Complications of Immunotherapy

Transcription

1 Complications of Immunotherapy Sarah Norskog, PharmD, BCOP Oncology Pharmacy Specialist University of Colorado Hospital Disclosures I have no relevant financial relationships with commercial interests pertaining to the content of this presentation. Objectives Compare and contrast the side effects of immunotherapy and chemotherapy. Identify common signs and symptoms of immunotherapy toxicities. Develop care plans for the treatment of autoimmune induced complications including colitis, pneumonitis and endocrinopathies.

2 Checkpoint Inhibitors Ipilimumab Nivolumab Pembrolizumab Melanoma Melanoma NSCLC Renal Cell Carcinoa Hodgkin s Lymphoma Head and Neck Cancer Melanoma NSCLC Hodgkin s Lymphoma Metastatic Disease w/ MSI-H or MMR deficiency Atezolizumab Avelumab Darvalumab NSCLC Merkel Cell Carcinoma NSCLC Non-small Cell Lung Cancer, MSI-H Microsatellite Instability-High, MMR DNA Mismatch Repair Mechanisms of Action CTLA-4 Inhibitor - Ipilimumab PD-1 Inhibitors - Nivolumab - Pembrolizumab PD-L1 Inhibitors - Atezolizumab - Avelumab - Durvalumab Image: Rebas N Engl J Med. 2012;366(26):2517 Chemotherapy vs Immunotherapy Mechanism of Action Chemotherapy Kill or inhibit rapidly dividing cells Immunotherapy Activate the patient s own immune system to kill cancer cells Mechanism of Toxicity Direct damage to health dividing cells Autoimmune damage to healthy tissue Timing of Adverse Events Generally cycle dependent Delayed and variable Management of Adverse Events Supportive care Suppression of the immune system

3 Immune Related Adverse Events (iraes) Image: Kreamer. J Adv Pract Oncol (2014 Nov-Dec) Timing of iraes Onset of occurrence is delayed Not associated with drug half life Can occur after discontinuation of therapy Median time to onset varies by affected tissue Weber JS, et al. J Clin Oncol 2012; 30: Guidelines for the Management of iraes European Society for Medical Oncology Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. Published July 2017 American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) joint collaboration scheduled for release in late 2017 NCCN Melanoma Guidelines contain brief recommendations for the management of ipilimumab, nivolumab and pembrolizumab toxicities. J Natl Compr Canc Netw 2017;15:xxxvii-liii

4 Treatment of iraes Steroids, Steroids, Steroids High doses Prednisone 1-2 mg/kg daily Long tapers 4-8 weeks Alternative immunosuppressive agents for refractory cases Infliximab, mycophenolate mofetil, tacrolimus, etc Rash Most common adverse effect of checkpoint inhibitors Any grade 34-45% Severe or life threatening events are rare Presentation Maculopapular rash, erythema, pustulopapular rash, urticarial dermatitis Severe and fatal cases have been reported DRESS, Sweet syndrome, SJS, TEN Vitiligo Associated with improved efficacy in patients being treated for melanoma Image: Savoia. JAMA Dermatol 2016; 152: Lacouture ME, et al. J Am Acad Dermatol 2014; 71: Belum VR, et al. Eur J Cancer 2016; 60: Hua C, et al. JAMA Dermatol 2016; 152: Treatment of Rash Mild Topical steroids +/- topical antihistamines for itching Moderate Systemic steroids prednisone mg/kg daily Taper over 2-4 weeks Hold immunotherapy until resolves to mild Severe Systemic steroids IV methylprednisolone 1-2 mg/kg daily Dermatology consult Discontinue immunotherapy.

5 Colitis All grades 8-23% Severe or life threatening 1-7% CTLA-4/PD-1 > CTLA-4 > PD-1 or PD-L1 Presentation Rapid onset of symptoms Diarrhea Abdominal Pain Electrolyte abnormalities Hematochezia Bowel perforation Work Up Rule out infectious cause Consider imaging (CT or X-ray) Consider sigmoido/colonoscopy +/- biopsy Image: Rastogi S, et al World J Gastroenterol. Apr 14, 2015; 21(14): Treatment of Colitis Mild Supportive care oral fluids, loperamide Moderate Prednisone 1 mg/kg IV daily Taper over 3-4 weeks Severe Prednisone 1-2 mg/kg IV or PO equivalent daily Taper over 4-8 weeks Refractory No improvement or worsening in 72 hours Infliximab 5 mg/kg IV once Continue prednisone with slow taper Consider budesonide, mycophenolate mofetil or tacrolimus Pneumonitis All grades 2-10% Severe or life threatening 1-2% Combination CTLA-4 & PD-1 > PD-1 or PD-L1 > CTLA-4 Median time to onset is 2.8 months Range 9 days to 19.2 months Presentation Cough Dyspnea Work up Chest X-ray Infectious work up

6 Treatment of Pneumonitis Radiographic changes only Monitor for symptoms every 2-3 days Mild/moderate symptomatic Prednisone 1 mg/kg daily Taper over 6 weeks Severe Prednisone 2-4 mg/kg IV or PO equivalent daily Taper over 8 weeks Empiric antibiotic coverage Discontinue immunotherapy Refractory No improvement or worsening within 48 hours Infliximab 5 mg/k Iv once or mycophenolate mofetil Continue prednisone Endocrinopathies Any grade 4-21% Severe or life threatening 1-3% Common Conditions Hypothyrodism Primary or Secondary Hyperthyrodism Hypophysitis Type I Diabetes rate <1% Treatment Mild Hormone replacement therapy Moderate Consider holding checkpoint inhibitor Hormone replacement therapy Severe or Life Threatening Discontinue checkpoint inhibitor Hormone replacement therapy Consider Endocrine Consult Hepatitis Single agent CTLA-4, PD-1 or PD-L1 inhibitors Any grade 5-10% Severe or life threatening 1-2% Combination CTLA-4 and PD-1 inhibitors Any grade 25-30% Severe or life threatening 15% Presentation Asymptomatic Isolated transaminitis Work up LFTs, INR, albumin Liver screen: hepatitis panel, anti-ana/sma Review medication Consider imagine for metastasis or clot Robert C, et al. N Engl J Med 2015; 372:

7 Treatment of Hepatitis ALT or AST > ULN 3x ULN Monitor LFTs weekly ALT or AST 3-5x ULN Prednisolone 1mg/kg daily Taper over 2 weeks based on response ALT or AST 5-20x ULN Prednisolone 1-2 mg/kg equivalent IV or PO daily Taper over 4 weeks ALT or AST > 20x ULN Methylprednisolone 2 mg/kg IV daily Taper over 4 weeks Consider adding mycophenolate mofetil or tacrolimus if no improvement with steroids Case reports of anti-thymocyte globulin use Avoid infliximab due to risk of worsened hepatitis Additional Reported iraes Nephritis Neurologic Toxicity Polyneuropathy, myasthenia gravis, Guillain Barré syndrome, transverse myelitis, encephalitis, aseptic meningitis Cardiac Toxicity Myocarditis, pericarditis, arrhythmias, LV dysfunction Ocular Toxicity Uveitis, retinopathy Rheumatic Diseases ESMO Guidelines. Ann Oncol (2017) 28 (suppl 4): iv119 iv142 Clinical Pearls for Steroids High dose steroids Prednisone 1-2 mg/kg daily Prolonged taper based on severity of symptoms Prophylaxis Steroid induced gastritis Proton pump inhibitor or H2-antagonist PCP prevention Bactrim or dapsone Administration Take early in the day to avoid sleep disturbances May split into BID dosing Take with food

8 Do steroids reduce the efficacy of immunotherapy? No, the use of steroids for the treatment of iraes has not been shown to affect overall survival. Horvatz et al. J Clin Oncol 2015; 33: Pillars of Immunotherapy Toxicity Management Image: Champiat S, et al. Annals of Oncology 2016; 27: Take Home Points As opposed to chemotherapy, the adverse effects of immunotherapy are autoimmune in nature and generally have a delayed presentation The most common iraes are rash, colitis, pneumonitis, hepatitis and endocrinopathies Treatment for most iraes is high dose steroids with a prolonged taper The use of steroids for the treatment of irae has not been show to reduce immunotherapy efficacy

9 References Ribas A. Tumor Immunotherapy Directed at PD-1. N Engl J Med 2012; 366: Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: Lacouture ME, Wolchok JD, Yosipovitch G et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 2014; 71: Belum VR, Benhuri B, Postow MA et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: Hua C, Boussemart L, Mateus C et al. Association of vitiligo with tumorresponse in patients with metastatic melanoma treated with pembrolizumab.jama Dermatol 2016; 152: Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 28 (Supplement 4): iv119 iv142, 2017 NCCN News / Guidelines Planned on Management of Immunotherapy Side Effects: ASCO and NCCN to Collaborate on Development. J Natl Compr Canc Netw May 2017;15:xxxvii-liii; National Comprehensive Cancer Network. Melanoma (Version ). Accessed September 8 th, Savoia P, Fava P. Toxicities of New Drugs for Melanoma Treatment and their Management, Melanoma. Current Clinical Management and Future Therapeutics, May 2015, Prof. Mandi Murph (Ed.) Tirumani S et al. Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. Cancer Immunol Res 2015;3: Larkin J, Chiarion Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372: Horvat TZ, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015; 33: Champiat S, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Annals of Oncology 2016; 27: