Updates in the Management of Epidermal Growth Factor Receptor (EGFR) Inhibitors- Induced Skin Rash. Outline. Signal Transduction

Transcription

1 Updates in the Management of Epidermal Growth Factor Receptor (EGFR) Inhibitors- Induced Skin Rash Siu-Fun Wong, PharmD, FASHP, FCSHP Associate Professor of Pharmacy Practice Western University of Health Sciences Pomona, California Outline Overview of the pharmacology of EGFR inhibitors Pathophysiology of EGFR inhibitors- induced skin rash Review of current and new treatment options for EGFR-induced skin rash EGF Signal Transduction Epidermal Growth Factor Receptor or HER TGF- α Expression of EGF Receptors Extracellular Binding Domain Transmembrane Lipophilic Segment Intracellular Protein Tyrosine Kinase Domain Ligands Bind Activation of Signal Transduction EGF Receptor Dimerization ERBITUX Package Insert, February. Baselga J. J Clin Oncol. ;8s:s-s. Please see important safety information including WARNING regarding infusion reactions on slides to.

2 HER/EGFR Inhibitors Two major classes Monoclonal Antibodies Cetuximab ( Erbitux ) Panitumumab ( Vectibix ) Small Molecule Tyrosine Kinase Inhibitors (TKI) Erlotinib ( Tarceva ) Lapatinib ( Tykerb ) HER/EGFR & HER EGFR Inhibitor- Mechanism of Action Monoclonal Antibody and Small Molecule TK inhibitor Antibody Binds Small molecule EGFR TK inhibitors Receptor Internalized ERBITUX Package Insert, February. EGFR Inhibitor Induced Dermatologic Toxicity Dermatologic toxicities include: Papulopustular (Interfollicular and follicular-based erythematous papules and pustules) rash, xerosis, paronychial inflammation Papulopustular Rash: Onset: - weeks Usually occur on face, scalp, and upper body Symptoms: pain/tenderness and pruritus Inflammatory and infectious sequelae Papulopustular Rash is common 88% ( all grades) 6% ( grade or ) Dose reduction or discontinuation are recommended Potential marker for drug activity and clinical outcome

3 ERBITUX (Cetuximab) Safety Dermatologic Toxicity Representation of acneform rash on face* Representation of acneform rash on chest* *Photos courtesy of Memorial Sloan-Kettering Cancer Center. Current Recommended Treatments for Papulopustular Rash Mild to moderate: Cover make-up without worsening the existing rash Standard analgesic for pain Oral antihistamine for pruritus High-potency topical corticosteroids Topical immunomodulatory agent ( e.g. pimecrolimus aka Elidel) Avoid topical retinoids and benzoyl peroxide due to skin drying effect Secondary infection: Prophylactic intranasal mupirocin Oral antibiotic Severe: Systemic corticosteroids Interruption of treatment HER/EGFR Inhibitor Rash Management Forum Recommendations, Jan Current Recommended Treatments for Papulopustular Rash General: Maintain maximal hydration using emollient cream Sunblock - Sunlight can exacerbate any skin reactions Avoid topical or systemic corticosteroids Grade : Topical anti-acne products Grade : Oral minocycline or doxycycline Oral antihistamine or topical menthol cream for pruritus Grade or : Dosage adjustments Higher doses of oral antimicrobials Segaert S, et al. Annals of Oncology 6:5-, 5

4 What do we know about the pathophysiology of EGFR inhibitors-induced induced skin rash? It is not acne or acne vulgaris which has both: Non-inflammatory lesions (comedones) Inflammatory papules, pustules, and nodules caused by bacterial colonization Only secondary inflammatory response EGFR inhibitors-induced induced Skin Rash Histological characteristics: Suppurative superficial folliculitis Lymphocytic perifolliculitis No infection etiology Proposed MOA: EGFR primarily expressed in undifferentiated, proliferating keratinocytes in the basal and suprabasal layers of the epidermis and the outer layers of the hair follicle Expression of EGFR is lost as keratinocytes exit the basal layer Inhibition of EGFR in basal keratinocytes leads to follicular degeneration and destruction, causing a strong inflammatory response and release of inflammatory cytokines Lenz, H et al. Oncology 6, : 5 (S):5-. Lacouture M. Nat Rev Cancer 6, 6():8-8. Evaluation of the Current Treatment Recommendations Topical anti-acne acne products Intranasal antibiotic Oral antibiotics Oral antihistamine Topical high-potency corticosteroids Systemic corticosteroids Topical immunomodulatory agent ( e.g. Elidel) Dose reduction or interruption

5 Skin Rash and Clinical Outcomes A multivariate analysis of 9 clinical trials and compassionate-use program Positive correlation were observed between rash and response/survival in Erlotinib Cetuximab Trend between severity of rash and PFS in Panitumumab Less consistent results seen in gefitinib Perez-Solar R & Saltz L. J Clin Onco 5 : Principles of Skin Rash Treatment Elimination of skin rash is not necessarily desirable! Perhaps maintaining a grade rash is most optimal? Criteria for optimal supportive treatment: Treatments should not interfere with the anti-tumor tumor effects of EGFR inhibitors Maintain low side effect profile Ease of administration with rapid results to ensure patient compliance Individualize treatment according to presenting sign and symptoms Keep costs at minimal No prospective trial data available A Pilot Cross-Over Study to Evaluate the Use of Regenecare Topical Gel in Patients with Cutaneous Toxicity Caused by Epidermal Growth Factor Receptor (HER/EGFR) Inhibitors an Interim Analysis Wong SF Pharm. D, Lloyd K, M.S, Vasko C, NP, RN, OCN, Mummaneni M, M.D, Osann K, Ph.D. Western University of Health Sciences, Dept. of Pharmacy, Pomona CA; Hematology Oncology Medical Group of Orange County, Orange CA Poster Presentation at 9th International Conf. on Cancer Nursing Research Feb , Abstract 6.

6 Regenecare Topical Gel Ingredients Collagen Natural humectant, moisturizer Aloe Vera Gel Extract Enhances wound healing in animal models, increases fibroblasts and microcirculation % Lidocaine topical anesthetic Method Patients with grade skin rash ( symptomatic) apply gel to right side of face (- x daily) after rash onset (baseline) After week of application, subjects are allowed to cross-over over to apply gel to both sides of the face up to a total ot 6 weeks Weekly Assessment: Self-reporting by patients Clinical grading by provider Photos of right and left side of face Parameters: pain, itching, swelling, redness ( Scores: None = ; Mild = ; Moderate = ; Severe = ) Patient product satisfaction survey Improved Same Baseline vs Wk # 5 Patient Self-reported Pain and Itch Response at Baseline, Week, & Week Itch Baseline vs Wk # Wk # vs Wk # Baseline vs Wk # Baseline vs Wk # Pain Wk # vs Wk # Worse Total N = 6 ( cetuximab, erlortinib and panitumumab)

7 Change in Itch Score Mean Difference of Scores for Itching Relief Study Gel Treatment vs. Baseline SIDE GROUP No Treatment Treatment Difference in means = -.875; 95.% CI = -.96 to -.5 t = -.6; f = 6; p-value=.9 Change in Pain Score Mean Difference of Scores for Pain Relief Study Gel Treatment vs. Baseline SIDE GROUP No Treatment Treatment Difference in means = -.5; 95.% CI=-.8 to -.8 t = -.; df = 6; p-value =. Product Satisfaction Patient Questionnaire Survey Summary Five out of 5 patients rated gel "very" or "extremely" effective in reducing itching Five out of 5 patients rated gel "very" or "extremely" effective in reducing pain Four out of 5 patients rated gel "moderate" to "very" effective in skin healing properties Three out of 5 patients rated gel "moderate" to "very" effective in improving appearance of rash Five out of 5 patients rated gel "very" to "extremely" effective as to ease of use (easy to apply, messiness, etc.)

8 Product Satisfaction Patient Questionnaire Survey Summary The onset of pain relief was immediate to minutes and lasted - hours The onset of itch relief was 5- minutes Redness/Swelling Subject Treated with Panitumumab Redness/Swelling Subject Treated with Cetuximab

9 Conclusions Regenecare topical gel appears effective in relieving EGFR inhibitor-induced induced skin rash associated pruritus and pain symptoms in this preliminary evaluation The study gel was well tolerated and no adverse effects or secondary infections were noted The study gel helped to reduce rash- associated redness in some patients Study is ongoing with a goal to accrue a total of patients Summary EGFR inhibitors-induced induced skin rash should not be treated as acne vulgaris EGFR inhibitors-induced induced skin rash can have significant clinical implications in quality of life and, potential clinical outcome Better management of this adverse effect is needed Two other prospective clinical trials are ongoing A multi-center randomize trial to prospectively compare some of these recommended treatments is needed