TAO-Cancer Toxicity Management: Cutaneous Toxicities of Immunotherapies

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1 TAO-Cancer Toxicity Management: Cutaneous Toxicities of Immunotherapies Mario E Lacouture MD Director, Oncodermatology Program Attending, Dermatology www. MSKCC.org

2 Dermatologic Care With Immunotherapies Are we being too superficial? 8.5 million people with cancer yearly, 34 million survivors Prior to therapy, 45.1% with derm conditions (n=700) During therapy, 49% with dae (n=82) Upon completion of therapy, 55% with dae (n=82) Consequences of dermatologic events with immunotherapies Psychosocial impact Financial burden Physical health Anticancer treatment disruption Kilic et al, 2007; Ghandi et al, 2009; Sehouli et al, 2007; Rosen et al 2013; Hwang et al, 2015

3 Targeting the Immune System in Cancer. Sharma et al, Nat Rev Cancer 2011

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

5 Adverse Events to Immunotherapies: Oncologist Nivolumab (n=474) Weber et al. ASCO 2015

6 Publications on Rash to Immunotherapy Pubmed (rash ±nivoor ipior atezoor pembro)

7 Adverse Events to Immunotherapies: Dermatologist AE type nivo/pembro (n=82) AE onset % months Hwang et al, JAAD 2015

8 Maculopapular Rash to Immunotherapies Incidence Ipilimumab:19% Nivolumab: 34% Ipi+nivo: 40% Pembrolizumab: 39% Atezolizumab: 10% Maculopapular rash Treatment Grade 1/2 Oral Antihistamines Top Steroids Grade 3 PO steroids Minkis et al, JAAD 2013; Photo courtesy of Prof A Hauschild; Robert et al, NEJM 2015; Hamid et al, NEJM 2013; Margolin et al, Lancet Oncol 2012; Rosenberg et al, Lancet 2016

9 Lichenoid Rash (Dermatitis) to Immunotherapies PD-1/PD-L1 inhibitors (n=20) Lichen Epi Dermis Joseph et al, Cancer ImmunRes 2015; Shi et al, JAMA Derm 2016; Schaberg et al, J Cut Pathol 2016

10 Lichenoid Dermatitis from PD-1 inhibition Pd1/PDL1 inhibitors (n=5) Control PD1 inhibitor Control PD1 inhibitor Schaberg et al, J Cut Pathol 2016

11 PD-1 inhibitor Serious DAE: Stevens Johnson Syndrome SJS Lichenoid dermatitis PD-1 PD-L1 Goldinger et al, CCR 2016

12 PD-1 inhibitor DAE: Serious v non-serious 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) Maculopapular drug rash controls (n=8) Goldinger et al, CCR 2016

13 Blistering Disorders from PD1/PD-L1 Inhibitors Incidence: 2.4% (n=82) Tense bullae Pruritus Anti-BP180/230 Abs Oral involvement Treatment Steroids MMF Azathioprine Naidoo et al, Cancer ImmunolRes 2016: Curry et al, J Cut Pathol 2016; Hwang et al, JAAD 2015

14 Infrequent ir DAE from PD-1 inhibition Dermatomyositis (n=3) Psoriasis (n=21) Lacouture, unpublished; Bonigen et al, 2016; Sibaud et al,2016

15 Infrequent ir DAE from PD-1 inhibition Keratoacanthomas (n=4) Rosacea (n=3) H&E CD4 CD8 Lacouture, unpublished; Bonigen et al, 2016; Sibaud et al,2016

16 Pruritus to Immunotherapies Excoriations Incidence Ipilimumab: 4% Nivolumab: 17% Ipi+Nivo: 33% Pembrolizumab: 21% Atezolizumab: 7% Ensslin et al, JAAD 2014; Sanlorenzo et al, 2014 Valentine et al, JAAD 2015; Santoni et al, 2015; Rosenberg et al, 2016

17 Quantification of Pruritus n=25 ItchyQoL Patients responding Sometimes Often Always Desai et al, 2008; Zylicz et al, 2010

18 First line therapy for pruritus: PO antih1/steroids Topical steroids/anti pruritics (menthol, pramoxine) Patient-reported Pruritus 93% of patients responded to aprepitant (>50% reduction in pruritus) Median duration of one cycle effect 30 days (range 7-90 days), >50% did not recur Santini et al, Lancet Oncol 2012

19 Vitiligo to PD-1 inhibition Pembrolizumab n=67 Robert et al, NEJM 2015; Hamid et al, NEJM 2013; Margolin et al, Lancet Oncol 2012; Hua et al, JAMA Derm 2015

20 PD-1 Inhibition: Correlation between ir DAEs and Outcome Pembrolizumab PFS n=83 Nivolumab OS n=148 Freeman-Keller et al, ClinCancer Res 2015; Sanlorenzo et al, JAMA Dermatol 2015

21 Alopecia (immune-related) to PD-1 inhibition Target Patients (n) Agent Incidence Ipilimumab+Nivolumab CTLA-4 63 Ipilimumab 1.6% 296 Nivolumab 1% PD-1 NR Pembrolizumab NR PD-L1 NR Atezolizumab NR CTLA-4/ PD-1/PD-L1 496 Ipi Nivo Pembro Atezo 1.4% Treatment Steroids JAK inhibitors Belum et al, Ann Oncol 2015; Zarbo et al, Br J Dermatol2017

22 ird AE to PD-1 inhibition 52-year-old female with stage IV melanoma (unknown primary) Nivolumab+ipilimumab C4 Foreign body granuloma 10/14/2015 5:02:19 PM

23 Hyaluronic Acid Filler Granuloma to CTLA-4/PD-1 inhibition 10/14/2015 5:02:19 PM

24 ir DAE Treatment: More Than Steroids? Bisphosphonates macrophages JAK inhibitors T cells Psoriasis+AA Craiglow and King, JID 2014; Craiglow and King, JAMA Derm 2015

25 CTLA-4/PD-1 Inhibitor Combination: More Adverse Events Patients Reporting Event, % NIVO+ IPI (N=313) Any Grade Grade 3 4 NIVO (N=313) Any Grade Grade 3 4 IPI(N=311) Any Grade Grade 3 4 Treatment-related adverse event (AE) Treatment-relatedAE leading to discontinuation Treatment-related death* % of patients (81/120) who discontinued the NIVO + IPI due to AEs responded Wolchok et al. ASCO 2015; Larkin et al, NEJM 2015

26 Conclusions Dermatologic AE occur in the majority of patients Early/proactive approach is critical - Quality of life - Consistent dosing of immunotherapy Adverse events will increase in importance Adjuvant setting Dose escalation and combination studies Longer survival emphasis on QoL issues

27 Thank you

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