

severity of skin toxicity
EGFR mutation
Wild type (waved 2)

Schneider et al. Am J Pathol 2008; 173:14-24 Peeters et al. Cancer 2009; 115:1544-54

EGFRI skin toxicity drastically impairs quality of life Supportive treatment makes the difference!

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 Prophylactic minocycline 100 mg qd:
Study design

8 weeks

R Minocycline
A 100 mg qd
mCRC patients N + topical tazarotene 0.05% bid
preparing to on one side of face
Role of oral tetracyclines initiate cetuximab
D
O n = 24
Evaluation
of skin lesions by
( concomitant M dermatologist
chemotherapy) I on clinical pictures
n=48 S Placebo
E + topical tazarotene 0.05% bid
on one side of face
1:1
n = 24

Scope et al. J Clin Oncol 2007; 25:5390-6.

Prophylactic minocycline for acneiform eruption Prophylactic treatment of acneiform eruption

Study results Tetracycline 500 mg bid

Dermatologist lesion count

4 weeks

n=48 R
A
Tetracycline
p=0.005 Cancer* patients
to initiate N 500 mg bid 4 weeks
treatment with D
O
cetuximab, Follow-up
M
gefitinib, I
erlotinib S
n=61 E Placebo

Evaluation for rash and skin-specific QoL

Results:
Incidence of skin toxicity similar (70% for tetracycline vs. 76% for placebo)
But less severe reactions:
grade 2 in 17% for tetracycline vs. 55% for placebo
Week 1 Week 2 Week 4 Week 8
p* 0.05 0.0025 0.008 0.219
*Based on t-test of log total lesion count for each study time point.
*Lung, GI and other cancers
Scope et al. J Clin Oncol 2007;25:5390-6. Jatoi et al. Cancer 2008;113:847-53.

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Phase 2 Skin Toxicity Evaluation Protocol with
STEPP trial: incidence and time to first occurrence of
Panitumumab (STEPP) trial: prophylactic vs. reactive
grade 2 skin toxicities
skin treatment in 2nd-line treatment of metastatic CRC
Time to first occurrence of grade 2 skin toxicity
Prophylactic 1 Prophylactic
mCRC skin treatment Reactive
Weeks 16, starting Day -1 Tumour 0.8
PD or unacceptable

Probability (%)
toxicity with 1st-line response
R 0.6
fluoropyrimidine + evaluation
oxaliplatin-based CT Reactive Q8W or Q9W
0.4
(n=95) skin treatment
1:1 0.2
Stratification by CT Skin assessment QW, Weeks 17
0
Patients were treated with panitumumab (6 mg/kg) Q2W plus FOLFIRI or panitumumab (9 mg/kg) 0 2 4 6 8
Q3W plus irinotecan (investigators choice) Weeks
Prophylactic Reactive
Parametre (n=48) (n=47)
Prophylactic skin treatment regimen: skin moisturiser (daily); Patients with grade 2 skin toxicity, n (%) 14 (29) 29 (62)
topical steroid (hydrocortisone 1% daily); doxycycline (100 mg BID); Odds ratio (95% CI) 0.3 (0.10.6)
SPF 15 sunscreen before going outdoors Grade 2, n (%) 11 (23) 19 (40)
Grade 3, n (%) 3 (6) 10 (21)
BID, twice a day; CT, chemotherapy; Median time to first event, weeks (95% CI) NR 2.1 (2.16.3)
Lacouture et al. J Clin Oncol 2010;28:13517 SPF, sun protection factor;
www.amgentrials.com, protocol ID: 20050184; ClinicalTrials.gov identifier: NCT00332163. Q3W/Q8W/Q9W, once every 3/8/9 weeks. Lacouture et al. J Clin Oncol 2010;28:13517 NR, not reported.

A No treatment
B Reactive
C Prophylactic

Wehler et al. J Cancer Res Clin Oncol 139:1667-72, 2013

Br J Dermatol 2016; 175:1166-74

Any rash

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 Rash grade 2-4 What about topical steroids?

Petrelli et al. Br J Dermatol 2016; 175:1166-74

EGFR inhibitor skin toxicity treatment scheme EGFR INHIBITORS: papulopustular eruption

Type of skin toxicity Treatment recommendation

General measures:
- sun protection
- lukewarm water, bath/shower oil for hygiene
- emollients on hands and limbs
GRADE 1 (mild) TREATMENT
Acneiform eruption Mild: metronidazole cream bid vitamin K1 cream
Moderate: metronidazole cream bid vitamin K1 cream Topical
minocycline 100 mg qd Mild eruption
- Metronidazole cream 1/d
Severe: saline compresses 15 minutes bid No symptoms
metronidazole cream up to 5 times daily Rozex cream or emulsion, Rosaced, Nidazea
No impact on ADL
minocycline 200 mg qd
topical steroid (fluticasone propionate cream) Systemic
Add cetirizine 10 mg qd for itch
- Tetracycline antibiotics
Add cefuroxim axetil 500 mg bid for S. aureus superinfection
minocycline 1x100mg/d
Xerosis Emollients lymecycline 1x300mg/d
Eczema Weak topical corticosteroids or
Fissures Propyleneglycol 50% in water 30 minutes under occlusion qd
salicylic acid 10% ointment qd - postpone to grade 2

Paronychia Antiseptic soaks bid

Paste containing potent steroid, antiseptic and antifungal bid

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Segaert Targ Oncology 2008 3:245-51

EGFR INHIBITORS: papulopustular eruption EGFR INHIBITORS: papulopustular eruption

GRADE 2 (moderate) TREATMENT GRADE 3 (severe) TREATMENT

Refer to dermatologist
Topical Severe eruption
Moderate eruption - Metronidazole cream 1/d Topical
Some symptoms mainly itch Severe symptoms
Rozex cream or emulsion, Rosaced, Nidazea Major impact on ADL* - Corticoid: moderate potent
Minor impact on ADL* - Corticoid: mild or moderate potent
Systemic
Systemic - Tetracycline antibiotics
- Tetracycline antibiotics minocycline 2x100mg/d
minocycline 1 to 2x100mg/d lymecycline 2x300mg/d
lymecycline 1 to 2 x300mg/d or
- Isotretinoin 20-30mg/d
Symptomatic
antihistamine (older antihistamines stronger Symptomatic
itch reducing effect but more sedation) - Antihistamines (older antihistamines stronger
itch reducing effect but more sedation)
Re-evaluate after 2 weeks if not better refer to dermatologist 41 If not responding to therapy consider dose delay 42

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 After 2 weeks treatment:
- minocycline 2 x 100 mg/d
- saline compresses
- metronidazole 2% cream

1 week

4 weeks

After 2 weeks treatment:

- minocycline 2 x 100 mg/d
After 2 weeks treatment:
- saline compresses
- minocycline 100 mg/d
- metronidazole 2% cream
- metronidazole 2% cream
- cefuroxim axetil 2 x 500 mg (5 d)

After 1 week treatment:

- minocycline 2 x 100 mg/d After 1 week treatment:
- saline compresses - cefuroxim axetil 2 x 500 mg/d
- metronidazole 2% cream - topical fluticasonepropionate cream

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After 1 week treatment:
- propyleneglycol/water
- salicylic acid 10% in petrolatum Thank you for your kind attention