SHIVAANI KUMMAR, MD IMMUNE CHECKPOINT INHIBITORS IN CANCER PATIENTS WITH AUTOIMMUNE DISEASE

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SHIVAANI KUMMAR, MD IMMUNE CHECKPOINT INHIBITORS IN CANCER PATIENTS WITH AUTOIMMUNE DISEASE RELEVANT FINANCIAL RELATIONSHIPS IN THE PAST TWELVE MONTHS BY PRESENTER OR SPOUSE/PARTNER.

1 SHIVAANI KUMMAR, MD IMMUNE CHECKPOINT INHIBITORS IN CANCER PATIENTS WITH AUTOIMMUNE DISEASE RELEVANT FINANCIAL RELATIONSHIPS IN THE PAST TWELVE MONTHS BY PRESENTER OR SPOUSE/PARTNER. GRANT/RESEARCH SUPPORT: DYNAVAX TECHNOLOGIES CORPORATION, LOXO ONCOLOGY, BRISTOL-MYERS SQUIBB COMPANY, PFIZER, CORVUS PHARMACEUTICALS, BAYER HEALTHCARE PHARMACEUTICALS, JOUNCE THERAPEUTICS, MACROGENICS INC, PLEXXIKON, INC, ADC THERAPEUTICS,ADVENCHEN LABORATORIES, MUNDIPHARMA EDO GMBH BIOMEDICAL, EPICENTRX CONSULTANT: CORVUS PHARMACEUTICALS, NODUS THERPAEUTICS, SHANG PHARMA, MEDTREE STOCK SHAREHOLDER: DRISHTI INC. THE SPEAKER WILL DIRECTLY DISCLOSURE THE USE OF PRODUCTS FOR WHICH ARE NOT LABELED (E.G., OFF LABEL USE) OR IF THE PRODUCT IS STILL INVESTIGATIONAL. 14 th Annual California Cancer Conference Consortium August 10-12, 2018

Yarchoan M, et al. Nature Reviews Cancer 17, 209 222 (2017) Mellman et al.

activation pathways (CD137, OX40, CD40, CD40L), the upregulation of immunosuppressive pathways (PDL1, PDL2, LAG3, TIM3, IDO1, CTLA4),

2 Yarchoan M, et al. Nature Reviews Cancer 17, (2017) Mellman et al., Nature 480, (2011) Cancers acquire immune tolerance: immunogenic neoantigens are edited out; downregulation of immune activation pathways (CD137, OX40, CD40, CD40L), the upregulation of immunosuppressive pathways (PDL1, PDL2, LAG3, TIM3, IDO1, CTLA4), and changes in expression of cytokines and chemokines or their receptors (TGFβ, IL-10, VEGF), recruit immune cells that actively mediate tolerance (e.g. myeloid-derived suppressor cells (MDSCs), T reg cells).

3 Adverse reactions PEMBROLIZUMAB 2 mg/kg Q3W, 10 mg/kg Q2W or Q3W (N=2,799) All grades % (n) Grade 3 % Grade 4 % Grade 5 % Pneumonitis 3.4 (94) Colitis 1.7 (48) 1.1 <0.1 _ Hepatitis 0.7 (19) 0.4 <0.1 _ Hypophysitis 0.6 (17) 0.3 <0.1 _ Hyperthyroidism 3.4 (96) 0.1 Hypothyroidism 8.5 (237) 0.1 Nephritis 0.3 (9) 0.1 <0.1 _

4 IO related Adverse Events Adverse events associated with IO agents Mechanisms underlying Immune-related AEs N Engl J Med 378;2 (2018)

5 Nivolumab 3 mg/kg once every 2 weeks; melanoma; pooled analysis of 4 trials 576 patients; 71% had any-grade treatment related AE Administering immune modulating agents (steroids) to manage toxicities did not compromise efficacy (~30%) ORR was higher in patients who experienced any grade treatment related AE (48.6% vs 17.8%, p<0.001); Should we be excluding patients with prior immune related AEs or underlying autoimmune diseases? Weber JS, et al. J Clin Oncol 2017; 35(7):785

6 Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders Retrospecti ve review; 9 centers; 30 patients; Johnson et al., JAMA Oncol. 2016;2(2):

7 Autoimmune Exacerbations: Grade 3 to 5 Immune-Related Adverse Events Immune-related adverse events (iraes) (grade 3-5) occurred in 10 (33%) of the patients Johnson et al., JAMA Oncol. 2016;2(2):

8 Response, Duration of Ipilimumab Therapy, and Survival Johnson et al., JAMA Oncol. 2016;2(2):

9 Patients with Autoimmune Disorders Limitations of current reports: Retrospective; Recall bias Different disease severities at the time of initiating therapy Toxicity graded by CTCAE criteria with significant limitations Flare poorly defined No management guidelines of toxicity and cancer therapy

10 Nivolumab in AutoImmune Disorders (AIM-NIVO)NCI PI: Hussein Tawbi (MDACC), Co-Chairs: Elad Sharon (NCI-CTEP) and Mario Sznol (Yale) Dermatomyositis/Systemic Sclerosis- Stanford University Shivaani Kummar (Onc) David Fiorentino (Derm) Lorinda Chung (Rheum) Rheumatoid Arthritis (RA)- Hopkins Laura Cappelli/Bing Bingham (Rheum) Jarushka Naidoo (Onc) Systemic Lupus Erythematosis (SLE)- MDACC and Emory Maria Suarez-Almazor / Noha Abdelwahab / Ignacio Sanz (Rheum) Melinda Yushak/Hussein Tawbi (Onc) Inflammatory Bowel Disease (IBD)- MGH/DFCI Michael Dougan (GI) Osama Rahma (Onc) Basket Cohort [including Polymyalgia Rheumatica/Giant Cell Arteritis (PMR/GCA)]- DFCI Deepak Rao/Lydia Gedmintas(Rheum) Patrick Ott (Onc) Multiple Sclerosis (MS)-Yale and NINDS David Hafler/Matthew Schindler/Dan Reich (Neurology) Harriet Kluger/Mario Sznol (Onc)

11 Objectives Primary Objectives: To establish the safety, dose-limiting toxicity, and other toxicities associated with nivolumab in patients with varying severity of DM/SSc, RA, SLE, MS, IBD, and other autoimmune disorders (basket cohort). Secondary Objectives: To provide dosing recommendations based on the severity of the autoimmune disorder. To determine the impact of nivolumab on the disease severity indices for DM/SSc, RA, SLE, IBD, and MS. To determine the efficacy of nivolumab on ORR in patients with cancer and DM/SSc, RA, SLE, IBD, and MS. To determine the pharmacodynamic impact of nivolumab on serum chemokines and circulating immune cell, to identify predictors of response and toxicity, and set the stage for future combinatorial therapy in this population.

12 Disease DM/SSc Consistent Criteria For Underlying Severity as well as Grading Toxicities Cohorts based on Severity of autoimmune dysfunction* SS1- mild SS2- moderate SS3- Severe Disease Severity Index Modified Rodnan Skin Score (MRSS) RA SLE Basket Cohort MS DM1- mild DM2- moderate DM3- severe RA1- low disease activity or remission (CDAI 10) RA2- moderate or severe disease activity by the CDAI >10. SLE1- Mild SLE2- Moderate SLE3- Severe Cohort 1A Cohort 1B Cohort 2: if cohorts 1A and 1B are found to be safe, can accrue to cohort 2 MS1A- Stable MS ( > 5 years) MS1B Stable MS (> 1 year) MS2- Active MS or on natalizumab, fingolimod, or orecelizumab Physician Global Assessment Likert score Clinical Disease Activity Index (CDAI) Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) 53 Cohort 1A: No active autoimmune disease and NOT on steroids; No history of vital organ involvement Cohort 1B: Patients without active autoimmune disease and require low dose steroid up to 10 mg of prednisone. No history of vital organ involvement or severe autoimmune diseases. Cohort 2: history of vital organ involvement or severe autoimmune diseases, although the condition should be under control for enrollment on this trial. Low dose steroid is allowed. Brain and Spine MRI

13 A Unique Opportunity for Collaboration and Translational Research Proposed biomarkers- emphasis on circulating markers Immune monitoring (CyTOF) Antibody repertoire, TCR repertoire and single cell transcriptomics Plasmablast repertoire sequencing Chemokines/cytokines- Inflammatory markers SNPs Tissue will be encouraged but not required Microbiome profiling Imaging (MS cohort)

Immune-Related Adverse Events (IRAEs) due to Cancer Immunotherapy

Immune-Related Adverse Events (IRAEs) due to Cancer Immunotherapy Philip Mease MD Director, Rheumatology Clinical Research, Swedish- Providence St. Joseph Health Clinical Professor, University of Washington