Cutaneous adverse events to immune checkpoint inhibitor therapy

Transcription

1 Cutaneous adverse events to immune checkpoint inhibitor therapy 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 immune checkpoint inhibitor therapy CAEs as prognostic indicators

3 Legend 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 PD-L1 inhibitors Atezolizumab- May 2016, urothelial carcinoma Avelumab- Phase III trials Durvalumab- Phase III trials

4 Most common inflammatory CAE from ipilimumab? A. eczema B. psoriasis C. mucositis D. acneiform E. vitiligo Question 7

5 Most common inflammatory CAE from ipilimumab? A. eczema B. psoriasis C. mucositis D. acneiform E. vitiligo Question 7

6 Question 8 What is the sentinel irae from ipilimumab? A. Rash B. Colitis C. Pneumonitis D. Myocarditis E. Thyroiditis

7 Eczema EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors 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

8 Psoriasiform dermatitis EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors Treatment options: Flare regimen: Triamcinolone 0.1% BID (body) Hydrocortisone 2.5% BID x 5 days (face, genital area) RTC: 2 weeks Systemic retinoids Maintenance regimen: Topical steroid BIW Bland emollient daily

9 Granulomatous dermatitis EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors Treatment options: Topical steroid Oral steroid

10 Xerosis EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors Treatment options: Bland emollient BID Bath BID Keratolytics (ammonium lactate or salicylic acid) Topical steroid PRN

11 Bullous pemphigoid EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors Treatment options: Topical/oral/IV steroids Drug cessation Long latency (3-16 weeks)

12 Question 9 Definitive treatment for anti-pd1-induced bullous pemphigoid is: A. Dose reduction B. Dose cessation C. Systemic steroids D. Systemic non-steroidal immunosuppression

13 Vitiligo EGFR inhibitors Multikinase inhibitors MEK inhibitors BRAF inhibitors HER2 inhibitors CTLA4 inhibitors PD-1 inhibitors mtor inhibitors RET inhibitors Treatment options: Nothing Topical steroids or topical tacrolimus +/- light therapy Possible association with PFS and tumor response

14 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

15 Rashes as prognostic indicators

16 Question 10 CAE associated with tumor response? A. Acneiform B. Vitiligo C. Hand foot skin reaction (HFSR) D. A and B

17 Rashes as prognostic indicators 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

18 Acneiform eruption EGFR inhibitors Cancer types: Colorectal cancer Non-small cell lung cancer Head and neck SCC Rash characteristics: Early appearance Grade 2+ Correlation to: Progression-free survival Overall survival Tumor response Histo: Decreased p-egfr expression correlated to OS (normal skin) MEK inhibitors? RET inhibitors?

19 Vitiligo Immune checkpoint inhibitors UNDER REPORTED Retrospective Clinical trials run by oncologists Cancer types: Melanoma Correlation to: Progression-free survival Tumor response

20 5,737 patients Incidence of vitiligo: 3.4% Progression free survival: HR 0.51 Overall survival: HR 0.25 Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33(7):

21 (Anti-PD1) 67 patients Prospective Incidence of vitiligo: 25% Time to onset: 52 to 453 days median, 126 days Tumor response: Higher occurrence of vitiligo 71% vs. 28% 3/17 (18%) had a complete response 9/17 (53%) had a partial response 3/17 (18%) had stable disease 2/17 (12%) had progressive disease Hua C, Boussemart L, Mateus C, et al. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol. 2016;152(1):45-51.

22 (Anti-PD1) 148 patients Incidence of rash: 46 (40%) unresectable 18 (54.6%) resected 43% total Incidence of vitiligo: 11 (9.6%) unresectable 8 (24.2%) resected 13% total Time to onset: 5 weeks 3 had been previously treated with IL-2 Reported iraes: Rash Vitiligo Endocrinopathies Colitis Pneumonitis Improved OS: Rash: HR, Vitiligo: HR, Freeman-keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin Cancer Res. 2016;22(4):

23 Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol. 2015;151(11): (Anti-PD1) 83 patients Retrospective Cancer types: Metastatic melanoma Lung cancer Prostate cancer Merkel cell CA CAEs: 42% total incidence Macular papulareruption: 29% Pruritus: 12% Hypopigmentation: 8% (MELANOMA ONLY) Correlated with longer progression-free intervals HR depending on dose

24 Question 11 Vitiligo as a CAE has only been reported in melanoma patients: A. True B. False

25 Granulomatous reactions Indicate immune response Hodgkin s disease Gastric adenocarcinoma BRAF inhibitors Anti CTLA4 Anti PD-L1

26 Garrido MC, Gutierrez C, Riveiro-falkenbach E, Ortiz P, Rodriguez-peralto JL. BRAF Inhibitor-Induced Antitumoral Granulomatous Dermatitis Eruption in Advanced Melanoma. Am J Dermatopathol. 2015;37(10): Granulomatous dermatitis BRAF inhibitors 3 patients Time to onset: 2-10 months Erythematous, and violaceous papules Tumor response (2), progression of disease (1)

27 Suozzi KC, Stahl M, Ko CJ, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2(3): Sarcoidosis Ipilimumab (11), Anti-PD-L1 (1) Cancer type: Melanoma Prostate CA Lung adenoca Sarcoidosis presentation: Lung, kidney, spleen, skin Skin: 2 in combination with lung, 1 primary 4/8: Partial or complete response 1/8: Stable disease 3/8: Progression of disease

28 Question 12 Potential CAEs associated with tumor response? A. Eczema B. Psoriasis C. Granulomatous dermatitis D. All of the above

29 Kim JH, Choi YJ, Lee BH, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1-high T cells. J Allergy Clin Immunol. 2016;137(5): e3. Psoriasiform dermatitis Anti PD-1 PD-L1 expression is increased in melanoma tumor cells PD-1 expression is increased in Th17 cells in psoriatic lesions

30 Summary CAEs can be a window into drug mechanisms and tumor response Things we know: Acneiform eruption indicates a good prognosis for some cancers Vitiligo indicates a good prognosis for melanoma Potential correlations: Granulomatous reactions Psoriasiform dermatitis

31 Thank you Shelby Kubicki, MS2 Macartney Welborn, MS2 Osama Hashmi, MS4 Sana Zahirrudin, MD Saira George, MD

32 References Berthod G, Lazor R, Letovanec I, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30(17):e Coutinho I, Pereira N, Gouveia M, Cardoso JC, Tellechea O. Interstitial Granulomatous Dermatitis: A Clinicopathological Study. Am J Dermatopathol. 2015;37(8): Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology (Basel). 2009;218(1): Garrido MC, Gutierrez C, Riveiro-falkenbach E, Ortiz P, Rodriguez-peralto JL. BRAF Inhibitor-Induced Antitumoral Granulomatous Dermatitis Eruption in Advanced Melanoma. Am J Dermatopathol. 2015;37(10): Jansen YJ, Janssens P, Hoorens A, et al. Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib. Melanoma Res. 2015;25(6): Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71(1): Luke JJ, Lezcano C, Hodi FS, Murphy GF. Antitumor granuloma formation by CD4+ T cells in a patient with rapidly progressive melanoma experiencing spiking fevers, neuropathy, and other immune-related toxicity after treatment with ipilimumab. J Clin Oncol. 2015;33(6):e32-5. Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol. 2014;150(3): Suozzi KC, Stahl M, Ko CJ, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2(3): Toumeh A, Sakhi R, Shah S, Arudra SK, De las casas LE, Skeel RT. Ipilimumab-Induced Granulomatous Disease Occurring Simultaneously With Disease Progression in a Patient With Metastatic Melanoma. Am J Ther. 2016;23(4):e Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012;30(2):e7-e10.

33 References Parma J, Pavlick A, Schiff R, et al. Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer. Pharmacotherapy. 2013;33(10): Lee Y, Shim HS, Park MS, et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin Cancer Res. 2012;18(6): Jonker DJ, O'callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20): Klinghammer K, Knödler M, Schmittel A, Budach V, Keilholz U, Tinhofer I. Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res. 2010;16(1): Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2009;45(10):e Huang CL, Yang CH, Yeh KH, et al. EGFR intron 1 dinucleotide repeat polymorphism is associated with the occurrence of skin rash with gefitinib treatment. Lung Cancer. 2009;64(3): Parmar S, Schumann C, Rüdiger S, et al. Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. Pharmacogenomics J. 2013;13(2): Peréz-soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?. J Clin Oncol. 2005;23(22): Zaborowska-szmit M, Kowalski DM, Piórek A, Krzakowski M, Szmit S. A decrease in D-dimer concentration and an occurrence of skin rash as iatrogenic events and complementary predictors of survival in lung cancer patients treated with EGFR tyrosine kinase inhibitors. Pharmacol Rep. 2016;68(6): Kudo K, Hotta K, Bessho A, et al. Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. Cancer Chemother Pharmacol. 2016;77(5):

34 References Sugiura Y, Nemoto E, Kawai O, Ohkubo Y, Fusegawa H, Kaseda S. Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung adenocarcinoma in Japanese patients. Springerplus. 2013;2(1):22. Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-egfr tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer. 2012;78(1):8-15. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13): Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE. 2013;8(1):e Agulnik M, Da cunha santos G, Hedley D, et al. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol. 2007;25(16): Kim JH, Choi YJ, Lee BH, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1-high T cells. J Allergy Clin Immunol. 2016;137(5): e3.