TARGETED THERAPIES AND THEIR CUTANEOUS TOXICITIES Brussels, 14/1/2017 Cutaneous side effects of EGFRinhibitors and their management Siegfried Segaert Dermatology Dept University Hospital Leuven Belgium 4 th BADO meeting Brussels, January 14 th 2017 EGFR inhibitors Monoclonal antibodies - Cetuximab (Erbitux ) - Panitumumab (Vectibix ) Oral tyrosine kinase inhibitors - Erlotinib (Tarceva ) - Gefitinib (Iressa ) - Lapatinib (Tyverb ) - Afatinib (Giotrif ) EGFR inhibitors - Cetuximab (Erbitux ) - Panitumumab (Vectibix ) - Erlotinib (Tarceva ) - Gefitinib (Iressa ) - Lapatinib (Tyverb ) - Afatinib (Giotrif ) EGFR is abundantly expressed in the skin EGFR inhibitor skin toxicity Epidermis Hair follicle Acneiform eruption Xerosis, eczema, fissures Nail changes Hair changes Hyperpigmentation Telangiectasia Mucosal changes Albanell et al. J Clin Oncol 2001; 20:110-124 Segaert & Van CutsemAnn Oncol 2005; 16:1425-33 1
Acneiform eruption: grade 1 Acneiform eruption: grade 2 Acneiform eruption: grade 3 Acneiform eruption: grade 3 Xerosis, eczema, fissures 2
Nail changes Hair changes Hyperpigmentation Telangiectasia Mucosal changes Radiation and cetuximab combination therapy 3
Sparing of previously irradiated skin Acneiform eruption by MEK-inhibitor EGF EGFR Transgenic mice mimic EGFRi skin toxicity Wild type EGFR mutation (waved 2) Overall survival depends on severity of skin toxicity 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! 4
Prophylactic minocycline 100 mg qd: Study design Role of oral tetracyclines mcrc patients preparing to initiate cetuximab (± concomitant chemotherapy) n=48 R A N D O M I S E 1:1 8 weeks Minocycline 100 mg qd + topical tazarotene 0.05% bid on one side of face n = 24 Placebo + topical tazarotene 0.05% bid on one side of face n = 24 Evaluation of skin lesions by dermatologist on clinical pictures Scope et al. J Clin Oncol 2007; 25:5390-6. Prophylactic minocycline for acneiform eruption Study results Prophylactic treatment of acneiform eruption Tetracycline 500 mg bid Dermatologist lesion count 4 weeks n=48 p=0.005 Cancer* patients to initiate treatment with cetuximab, gefitinib, erlotinib n=61 R A N D O M I S E Tetracycline 500 mg bid Placebo 4 weeks Follow-up 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. Scope et al. J Clin Oncol 2007;25:5390-6. 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 *Lung, GI and other cancers Jatoi et al. Cancer 2008;113:847-53. 5
Phase 2 Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) trial: prophylactic vs. reactive skin treatment in 2 nd -line treatment of metastatic CRC mcrc PD or unacceptable toxicity with 1 st -line fluoropyrimidine + oxaliplatin-based CT (n=95) Stratification by CT 1:1 Prophylactic skin treatment Weeks 1 6, starting Day -1 Reactive skin treatment Patients were treated with panitumumab (6 mg/kg) Q2W plus FOLFIRI or panitumumab (9 mg/kg) Q3W plus irinotecan (investigator s choice) Prophylactic skin treatment regimen: skin moisturiser (daily); topical steroid (hydrocortisone 1% daily); doxycycline (100 mg BID); SPF 15 sunscreen before going outdoors Lacouture et al. J Clin Oncol 2010;28:1351 7 www.amgentrials.com, protocol ID: 20050184; ClinicalTrials.gov identifier: NCT00332163. R Skin assessment QW, Weeks 1 7 Tumour response evaluation Q8W or Q9W BID, twice a day; CT, chemotherapy; SPF, sun protection factor; Q3W/Q8W/Q9W, once every 3/8/9 weeks. STEPP trial: incidence and time to first occurrence of grade 2 skin toxicities Probability (%) 1 0.8 0.6 0.4 0.2 0 0 2 4 6 8 Weeks Lacouture et al. J Clin Oncol 2010;28:1351 7 Time to first occurrence of grade 2 skin toxicity Prophylactic Reactive Parametre Prophylactic (n=48) Reactive (n=47) Patients with grade 2 skin toxicity, n (%) 14 (29) 29 (62) Odds ratio (95% CI) 0.3 (0.1 0.6) Grade 2, n (%) 11 (23) 19 (40) Grade 3, n (%) 3 (6) 10 (21) Median time to first event, weeks (95% CI) NR 2.1 (2.1 6.3) 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 6
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 Acneiform eruption Mild: metronidazole cream bid ± vitamin K1 cream Moderate: metronidazole cream bid ± vitamin K1 cream minocycline 100 mg qd Severe: saline compresses 15 minutes bid metronidazole cream up to 5 times daily minocycline 200 mg qd topical steroid (fluticasone propionate cream) Add cetirizine 10 mg qd for itch Add cefuroxim axetil 500 mg bid for S. aureus superinfection Xerosis Eczema Fissures Emollients Weak topical corticosteroids Propyleneglycol 50% in water 30 minutes under occlusion qd salicylic acid 10% ointment qd GRADE 1 (mild) Mild eruption No symptoms No impact on ADL TREATMENT Topical - Metronidazole cream 1/d Rozex cream or emulsion, Rosaced, Nidazea Systemic - Tetracycline antibiotics minocycline 1x100mg/d lymecycline 1x300mg/d or - postpone to grade 2 Paronychia Antiseptic soaks bid Paste containing potent steroid, antiseptic and antifungal bid Segaert Targ Oncology 2008 3:245-51 40 EGFR INHIBITORS: papulopustular eruption EGFR INHIBITORS: papulopustular eruption GRADE 2 (moderate) Moderate eruption Some symptoms mainly itch Minor impact on ADL* TREATMENT Topical - Metronidazole cream 1/d Rozex cream or emulsion, Rosaced, Nidazea - Corticoid: mild or moderate potent Systemic - Tetracycline antibiotics minocycline 1 to 2x100mg/d lymecycline 1 to 2 x300mg/d Symptomatic antihistamine (older antihistamines stronger itch reducing effect but more sedation) Re-evaluate after 2 weeks if not better refer to dermatologist 41 GRADE 3 (severe) Severe eruption Severe symptoms Major impact on ADL* TREATMENT Refer to dermatologist Topical - Corticoid: moderate potent Systemic - Tetracycline antibiotics minocycline 2x100mg/d lymecycline 2x300mg/d or - Isotretinoin 20-30mg/d Symptomatic - Antihistamines (older antihistamines stronger itch reducing effect but more sedation) If not responding to therapy consider dose delay 42 7
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 - saline compresses - metronidazole 2% cream After 1 week treatment: - minocycline 2 x 100 mg/d - saline compresses - metronidazole 2% cream After 2 weeks treatment: - minocycline 100 mg/d - metronidazole 2% cream - cefuroxim axetil 2 x 500 mg (5 d) After 1 week treatment: - cefuroxim axetil 2 x 500 mg/d - topical fluticasonepropionate cream 8
After 1 week treatment: - propyleneglycol/water - salicylic acid 10% in petrolatum Thank you for your kind attention 9