DERMATOLOGIST, MOHS SURGEON CHUGLD, MONCTON NB Disclosures / - PowerPoint PPT Presentation

DR MARTIN LEBLANC MD FRCPC FCDA DERMATOLOGIST, MOHS SURGEON CHUGLD, MONCTON NB

Disclosures / Conflicts of interest ▪ Honorariums : ▪ AbbVie ▪ Sanofi-Genzyme Canada ▪ LEO

Objectives : ▪ Overview of the cutaneous adverse effects of immunotherapy ▪ Is there a survival benefit for patients receiving immunotherapy in the advent of these cutaneous advserse events

Overview of the cutaneous adverse effects of immunotherapy ▪ Classification...

Overview of the cutaneous adverse effects of immunotherapy ▪ Enumeration ! ▪ Morbilliform eruption ▪ Eczema like (spongiotic dermatitis) ▪ Pruritus ▪ Lichenoid eruption ▪ Psoriasis or psoriasiform eruption ▪ Acneiform ▪ Vitiliginous ▪ Hypersensitivity syndrome : DRESS ▪ Auto-immune (Bullous, dermatomyositis, Alopecia areata) ▪ Other (sarcoidosis, nail, oral mucosal changes)

Overview of the cutaneous adverse effects of immunotherapy ▪ Morbilliform eruption ▪ Aka ‘ Maculopapular eruption ’ ▪ The most frequent ▪ CTLA4 inh (1/4pts) > PD-1 (1/6pts) ▪ ** PD-L1 preliminary data 1/10pts ▪ Rate of grade 3, less than 3%

Overview of the cutaneous adverse effects of immunotherapy ▪ Morbilliform eruption – Management: ▪ Mid to high potency topical steroid : ▪ (Betamethasone valerate – 450g! ) ▪ +/- anti-histamine ▪ Systemic steroid – case by case ▪ If so, hold immunotherapy and restart once <10mg/day ▪ Does not interfere with anticancer immune response

Overview of the cutaneous adverse effects of immunotherapy ▪ Lichenoid eruption ▪ More violaceous ▪ Later onset ▪ Intensly pruritic

Overview of the cutaneous adverse effects of immunotherapy ▪ Psoriasis ▪ Better delineated ▪ Key areas (extensory, nails..) ▪ Arthritis

Overview of the cutaneous adverse effects of immunotherapy ▪ Life threatening ▪ Stevens-Johnson ▪ TEN (toxic epidermal necrolysis) ▪ DRESS ▪ Other (Vasculitis, Sweet syndrome, Bullous pemphigoid)

SJS-TEN

DRESS – Drug rash with eosinophilia and systemic symptoms ▪ Often morbilliform presentation plus… ▪ Fever ▪ Swelling (face)! ▪ Adenopathy ▪ Eosinophilia ▪ Hepatitis ▪ Nephritis ▪ Pneumonitis ▪ Etc…

Objective #2 : ▪ Is there a survival benefit for patients receiving immunotherapy in the advent of these cutaneous advserse events ?

Preamble :

Is there a survival benefit for patients receiving immunotherapy in the advent of these cutaneous advserse events Australian study – Westmead hospital

Method ▪ P rospective cohort study, stage IIIC/IV melanoma pt tx Pembrolizumab or Nivolumab ▪ May 1 st 2012 → Feb 1st 2018 ▪ Tumor response evaluated using ir-RECIST

Method ▪ 82 pts (5 Nivolumab, 77 Pembrolizumab) ▪ Median follow up = 40 months ▪ 33 pts who developed at least one target skin reaction (TSR) = Eczema, Lichenoid, vitiligo-like

Method ▪ Analysis ▪ Cox proportional hazards model with time dependent covariates to assess the association between the development of the CAE and disease progression or death ▪ Landmark studies

▪ Results ▪ Primary analysis : time-dependent Cox proportional hard model for disease progression/death ▪ At any point in time on tx with PD-1, individuals who had one or more CAE had a 54% less instantaneous risks of experiencing progressive disease/death who had not developed any reaction by this time ▪ Hazard ratio 0.46 with 95% CI (0.23-0.91) p=0.025

▪ Results ▪ Landmark analyses at 6 and 12 months ▪ 6 months = 50% less risk of disease progression/death ▪ 12 months= 66% less risk of disease progression/death

▪ Limitation ▪ Low sample size ▪ Only studied the univariate association between the development of one or more CAE and disease progression/death ▪ Landmark time reduces the event rate within this population

Take away ▪ Morbilliform eruption ▪ look for any criteria of severity (mucous membrane involvment, Nikolsky sign, purpura, palmarplantar...) ▪ Usually self-limiting and manageable ▪ Combination ICI = more frequent, severe and earlier cutaneous irAE

Take away ▪ The relation between cutaneous adverse events and impact on final outcome ▪ Interesting surrogate marker

References : ▪ The oncological survival and prognosis of individuals receiving PD-1 inhibitor with and without immunologic cutaneous adverse events, J Am Acad Dermatol. 2019 Jun 21. pii: S0190-9622(19)31024-2. doi: 10.1016/j.jaad.2019.06.035 ▪ Dermatologic Reactions to Immune Checkpoint Inhibitors, American Journal of Clinical Dermatology, June 2018, Volume 19, Issue 3, pp 345 – 361 ▪ Bullous Lupus Under Nivolumab Treatment for Lung Cancer: A Case Report With Systematic Literature Review. Anticancer Res. 2019 Jun;39(6):3003- 3008. doi: 10.21873/anticanres.13432. ▪ Anticancer Res. 2019 Jun;39(6):3003-3008. doi: 10.21873/anticanres.13432. Dermatol Clin. 2019 Oct;37(4):555-568. doi: 10.1016/j.det.2019.05.013. Epub 2019 Jul 27. ▪ Nivolumab-induced lichen planus. J Oncol Pharm Pract. 2019 Aug 5:1078155219866248. doi: 10.1177/1078155219866248 ▪ Diverse cutaneous adverse eruptions caused by anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies: clinical features and management, Ther Adv Med Oncol. 2018; 10: 1758834017751634. ▪ BOLOGNIA and al. Dermatology , 3rd Edition, 2012 ▪ FITZPATRICK’s , Dermatology in general medicine , 8th edition, 2012. ▪ Up to Date ▪ Pubmed

Thank you, Questions?