Cancer Immunotherapy

Transcription

1 Cancer Immunotherapy Early Recognition and Effective Management of Immune Related Adverse Events This slide deck in its original and unaltered format is for educational purposes and is current for the dates of this series. All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s). Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Disclaimer Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. 1

2 Learning Objectives 1) Outline the dynamic interaction between cancer and the immune system and rationale for use of cancer immunotherapy. 2) Compare and contrast mechanism of action, efficacy, and safety of current and emerging immune checkpoint inhibitors. 3) Anticipate common warning signs and symptoms of immune related adverse events (iraes) associated with CTLA 4 andpd 1/PD L1 immune checkpoint blockade. 4) Evaluate strategies members of the healthcare team can employ to monitor and effectively manage iraes associated with CTLA 4 and PD 1/PD L1 immune checkpoint blockade to improve patient safety and outcomes. Immune System and Cancer Dynamic Interaction Reproduced from Immunity, Vol. 39, Daniel S. Chen and Ira Mellman, Oncology Meets Immunology: The Cancer Immunity Cycle, Page 2, Copyright 2013, with permission from Elsevier via Copyright Clearance Center. 2

3 Cancer Immunoediting Immunosurveillance Immunosubversion Pre malignant lesion Elimination Immunosurveillance Advanced oncogenesis Equilibrium Immunoselection Tumor growth Escape Immunosubversion Adapted from Zitvogel L, et al. Nat Rev Immunol Cancer Immunotherapy Rationale for Use To overcome the mechanisms by which tumors suppress and evade the immune response Restore efficient immunosurveillance and tumor elimination, and shift the balance from immune evasion to immune protection Disis ML. Semin Oncol

4 Immune Checkpoint Blockade CTLA 4 and PD 1/PD L1 Inhibitors Reproduced from N Engl J Med, Antoni Ribas, MD, PhD, Tumor Immunotherapy Directed at PD 1, Vol. 366, Page Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society via Copyright Clearance Center. CTLA 4 and PD 1/PD L1 Inhibitors Current FDA Status and Indications 4

5 CTLA 4 Inhibitors Ipilimumab (Human IgG1 mab) Approved Treatment of unresectable or metastatic melanoma Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy CTLA 4 Inhibitors (cont.) Tremelimumab (Human IgG2 mab) Orphan drug designation Malignant mesothelioma 5

6 PD 1 Inhibitors Nivolumab (Human IgG4 mab) Approved BRAF V600 wt unresectable or metastatic melanoma, as a single agent Metastatic NSCLC and progression on or after platinum based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving nivolumab Advanced RCC in patients who have received prior antiangiogenic therapy PD 1 Inhibitors Nivolumab (cont.) Accelerated approval BRAF V600 mutation positive unresectable or metastatic melanoma, as a single agent Unresectable or metastatic melanoma, in combination with ipilimumab Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post HSCT brentuximab vedotin 6

7 PD 1 Inhibitors Pembrolizumab (Humanized IgG4 mab) Approved Unresectable or metastatic melanoma PD 1 Inhibitors Pembrolizumab (cont.) Accelerated approval In patients with metastatic NSCLC whose tumors express PD L1 as determined by an FDA approved test and who have disease progression on or after platinum containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving pembrolizumab 7

8 PD L1 Inhibitors Atezolizumab (Humanized IgG1 mab) Accelerated approval In patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinumcontaining chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum containing chemotherapy PD 1/PD L1 Blockade Selected Emerging Agents Agent Class On going Phase III Studies Atezolizumab (MPDL3280A) Durvalumab (MEDI4736) Avelumab (MSB C) Anti PD L1 Anti PD L1 Anti PD L1 NSCLC HNSCC RCC Triple negative breast cancer NSCLC Bladder cancer HNSCC Pancreatic cancer Merkel cellcarcinoma Gastric cancer NSCLC Bladder cancer Ovarian cancer 8

9 Immune Checkpoint Blockade Unique Clinical Features Tumor Response Kinetics Immune mediated response patterns may differ from those associated with conventional therapies, which has prompted the development of immune related response criteria (irrc) a Immune Related Adverse Events (iraes) By enhancing immune system function, immune checkpoint blockade can lead to autoinflammatory side effects called iraes b a Wolchok JD, et al. Clin Cancer Res. 2009; b Weber JS, et al. J Clin Oncol PD 1 Blockade Kinetics of Response to Pembrolizumab Metastatic Melanoma NSCLC Wolchok J, et al. ASCO

10 Immune Checkpoint Blockade RECIST vs irrc Factor RECIST irrc Measurement of Unidimensional Bidimensional tumor burden Complete Response (CR) Partial Response (PR) Progressive Disease (PD) Stable Disease (SD) Agarwala SS. Semin Oncol Disappearance of all target and nontarget lesions Lymph nodes must regress to <10mm short axis No new lesions Requires confirmation 30% decrease in tumor burden compared to baseline Requires confirmation 20% plus 5mm absolute increase in tumor burden compared with nadir Progression of non target lesions and/or appearance of new lesions (at any single time point) Any response pattern that does not meet criteria for CR, PR, or PD Same as RECIST 50% decrease in tumor burden compared to baseline Requires confirmation 25% increase in tumor burden compared to most recent prior evaluation New lesions added to tumor burden Requires confirmation Same as RECIST Immune Checkpoint Blockade Key Points About Evaluating Activity Antitumor activity may appear to be delayed compared to response times associated with cytotoxic therapies Patients may experience response after the appearance of progressive disease Development of progressive disease should be confirmed prior to discontinuation of therapy Development of small lesions in the presence of other responsive lesions may be clinically insignificant Durable stable disease may be indicative of response Agarwala SS. Semin Oncol

11 iraes Clinical Spectrum Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune related adverse events with immune checkpoint blockade: a comprehensive review, Page 144, Copyright 2015, with permission from Elsevier via Copyright Clearance Center. Immune Checkpoint Blockade iraes and Outcomes Preclinical melanoma tumor models using CTLA 4 knock outs have demonstrated enhanced immunemediated tumor rejection AND immune related depigmentation, but not iraes as seen in patients a Although still somewhat controversial, iraes do not seem to correlate with response b,c There does, however, appear to be a weak association with CTLA 4 blockade and stronger one with PD 1 blockade d,e a Weber JS, et al. J Clin Oncol. 2012; b Spain L, et al. Cancer Treat Rev. 2016; c Horvat TZ, et al. J Clin Oncol. 2015; d Downey SG, et. Clin Cancer Res. 2007; e Freeman Keller M, et al. Clin Cancer Res

12 iraes General Issues Infections and other etiologies should be ruled out or deemed unlikely as contributing to the iraes Most iraes occur during the first 3 4 months Late iraes, however, also can occur (eg, one episode has been seen at month 47 during maintenance phase of therapy) Each irae has different kinetics of onset and some can wax and wane, particularly colitis Corticosteroids can be used to manage almost all iraes Prolonged steroid tapers are required Weber JS, et al. J Clin Oncol. 2012; Weber JS, et al. ASCO. 2015; Weber JS, et al. J Clin Oncol CTLA 4 Blockade With Ipilimumab Kinetics of iraes in Melanoma Diarrhea, colitis Toxicity Grade Rash, pruritis Hypophysitis Liver toxicity Time (weeks) Weber JS, et al. J Clin Oncol

13 PD 1 Blockade With Nivolumab Kinetics of iraes in Melanoma Approximate proportion of patients (%) Gastrointestinal Skin Hepatic Pulmonary Renal Time (weeks) Endocrine Weber JS, et al. ASCO CTCAE Severity Grade Definitions An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. An AE is a term that is a unique representation of a specific event used for medical documentation and scientific analyses Severity General Description CTCAE Grade Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 1 intervention not indicated. 2 3 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living (shopping, using telephone, managing money, etc). Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living (bathing, toileting, dressing, ambulating, etc). 4 Life threatening consequences; urgent intervention indicated. CTCAE= Common Terminology Criteria for Adverse Events (v 4.0) _QuickReference_5x7.pdf. 13

14 CTLA 4 and PD 1/PD L1 Blockade Distribution of Grade 1 2 iraes CTLA 4 PD 1 PD L1 % patients Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune related adverse events with immune checkpoint blockade: a comprehensive review, Page 142, Copyright 2016, with permission from Elsevier via Copyright Clearance Center. CTLA 4 and PD 1/PD L1 Blockade Distribution of Grade 3 5 iraes CTLA 4 PD 1 PD L1 % patients Reproduced from the European Journal of Cancer, Vol. 54, JM Michot, et. al., Immune related adverse events with immune checkpoint blockade: a comprehensive review, Page 142, Copyright 2016, with permission from Elsevier via Copyright Clearance Center. 14

15 Ipilimumab vs Nivolumab vs Combo iraes Reported in 10% of Patients Patients Reporting Event, % Wolchok J, et al. ASCO LBA1. 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 Skin Pruritus Rash Rash maculopapular Gastrointestinal Diarrhea Colitis Hepatic alanine aminotransferase aspartate aminotransferase Endocrine Hypothyroidism Management of iraes General Principles Responsibility of all health care providers Early reporting by patients with close monitoring, and early intervention by health care providers Provide thorough and continuous patient education about the signs and symptoms of iraes Assess for signs and symptoms of iraes before each cycle of immunotherapy Know management algorithm specific to each irae Safety profiles of immunosuppressants Monitor and manage toxicities of immunosuppressants Hyperglycemia and diabetes Opportunistic infection 15

16 Management of iraes Based on CTCAE Severity Grade Severity CTCAE Grade Type of Patient Care Steroids Other Immunosuppressive Drugs Immunotherapy and Subsequent Approach 1 Ambulatory Not recommended Not recommended Continue 2 Ambulatory 3 Hospitalization 4 Hospitalization consider the intensive care unit Topical steroids or systemic steroids oral mg/kg/day Systemic steroids oral or IV 1 2 mg/kg/d for 3 d then reduce to 1 mg/kg/day Systemic steroids IV methylprednisolone 1 2 mg/kg/d for 3 d and then reduce to 1 mg/kg/day Not recommended To be considered for patients with unresolved symptoms after 3 5 days of steroid course Organ specialist advised To be considered for patients with unresolved symptoms after 3 5 days of steroid course Organ specialist advised *Outside skin or endocrine disorders, where immunotherapy can be maintained. Michot JM, et al. Eur J Cancer Suspend* temporarily Suspend and discuss resumption based on risk/benefit ratio with patient Discontinue permanently iraes Dermatitis Low grade rashes common Reticular erythema Papules to plaques Other dermatologic symptoms Pruritus Vitiligo Rare toxic epidermal necrosis Recent retrospective analysis suggests that skin side effects with PD 1 blockade may be associated with response and survival Postow MA. Am Soc Clin Oncol Educ Book. 2015; Freeman Keller M, et al. Clin Cancer Res

17 Dermatitis Management Encourage the preventative use of moisturizers Photograph, document, and follow Dermatology biopsy Mild (grade 1) Topical therapies including emollient skin creams, topical antihistamines, topical steroid creams Moderate (grade 2) Hold immunotherapy, consider more potent topical steroid, systemic anti histamines, systemic corticosteroids Severe (grade 3+) Hold/discontinue immunotherapy, aggressive topical therapies, high dose systemic corticosteroids Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist iraes Colitis and Enteritis Diarrhea is a common irae (37% all grade and 12% grades 3/4) with ipilimumab; less common with PD 1 blockade Colonoscopy or sigmoidoscopy shows diffusely erythematous, friable, and occasionally ulcerated mucosa Colon biopsy usually demonstrates inflammatory colitis with CD4>CD8 infiltrate in interstitium Most cases respond to symptomatic treatment or highdose steroids with a long taper (over a month) Infliximab is used in steroid refractory cases Can rarely lead to gastrointestinal perforation (1%), profound ileus or megacolon requiring surgery Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol

18 Colitis and Enteritis Colonoscopy and Histopathology Findings Colonoscopy Multifocal circumscribed erythematous lesions Histopathology Predominantly chronic inflammation Eosinophils and focal active cryptitis iraes Colitis vs Diarrhea Differentiate diarrhea from colitis Typical presentation is quick escalation of uncontrollable diarrhea that is not responsive to typical anti diarrheal therapies Quick intervention with corticosteroids is essential to prevent escalation and bowel perforation Endoscopic evaluation Supportive care Dietary modifications, fluid repletion, electrolyte repletion, anti motility agents Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol

19 Colitis and Enteritis Management Grade 1,2 Rule out other causes Treat symptomatically No corticosteroids Follow closely for resolution Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol Colitis and Enteritis Management Grade 3,4 Assess duration and magnitude to determine need for hospitalization Endoscopy is often useful, even for prolonged grade 2 diarrhea High dose corticosteroids 120 mg methylprednisolone IV daily Slow taper, over 1 month If persists (eg, 72 hours), consider infliximab 5mg/kg (TNF blocking antibody) Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol

20 iraes Hepatitis Liver function test (LFT) elevations in patients may be associated with symptoms of hepatotoxicity (jaundice, right upper quadrant pain, vomiting) or may be completely asymptomatic; many patients have other non specific symptoms (fever, malaise) LFT must be assessed prior to administration of each dose of ipilimumab or PD 1/PD L1 inhibitors All subjects must meet LFT criteria before each dose of ipilimumab With no liver metastases < 2.5X ULN for AST, ALT With liver metastases; < 5X ULN for AST, ALT, < 2.5X ULN for total bilirubin Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist Hepatitis Management Elevation LFTs > 3 fold baseline (>2.5 X ULN; grade 2) requires close attention Intensified monitoring; labs every 3 days Consider disease burden, medications, infections, particularly viral; other metabolic disorders; imaging; consider biopsy if LFTs persist and the etiology is unclear Consider corticosteroid therapy Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist

21 Hepatitis (cont.) Management LFTs >8x or total bilirubin >5x Intensified monitoring; labs every 1 3 days until begin to resolve High dose steroids, eg, methylprednisolone 1 2 mg/kg/day; if LFTs decrease convert to oral steroids If after 3 days, no improvement or rebound, add mycophenolate 1 g BID PO If no improvement in 5 7 days, add tacrolimus 0.1 to 0.15 mg/kg/day IV (trough level 5 20 ng/ml) Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist iraes Endocrinopathies Include panhypopituitarism, hypothyroidism, hyperthyroidism, pancreatitis, and adrenal insufficiency Up to 10% (all grades) with ipilimumab or anti PD 1/PD L1 Management of primary hypo or hyperthyroidism Hyperthyroidism: most cases resolve spontaneously, with subsequent development of hypothyroidism; if symptomatic, use beta blocker as initial management Hypothyroidism thyroid hormone replacement Typically, do not require corticosteroid therapy or suspension of checkpoint inhibitors Symptoms resolve with treatment Weber JS, et al. J Clin Oncol. 2012; Postow, Am Soc Clin Oncol Educ Book. 2015; Villadolid J, et al. Transl Lung Cancer Res. 2015; Naidoo J, et al. Ann Oncol

22 Endocrinopathies Hypophysitis Can present with severe headache, fatigue, weakness, memory loss, impotence, personality changes, and visual impairment Pituitary dysfunction can cause downstream effects on all hormone levels Differential includes CNS metastases Monitor TSH before each dose Diagnostic MRI with pituitary cuts as well as laboratory evaluation of hormone levels Blansfield JA, et al. J Immunother. 2005; Attia P, et al. J Clin Oncol. 2005; Phan GQ, et al. Proc Natl Acad Sci USA Hypophysitis Management Discontinue checkpoint inhibitors High dose corticosteroid administration with a taper over 4 weeks Obtain endocrine consult Replace deficient hormones Symptoms will resolve with treatment Slow return of some endocrine function Most patients require life long hydrocortisone supplement Use stress dose hydrocortisone in perioperative period and critical illness Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist

23 iraes Neurological Toxicities Relatively infrequent (<1% all grades) with IPI or PD 1 Symptoms: Numbness, tingling, foot drop and localized muscle weakness, or generalized ascending motor and diaphragmatic weakness Observed so far: Myasthenia gravis (MG) like syndrome Peripheral neuropathy Management: get a neurologic consult! For grade 2 or more, discontinue antibodies, work up including labs and brain MRI, high dose corticosteroid administration with a prolonged taper, neurology consultation, EMG if appropriate Hospitalize if MG like syndrome Consider rapidly moving to IVIG and infliximab if grades 3 4 and without resolution of symptoms within hours Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist iraes Pneumonitis Relatively rare: 0.5 to 1.5% of patients at grades 2 3 Very uncommon with PD L1 antibodies Check pulse oximetry in all patients Get a chest X ray in anyone with SOB, chronic cough, increased sputum, and have a low threshold for obtaining a CT of the chest CT findings may lag behind the patient s symptoms High dose steroids with at least day tapers with starting doses of at least 1 2 mg/kg are required Steroids may need to be re escalated if symptoms return Use infliximab at 5 mg/kg if without relief in one week Postow MA. Am Soc Clin Oncol Educ Book. 2015; Fecher LA, et al. Oncologist

24 Immune Checkpoint Blockade Other iraes Pancreatitis Amylase/lipase elevation, abdominal pain low, and out of proportion to elevation of lab tests Uveitis Redness, change in vision; ophthalmology evaluation Topical corticosteroid eye drops Nephritis (rare) CT scans show stranding = inflammation Consider steroids if Cr > 2.0 Arthritis Late manifestation with chronic PD 1/PD L1 Often exacerbation of pre existing arthritis Postow MA. Am Soc Clin Oncol Educ Book. 2015; Weber JS, et al. J Clin Oncol Immune Checkpoint Blockade iraes in Elderly Patients No difference in incidence of toxicity or grade of toxicity for the use of IPI or PD 1 under or over 65 The overall survival for those treated with ipilimumab does not vary significantly by age It appears that ipilimumab and PD 1/PDL1 antibodies can be safely given to those at any age Caution should be used in using IPI or IPI/NIVO in those functionally over 80 with co morbidities, who will not tolerate the colitis or prolonged steroid taper very well 24

25 Management of iraes Patient and Caregiver Education Describe signs and symptoms, including complications if not treated promptly Emphasize early recognition and prompt reporting Discuss preventative measures, if applicable Instruct patient to present agent specific wallet card to all healthcare providers Stress adherence with corticosteroid therapy Provide supportive care instructions Enforce early reporting of worsening condition Fecher LA, et al. Oncologist Patient and Caregiver Evaluate Education Needs Assess both patient and caregiver Knowledge of therapy and the disease process Educational level and preferred learning methods Develop a plan Implement teaching, use a variety of materials and methods Evaluate patient and caregiver for continued educational needs related to the therapy and disease process Fecher LA, et al. Oncologist

26 Patient and Caregiver Education Provide Contact Information Whom to call Why to call When to call Where to call (MUST HAVE 24/7 clinician availability) Fecher LA, et al. Oncologist Patient and Caregiver Education Challenges General Effect of treatment is on the immune system, not directly targeting the tumor Extensive side effect profile, when to notify clinician Variability in when iraes may occur Variability in response to treatment Benefits of therapy outweigh potential risks, particularly when iraes are recognized early and treated quickly 26

27 Management of iraes FAQs by Oncologists & the Oncology Team How often severe or dose limiting iraes occur? What are the most common iraes? What are the resources available for dealing with the severe iraes? How best to monitor the patients for iraes, and how often to monitor after they occur? When to call the subspecialist? Key Take Home Points Cancer immunotherapy (eg, immune checkpoint blockade) associated with unique clinical features Immune mediated response patterns (irrc developed) iraes (autoinflammatory in nature) Early recognition and effective management of iraes crucial to optimal use of cancer immunotherapy Responsibility of all healthcare providers, and facilitated by well coordinated interprofessional team Thorough and continuous patient and caregiver education essential 27

28 Abbreviation Key ALK Anaplastic lymphoma kinase CTLs Cytotoxic T lymphocytes ALT Alanine aminotransferase EGFR Epidermal growth factor receptor APCs Antigen presenting cells Endoc Endocrine AST Aspartate aminotransferase FDA Food and Drug Administration BID Twice a day GI Gastro intestinal CNS Central nervous system IPI ipilimumab CR Complete response iraes Immune related adverse events Cr Creatinine irrc Immune related response criteria CT Computerized tomography IV Intravenous CTLA 4 Cytotoxic T lymphocyte associated antigen 4 LFT Liver function test Abbreviation Key (cont.) MG Myasthenia gravis Pulm Pulmonary MRI Neurol or ocul NIVO NSCLC PD Magnetic resonance imaging Neurological or ocular Nivolumab Non Small Cell Lung Cancer Progressive disease RCC RECIST SD SOB Renal cell carcinoma Response Evaluation Criteria In Solid Tumors Stable disease Shortness of breath PD 1 Programmed cell death protein 1 TNF Tumor necrosis factor PD L1 PO Programmed cell death protein 1 ligand By mouth TSH ULN Thyroid stimulating hormone Upper limit of normal PR Partial response wt Wild type 28