Immune-Related Adverse Events: Dermatologic

Transcription

1 Immune-Related Adverse Events: Dermatologic Mario E Lacouture, MD Director, Oncodermatology Program Attending, Dermatology Dermatology Service, Department of Medicine lacoutum@mskcc.org

2 Disclosures Research funding Berg, BMS, Genentech/Roche, RJR Fund, Galderma, Paxman Consulting/Advisory Novartis, Janssen, BMS, Genentech/Roche, Galderma, Debio, Pfizer, Helsinn, Silk Therapeutics, Foamix, Boehringer Ingelheim, Medische Voet, Legacy

3 You are Targeting the Immune System. Drake et al, Nat Rev Clin Oncol 2013

4 And You Are Targeting the Skin Macrophages T cell Mast cells DDC Vessels Tong et al, J Invest Dermatol 2015

5 Santini et al, ASCO Annual Meeting 2017, Abs 9012; Sznol et al, J Clin Oncol 2017; Khoja e al, Ann Oncol 2017 There is a Time and a Place for IO Toxicities A Ipi+Nivo G3/4 AE (n=448) 48% 26% 26% B All Grade AE (n=6,938) Recurrent irae New irae No subsequent irae

6 Hwang et al, JAAD 2015; Wolchok et al. ASCO 2015; Larkin et al, NEJM 2015 IO Toxicities: The Eye of The Beholder Ipi+Nivo (n=313) Nivo/Pembro (n=82) `

7 Barrios et al, AAD Annual Meeting 2017 Toxicity Assessment: Dermatologist vs Oncologist Are diagnoses concordant? n=113 Is agent interruption indicated? n=150 Yes No Oncologist Dermatologist

8 Immune-related Adverse Event: Skin Maculopapular rash Eczema/urticaria Rash incidence (n=2,344) Ipilimumab:24.3% Nivolumab: 14.3% Ipi+nivo: 40% Pembrolizumab: 16.7% Atezolizumab*: 10% Vitiligo-like Lichenoid rash Minkis et al, JAAD 2013; Belum et al, Eur J Cancer 2016; Joseph et al, Cancer Immun Res 2015; Larsabal et al, JAAD 2016

9 Genetic Profile of PD-1i Rash is Similar to SJS/TEN Genes upregulated PD-1i rash - CCL27, NURR1, GNLY, FASLG, and PRF1 PD-1i rash and SJS/TEN PI3, SPRR2B, GZMB, CXCL9, CXCL10, and CXCL11 PD-1 inhibitor rash (n=5) Maculopapular drug rash controls (n=8) Goldinger et al, CCR 2016

10 Genetic Profile of PD-1i Rash is Similar to SJS/TEN Genes upregulated PD-1i rash - CCL27, NURR1, GNLY, FASLG, and PRF1 PD-1i rash and SJS/TEN PI3, SPRR2B, GZMB, CXCL9, CXCL10, and CXCL11 PD-1 inhibitor rash (n=5) SJS/TEN (n=5) Goldinger et al, CCR 2016

11 Maculopapular rash/derma00s Grade Descrip,on Management 1 Macules/papules covering <10% BSA with or without symptoms (e.g., pruritus, burning,,ghtness) Con,nue ICI Oral an0histamines Topical cor0costeroids Derm Referral 2 Macules/papules covering 10-30% BSA with or without symptoms; limi,ng instrumental ADL Con,nue ICI Non-acute dermatology referral Oral an0histamines Topical cor0costeroids ü 3 Macules/papules covering >30% BSA with or without associated symptoms; limi,ng self care ADL Hold ICI Same day dermatology consult Rule out systemic hypersensi,vity: CBC with differen,al, CMP Oral an,histamines Systemic cor0costeroids Prednisone 0.5 1mg/kg/day (or equivalent dose of methylprednisolone) un,l rash resolves to grade 1 ü Puzanov et al, J Immunother Cancer 2017

12 Skin Toxicity Treatment: Results 70 IO treated patients (n=66) Patient number p< G0 Before treatment Post treatment G1/2 G3 G0 G1/2 G3 N/A Baseline Followup Wu et al, ESMO IO 2017; ASCO Annual Meeting 2018

13 IO Skin Toxicity Treatment: Clinical Response 57 F, melanoma s/p ipilimumab + nivolumabà nivolumab Wu et al, ESMO IO 2017

14 Are There Skin Toxicity Actionable Targets? 600 IO treated patients (n=37) Serum levels G2 rash <G2 rash IL-6 IgE IL-5 IL-8 IL-10 Elafin pg/ml ku/l pg/ml pg/ml pg/ml ng/ml

15 Targeting Toxicities: Rituximab for IO Bullous Pemphigoid Melanoma-Ipi+Nivo Rituximab 4 cycles+mp RCC-atezolizumab Rituximab 4 cycles Wu et al, ESMO IO 2017

16 Targeting Toxicities: IL12/23 Blockade for IO Psoriasis Atezolizumab for lymphoma Ustekinumab 2 cycles Wu et al, ESMO IO 2017

17 Immune-related Adverse Event: Pruritus Targets All-grade% (grade 3) Anti-CTLA (1) Anti-PD (1) Combination (2) Anti-PD-L (1) Ensslin et al, JAAD 2014

18 IO Pruritus-ItchyQoL Impact on QoL HD patients n= * 2.0 Location: distal limbs in 82% Symptoms Functioning Emotions Wu et al, AAD Annual Summer Meeting 2017

19 Wu et al, AAD Annual Meeting 2018 Management of IO Pruritus-GABA Agonists 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Response to oral steroids (N=25) 32.0% 28.0% 28.0% 12.0% CR PR SD PD 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Response to GABA agonist 41.4% 44.8% 13.8% 0.0% CR PR SD PD (N=29)

20 IO Dermatologic Toxicities Are Good Pembrolizumab PFS n=83 Nivolumab OS n=148 Freeman-Keller et al, Clin Cancer Res 2015; Sanlorenzo et al, JAMA Dermatol 2015

21 Infrequent ICI Dermatologic Adverse Event: Alopecia Areata Alopecia reported in 1-1.6% (n=855) Biopsy: CD4+ T cells, scant CD8+ T cells Baseline Ipilimumab+Nivolumab Followup Areata (totalis, universalis) PD-L1 is expressed on the hair follicle dermal sheath cup cell Melanocyte-specific cytotoxic T cells in melanoma patients treated with ICI Zarbo et al, Br J Dermatol 2016

22 Harding et al, NEJM 2012; Imafuku et al, JEADV 2016 Inflammatory Toxicities: The Body Does Not Forget IO Ipilimumabàvemurafenib patients (n=13) Rechallenge possible after interruption

23 The Hypersensitivity Rash is Not Vemurafenib-specific T cells absent Aryl Hydrocarbon Receptor (AhR) Gerber et al, 2017

24 IO Skin Toxicities-Conclusions Pathogenic mechanisms diverse and actionable B cells, IL-17, 12/23, IgE, IL-6 Tailored supportive care is critical for QoL and dosing IO toxicities will increase in importance - Combined therapies and longer survival

25 Thank you

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