Immunotherapy: Current Uses, Toxicity and its Management. Dr Kortnye Smith July 2018

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1 Immunotherapy: Current Uses, Toxicity and its Management Dr Kortnye Smith July 2018

2 Overview Immunotherapy Cancer and the Immune System History of Immunotherapy Anti-CTLA4 Anti-PD1 Toxicity Immune Related Toxicity Common Toxicity Additional Psychosocial Stress Questions

3 T Cell Activation Individual human tumours harbour a multitude of somatic mutations and epigenetically dysregulated genes. The products of these gene changes are potentially recognizable as foreign antigens on the surface of the cancer cell. These foreign can be recognized by APC and presented to the T Cells for destruction of the cancer cell. Despite this, the overriding relationship between the immune system and growing cancers is one of tolerance, in which, paradoxically foreign molecules expressed by tumour cells are viewed as self.

4 Immune Response to Tumours 1. Elimination Immune cells able to destroy all cancer cells. 2. Equilibrium Immune cells become unable to eliminate all cancer cells, but may be able to prevent expansion and metastasis: this keeps the tumour at bay produces a static phase called equilibrium. Selection occurs for cancer cells with higher ability to metastasise Dunn (2004) Immunity 3. Escape Over time: dynamic interaction between tumour and immune system result in selection for tumour cells which can escape the immune system clinically detectable tumours

5 Tumour Evasion of the Immune System Beatty (2015) Clin Can Research Loss of antigenicity - Acquisition of defects in antigen processing and presentation - Loss of immunogenic tumour antigens loss of proteins of cell surface to create peptide-mhc complex Gain of immunosuppressive properties - Increased expression of PD-LA - Secretion of suppressive cytokines (ie. IL- 10, TGFB) Creating an immunosuppressive environment Recruiting immunosuppressive leukocytes

6 History of Cancer Immunotherapy WILLAM COLLEY Tumours can be eliminated in response to bacteria MACFARLANE BURNET Concept of Cancer Immunosurveillance: tumours can be attacked by immune system

7 Anti-CTLA4 Ipilimumab

8 Anti-CTLA4 T Cell Activation Tumour Cells have foreign antigen/peptide on their surface. They are surveyed by Antigen Presenting Cells (APC) APC present the antigen as a MHC/Antigen complex which bind with the T cell receptor (TCR) Signals from the TCR are then amplified by co-stimulatory molecules (CD28/B7) This results in T cell proliferations and differentiation allowing for destruction of the tumour cells via lysis Ribas et al, NEJM 2012 Buchbinder et al. JCI 2015

9 Anti-CTLA4 T Cell Inhibition Following activation of the T cell; Cytotoxic T- Lymphocyte-associated antigen 4 (CTLA-4) is up regulated in the T cell CTLA4 has a much higher affinity for B7 (cf CD28) Approximately 48 hours post T cell activation CTLA4 begins to bind with the B7 molecule on the APC surface in This provides inhibitory signals to the T cells to decrease activity

10 Anti-CTLA4 Mechanism of Action Anti-CTLA- 4 (Ipilimumab) is a monoclonal antibody (given IV x4 doses, 3 weeks apart, 3mg/kg) It binds to CTLA-4 when it is expressed on the surface of the T cell CTLA-4 bound to Ipilimumab is then not able to bind with B7, leaving B7 free to continue to bring to CD28 and provide ongoing co-stimulation of the T cell T cell continues to receive activation Signals with ongoing cell lysis and further immune activation

11 Anti-CTLA4 Summary Anti CTLA4 provides superior overall survival benefit compared to Chemotherapy in melanoma Lower rates of overall survival and response rate compared with Anti-PD1 agents and combination therapy Median Overall Survival Ipilimumab: (CHECKMATE 067): 19.9 months (95% CI ) Toxicity (Immune Related Adverse Events) Grade 3-4 Immune Related Adverse Events *(CHECKMATE 067): 19.6% (11% GI related)

12 Anti-PD1 and Anti-PDL1 Nivolumab Pembrolizumab Avelumab Atezolizumab Durvalumab Cemiplimab (and more in development)

13 Role of PD-1 in Cancer and Immune tolerance PD-1 is a surface co-inhibitory receptor expressed on T cells, B cells, and NK following activation It has two ligands: PD-L1 and PD-L2, binding to these ligands inhibits T cell receptor signaling and downregulates immune response Promotes tolerance and prevents tissue damage in the setting of chronic inflammation, promote peripheral tolerance and balance Many solid tumours express or over express PD ligand 1 (PD-L1) McDermott (2013) Cancer Med

14 Anti PD-1 Therapy Mechanism of Action Cancer cells can upregulate the amount of PD-L1 expressed on the surface of the cell downregulation of the T cell activity using the negative feedback of PD1-PDL1 binding Anti- PD1 Antibodies attach to PD-1 on the circulating T-cells This leaves the ligand unable to bind with PD-L1 and therefore stimulates ongoing immune response Given regularly on an ongoing basis ( different compounds given on different dosing schedules, either mg/kg or flat dosing) Length of treatment not established, possibly 2 years

15 Anti-PD1 Monotherapy and Efficacy Increasing number of cancers being treated with Anti-PD1 therapies Efficacy is dependent on immunogenicity of the tumour

16 Current Clinical Use of Anti-PD1 therapies Current PBS Indicated Current Access Schemes Current Clinical Trials Melanoma Lung Cancer, 2 nd line therapy Renal Cell Carcinoma, 2 nd line therapy Lung Cancer 1 st line thearpy (PDL1 >50%) Cutaneous Squamous Cell Carcinoma Merkel Cell Carcinoma Colorectal Cancer Triple Negative Breast Cancer Upper GI Hodgkin s Lymphoma, post transplant Rare Cancer Bladder Carcinoma, 2nd line Phase 1

17 Combination Therapy Ipilimumab + Nivolumab

18 Combination Therapy Dual blockade of Checkpoints Inhibitors CTLA4 and PD-1 inhibit antitumour immunity through complementary and non-redundant mechanisms to downregulate the immune response. The use of the two treatments together shows synergistic improvement in antitumor responses. Dual Blockade for 3 months, followed by up to 2 years of Anti-PD1 therapy Okazai (2013) Nature Immunology

19 Long Term Efficacy of Immunotherapy

20 Long Term Efficacy: 5 year data Phase I (CA ) Possibility of durable long term responses with Anti-PD1 (in melanoma, other cancers still pending) 34% of patients alive at 5 years Nivo (3mg/kg) All Nivo doses 12 months 64.7% ( ) 62.7% ( ) 24 months 47.1% ( ) 48.0% ( ) 48 months 35.3% ( ) 34.8% ( ) 60 months 35.3% ( ) 33.6%( ) mos 20.3% (7.2-NR) 17.3 ( ) Hodi (2016) AACR

21 Long Term Overall Response Rate Pooled Analysis of 1,861 patients from 12 studies AND expanded access portal 2,985 patients The most important finding regarding Ipilimumab from the initial clinical trials is that it has the potential for LONG TERM RESPONSE (?CURE) 10 year follow up data shows ongoing survivors from metastatic melanoma at 20% Median Overall Survival 3 year Overall Survival 9.5m ( ) 21% (20-22) Schadenorf (2015) JCO

22 Immunotoxicity

23 Immune Related Adverse Events Specific Immune Related Adverse Effects

24 Mechanism of Immunotoxicity Normal role of the the checkpoints PD-1 and CTLA-4 is to retain balance between activity and quiescence in the immune system. By blocking these checkpoints, Anti-PD1 and Anti-CTLA4 disrupt this balance. This can result in unopposed immune activation and T-cell dysregulation results in inflammation and tissue damage Can occur to ANY tissue in the body, indiscriminate in nature Yoest (2017) Immunotargets

25 Immune Related Adverse Events Subgroup of Adverse Events from Drugs Separate from standard side effects More common in some organ types than others - Skin - GI tract - Liver - Endocrine (Thyroid, Adrenal Pituitary) - Lung

26 Immunotoxicity Onset of Symptoms varies, peak time in first 3 months Symptoms can occur at any time including after months of therapy Variables include: - Which immunotherapy used - Underlying immune related disease - Underlying cancer diagnosis Champiat et al. Annals of Oncology 201 Tepley et al. Oncology 2014 Weber et al. JCO 2015

27 Rates of Toxicity Ipi/Nivo > Ipi > Nivo Ipilimumab 28% Grade toxicity Higher rates of: GI involvement Nivolumab 21% Grade Toxicity Higher rate of: endocrine Combination Therapy 59% Grade toxicity Higher rates of: hepatic ++, lung, multiple concurrent tox Wolchok (2017) NEJM

28 Immunotoxicity Unless there is a good alternative diagnosis for inflammation, symptoms should be considered autoimmune in nature and treated as such. Most irae are reversible provided vigilant monitoring and early treatment *excludes most endocrinopathies which are rarely reversible BMS + Trial Investigators developed protocol-specific treatment guidelines for management of irae

29 Management of Immunotoxicity Generalised Overview of Management + Increase monitoring + Rule out non-immune related causes + Look at individual management guidelines for specific toxicities + Involve specialist teams + often very slow wean of steroids over 2-3 months

30 Medication for Management of Immunotoxicity First line: Steroids: oral, IV Second and additional lines of treatment (with expert advice) Infliximab Mycophenolate Azathioprine Budesonide IVIG Plasmaphoresis Anti-Thymocyte Globulin

31 Cutaneous Most common toxicity from Immunotherapy Presentation Most common macular papular rash over the trunk and chest Less common Stephen Johnson Sweet Syndrome Bullous Pemphigoid Can worsen Psorasis Lupus Management Mild Symptomatic Localised steroid cream Moderate Systemic sral steroids Severe Supportive care, admission, IV immunosuppression

32 Rheumatology Also Flare of Previous Disease (can occur de novo also) Polymyalgia Rheumatica Myositis Rhematoid Arthritis Psoriatic Arthritis Sjorgens Syndrome Inflammatory Arthropathies Vasculitis/ Artiritis Dermatomyositis SLE Management Mild Symptomatic Simple Analgesia Moderate Low dose oral steroids +/- pulse Steroid sparing agents Try to continue on drugs Severe If multi-organ involvement may need high dose immunosuppression

33 Colitis And other additional GI toxicity Presentation Colitis Diarrhoea (>4 above baseline) PR blood loss/ mucus Cramping abominal pain Oesophagitis/ / Gastritis/ Enterocolitis Management Exclude infectious cause, C.diff Mild IV fluids, stool chart, hospital admission Moderate- Severe IV methylprednisolone 2mg/kg for 3/7 Infliximab Slow wean of steroids Stop drugs

34 Endocrinopathies Thyroiditis, Hypophysitis, Adrenalitis Presentation Thyroiditis Hypo or Hyperthyroidism Hypophysitis Acute, visual change, headache Lethargy, fluid/electrolyte imbalance Decrease Libido Adrenalitis Lethargy, weight loss, anorexia, nausea fatigue Hypotension Management during treatment Regular review of Sx Blood tests: thyroid levels, random cortisol Management Determine cause Replace hormone Will not recover function of endocrine glands with immunosuppression Continue immunotherapy

35 Pneumonitis Presentation Imaging Changes Dry cough Shortness of breath Tachypnoea Management Exclude radiation change, infection Mild Monitor, reimage and review frequently Moderate- Severe Admit Support O2 supplementation and ventilation Commence methylprednisilone

36 Hepatitis Presentation Management Increased liver function tests Lethargy Mild Observation Moderate Cease immunotherapy Steriod Mycophenolate

37 Rare Immunotoxicities High level of suspicion required Neurological - Gullian Barre, Myelopathy, Encephalitis, Myasthenia - Peripheral Sensory Motor Neuropathy - Myasthenia Gravis Blood Haemolotyic Anaemia Neutropenia Activation of CLL Renal Nephritis Cardiac - Myositis Endocrine Endocrine Failure of Pancreas: Brittle T1 DM Renal Nephritis Champiat et al. Annals of Oncology 201

38 Less reported but common side effects

39 Fatigue A distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. NCCN definition 2017 Fatigue affects caregiver and patients QoL Burden of care increases on care givers Minimal effective strategies for managing effects of fatigue

40 Fatigue Mechanism not well understood? Tumor related substances? Cytokine production? Muscular/Neuromuscular junction abnormalities Not well captured on trials, likely under-reported at 20-40%

41 Psychological Effects and Impact of Treatment New concept of long/longer term survival cf an inevitably fatal disease Challenging to council patients and to gain understanding Fear of Cancer Recurrence Scan related Anxiety Fear of Second Cancer Impact on Work Cost of treatment, accommodation and travel

42 Adjuvant Therapy

43 Adjuvant Therapy in Melanoma Is not currently standard of care in Australia, not PBS listed Previous evidence for Inteferon in Stage III disease Stage III disease High rates of recurrence of melanoma and subsequent metastatic disease in Stage III disease, Aims to decrease disease recurrence post surgical resection Disease specific survival (10 year) IIIA: 88% IIIB: 77% IIIC: 60% IIID: 24% Gershenwald (2017) CA

44 Adjuvant Immunotherapy Summary Very active space Inteferon is currently PBS approved in Australia for treatment of Stage III melanoma. Low uptake due to poor OS benefit High levels of toxicity Dabrafenib/Trametinib shows improved OS in BRAF +ve patients Ipiliumab has shown an overall survival benefit compared to placebo (not inteferon) Nivolumab has shown improvement in recurrence free survival compared Ipilimumab No overall survival benefit reported as yet Current trial investigating: Use of combination Ipilimumab/ Nivolumab vs. Nivolumab

45 Future Directions

46 Any questions