Checkpoint inhibitors: Strategies to checkmate T-cell mediated toxicity Adam J. DiPippo, PharmD Clinical Pharmacy Specialist Leukemia Texas Society of Health-System Pharmacists 2017 Annual Seminar April 29, 2017 Disclosure Statement Adam DiPippo has no relevant financial relationships to disclose 1 Learning Objectives 1. Recognize signs and symptoms of immunerelated adverse reactions from checkpoint inhibitors 2. Contrast the immune-related adverse reactions associated with specific checkpoint inhibitors 3. Implement a supportive care plan for a patient presenting with an immune-related adverse event 2 1
Mechanism of Action T cell activation T cell response to inflammation Pardoll DM. Nat Rev Cancer. 2012; 12(4):252-264. Figure 3, Immune checkpoints regulate different components in the evolution of an immune response; p. 258. 3 Immune Therapy vs. Cytotoxic Therapy Mechanism of action Immune therapy Enhance anti tumor immunity Cytotoxic therapy Direct tumor cell kill Target Immune cells Rapidly dividing cancer cells Mechanism of toxicity Loss of immunologic tolerance to self antigens Onset of adverse events Unpredictable Predictable Off target cytotoxicity Drug specific toxicities from metabolism/metabolites Supportive care measures Targets immune system Targets adverse effect Gangadhar TC, et al. Nat Rev Clin Oncol [Internet]. 2014; 11(2):91-9. 4 Toxicity Incidence Summary Atezolizumab Pembrolizumab Ipilimumab Skin ++ ++ ++ +++ Gastrointestinal (GI) ++ ++ ++ +++ Pulmonary +++ +++ +++ + Liver ++ ++ ++ +++ Pituitary ++ ++ ++ ++ + = lowest relative likelihood of immune related adverse event of any grade +++ = highest relative likelihood of immune related adverse event of any grade Atezolizumab (Tecentriq ) prescribing information. Genentech, Inc; 2016. Ipilimumab (Yervoy ) prescribing information. Bristol-Myers Squibb; 2015. Pembrolizumab (Keytruda ) prescribing information. Merck Sharp & Dohme Corp; 2015. (Opdivo ) prescribing information. Bristol-Myers Squibb; 2016. 5 2
Toxicity Severity Summary Atezolizumab Pembrolizumab Ipilimumab Skin + + + +++ Gastrointestinal (GI) + + + +++ Pulmonary +++ +++ +++ + Liver + + + ++ Pituitary + + + ++ + = lowest relative likelihood of immune related adverse event of grade 3 or 4 +++ = highest relative likelihood of immune related adverse event of grade 3 or 4 Atezolizumab (Tecentriq ) prescribing information. Genentech, Inc; 2016. Ipilimumab (Yervoy ) prescribing information. Bristol-Myers Squibb; 2015. Pembrolizumab (Keytruda ) prescribing information. Merck Sharp & Dohme Corp; 2015. (Opdivo ) prescribing information. Bristol-Myers Squibb; 2016. 6 Toxicity Onset Summary PD 1/PDL 1 Inhibitors Toxicity Rash, pruritis Liver toxicity Diarrhea, colitis Hypophysitis Pneumonitis 0 10 20 30 40 50 Time (Weeks) Borghaei H, et al. N Engl J Med [Internet]. 2015; 373(17):1267-39. Brahmer J, et al. N Engl J Med [Internet]. 2015; 373(2):123-35. 7 Toxicity Onset Summary Ipilimumab Weber JS, et al. J Clin Oncol. 2012; 30(21):2691 2697. Figure 2, Kinetics of appearance of immune-related adverse event; p. 2693. 8 3
Approach to Management Patient education on early reporting of symptoms Know toxicity spectrum Prevent Anticipate Assess signs and symptoms prior to each cycle Improvement of symptoms Need to escalate supportive care Monitor Detect and treat Early identification Symptom management Adapted from Champiat S, et al. Ann Oncol. 2016; 27(4): 559-574. 9 Skin Toxicity Signs and symptoms Rash Pruritus Vitiligo Oral mucositis Gingivitis Stevens-Johnson Syndrome (SJS) Toxic Epidermal Necrolysis (TEN) Rash most often maculopapular and erythematous Rash can also be lichenoid or bullous Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Fecher LA, et al. Oncologist [Internet]. 2013; 18(6):733-43. 10 Skin Toxicity University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology. Skin toxicity from checkpoint inhibitors. [Photograph]. 2016. 11 4
Skin Toxicity Skin Toxicity 1 Macules/papules covering < 10% body surface area (BSA) With or without symptoms (pruritus, burning, tightness) 2 Macules/papules covering 10 30% BSA With or without symptoms (pruritus, burning, tightness) Limiting instrumental activities of daily living (ADL) 3 Macules/papules covering > 30% BSA With or without associated symptoms Limiting self care ADL 4 Signs of SJS or TEN Skin sloughing covering > 10% BSA with associated signs (erythema, purpura, epidermal detachment and mucous membrane detachment) 5 Death Common Terminology Criteria for Adverse Events (CTCAE) [Internet]. Version 4.03. Washington, DC. U.S. Department of Health and Human Services. June 2010. 12 Approximating BSA Lund Browder Chart Fecher LA, et al. Oncologist [Internet]. 2013; 18(6):733-743. Figure 3, Lund Browder chart for estimating body surface area involved by rash; p.736. 13 Skin Toxicity Incidence Atezolizumab (23)* Pembrolizumab (15, 20, 22)* (9, 10, 11, 12, 13, 14, 17, 18, 19)* Ipilimumab (8, 14, 16)* Ipilimumab + (14)* Toxicity (%) Rash 15 < 1 4 12 0 4 4 26 1 14 33 0.8 2 40 5 Pruritus 13 < 1 8 21 0 2 19 < 1 24 35 < 1 33 2 *Full citation in Reference List 14 5
Skin Toxicity Management Specific Immunotherapy Management Supportive Care 1 Continue Topical moisturizers Oral antihistamines if pruritus Topical corticosteroids Low potency If no improvement in 72 hours 2 Hold Resume only if improves to grade <1 and patient taking <7.5 mg/day prednisone equivalents Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Gangadhar TC, et al. Nat Rev Clin Oncol [Internet]. 2014; 11(2):91-99. Topical corticosteroids Moderate to high potency If no improvement in 72 hours Oral: 0.5 1 mg/kg/day prednisone 1 2 week taper after symptoms improve Oral antihistamines if pruritus 15 Skin Toxicity Management Specific Immunotherapy Management 3 Permanently discontinue May consider rechallenging if reaction not SJS or TEN Risk versus benefit evaluation Supportive Care Oral: 2 mg/kg/day prednisone Consider additional immunosuppression for persistent symptoms After symptoms improve, taper over >4 weeks Consider dermatology consult 4 Hospitalization indicated Dermatology consult recommended IV: 2 mg/kg/day methylprednisolone Consider additional immunosuppression for persistent symptoms After symptoms improve, taper over >4 weeks Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Gangadhar TC, et al. Nat Rev Clin Oncol [Internet]. 2014; 11(2):91-99. 16 Gastrointestinal Toxicity Signs and symptoms Diarrhea or increased bowel movements Increased ostomy output Bloody stool Mucous in stool Abdominal pain Possible Complications Colitis Small bowel obstruction Gastrointestinal perforation Ipilimumab (Yervoy ) prescribing information. Bristol-Myers Squibb; 2015. Pembrolizumab (Keytruda ) prescribing information. Merck Sharp & Dohme Corp; 2015. (Opdivo ) prescribing information. Bristol-Myers Squibb; 2016. 17 6
Gastrointestinal Toxicity Chen JD. [Internet]. European Congress of Radiology. 2013 Mar 7-11; Figure 2, A 75-year-old male with pseudomembranous colitis; [about p. 7]. 18 Gastrointestinal Toxicity Diarrhea and Colitis 1 Increase of < 4 stools per day over baseline No abdominal pain or bloody stool 2 Increase of 4 6 stools per day over baseline Abdominal pain Mucus or blood in stool 3 Increase of >7 stools per day over baseline Incontinence Hospitalization required Limiting self care ADL Severe abdominal pain Fever, ileus, or peritoneal signs 4 Life threatening consequences (e.g. impending bowel perforation) 5 Death Common Terminology Criteria for Adverse Events (CTCAE) [Internet]. Version 4.03. Washington (DC). U.S. Department of Health and Human Services. June 2010. 19 Gastrointestinal Toxicity Incidence Atezolizumab (23, 24, 25, 39)* Pembrolizumab (15, 22)* (9, 10, 11, 12, 13, 14, 17, 18, 19)* Ipilimumab (8, 14, 16)* Ipilimumab + (14)* Toxicity (%) Diarrhea 7 20 1 2 8 14 < 1 4 7 19 0 2 23 33 3 6 44 9 Colitis 1 1 1 2 <1 2 1 <1 8 12 5 9 12 8 *Full citation in Reference List 20 7
Gastrointestinal Toxicity Management Specific Immunotherapy Management Supportive Care 1 Continue Anti diarrheals as needed Fluid replacement If no improvement in 24 hours 2 Hold Resume only if improves to grade <1 and patient taking <7.5 mg/day prednisone equivalents Sznol M, et al. Commun Oncol [Internet]. 2013; 10:351-58. Weber J, et al. Clin Cancer Res [Internet]. 2009; 15(17):5591-8. Combination anti diarrheals Fluid replacement Consider budesonide If no improvement in 24 hours Oral : 2 mg/kg/day prednisone After symptoms improve, taper over >4 weeks 21 Gastrointestinal Toxicity Management Specific Immunotherapy Management 3 or 4 Permanently discontinue Supportive Care Hospitalization indicated Bowel rest IV fluid replacement Gastrointestinal and surgery consults Evaluate for bowel perforation IV: 2 mg/kg/day methylprednisolone Consider infliximab 5 mg/kg for persistent symptoms After symptoms improve, taper steroids over >4 weeks Sznol M, et al. Commun Oncol [Internet]. 2013; 10:351-58. Minor DR, et al. Cancer Biother Radiopharm [Internet]. 2009; 24(3):321-5. 22 Pulmonary Toxicity Pneumonitis Inflammation of lung parenchyma Signs and symptoms Shortness of breath New or worsening cough Chest pain Decreased oxygen saturation Radiographic changes Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. 23 8
Pulmonary Toxicity Teply BA, et al. Oncology [Internet]. 2014;28(11 Suppl 3): Figure 3, Different radiographic patterns of checkpoint blockade-associated pneumonitis seen on CT scanning in a single patient treated with ipilimumab and nivolumab; [about p. 8]. 24 Pulmonary Toxicity Pneumonitis 1 Asymptomatic Radiographic changes only 2 Symptomatic Medical intervention indicated Limiting instrumental ADL 3 Severe symptoms Limiting self care ADL Oxygen indicated 4 Life threatening respiratory compromise Impending tracheotomy or intubation 5 Death Common Terminology Criteria for Adverse Events (CTCAE) [Internet]. Version 4.03. Washington (DC). U.S. Department of Health and Human Services. June 2010. 25 Pulmonary Toxicity Incidence Atezolizumab (23, 25, 39)* Pembrolizumab (15, 22)* (9, 10, 11, 12, 13, 14, 18)* Ipilimumab (8, 14, 16)* Ipilimumab + (14)* Toxicity (%) Pneumonitis 3 1 2 6 <1 3 1 5 < 1 # 0 1.5 < 1* 6 1 *Postmarketing case reports of single agent grade 3 immune pneumonitis # Five fatalities in dose finding study (1 mg/kg and 3 mg/kg [2 patients each]; 10 mg/kg [one patient]) *Full citation in Reference List 26 9
Pulmonary Toxicity Management Specific Immunotherapy Management Supportive Care 1 Continue Monitor for symptoms every 72 hours 2 Hold Resume only if improves to baseline and patient taking <7.5 mg/day prednisone equivalents Consult pulmonary and infectious diseases services Monitor for symptoms daily Oral: 1 mg/kg/day prednisone After symptoms improve, taper over >4 weeks Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Champiat S, et al. Ann Oncol [Internet]. 2016; 27(4):559-574. 27 Pulmonary Toxicity Management Specific Immunotherapy Management Supportive Care 3or 4 Permanently discontinue Hospitalization indicated Consult pulmonary and infectious diseases service IV: 2 mg/kg/day methylprednisolone Consider additional immunosuppression for persistent symptoms After symptoms improve, taper over >4 weeks Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Champiat S, et al. Ann Oncol [Internet]. 2016; 27(4):559-574. 28 Patient Case Immune-related pneumonitis 29 10
Patient Case NO is a 52 year old male with metastatic non-small cell lung cancer on treatment with nivolumab He presents to clinic on cycle 12 day 1 of therapy complaining of worsening dyspnea on exertion, cough and mild fever These symptoms are impacting some of his daily activities but he is still able to care for himself Chest x-ray shows consolidation in the left lower lobe of the lung 30 Patient Case Questions What are three things that should be in the differential diagnosis at this point? Infection Disease progression Immune-related pneumonitis 31 Patient Case It is decided that NO has 2 immunerelated pneumonitis from nivolumab How would you recommend managing NO s Cycle 12 of nivolumab? Continue Hold Resume only if improves to baseline and patient taking < 7.5 mg/day prednisone equivalents Permanently discontinue 32 11
Patient Case What supportive care measures should be considered? Oral corticosteroids What dose? 1 mg/kg/day prednisone What duration? After symptoms improve, taper over > 4 weeks What adjunctive medications can we recommend? Inhalers or nebulizer treatments as needed 33 Pituitary Toxicity Hypophysitis Inflammation of the pituitary gland Signs and symptoms Fatigue Headache Nausea/Vomiting Visual changes Myalgia Loss of appetite Chow LQ. Am Soc Clin Oncol Educ Book [Internet]. 2013. 34 Pituitary Toxicity Workup Adrenocorticotropin hormone (ACTH) and cortisol Thyroid stimulating hormone (TSH) and Free T4 Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) Testosterone (if male) Prolactin MRI to look for pituitary inflammation Chow LQ. Am Soc Clin Oncol Educ Book [Internet]. 2013. Kähler KC, et al. J Dtsch Dermatol Ges. 2011; 9(4):277-86. Figure 5, Hypophysitis with thickened pituitary gland and stalk; p.283. 35 12
Pituitary Toxicity Incidence Atezolizumab (23, 24, 25, 39)* Pembrolizumab (15, 22)* (9, 10, 11, 12, 13, 14)* Ipilimumab (8, 14, 16)* Ipilimumab + (14)* Toxicity (%) Hypophysitis < 1 <1 < 1 <1 < 1 < 1 1.5 4 1.5 2 8 1.5 *Full citation in Reference List 36 Pituitary Toxicity Management Specific Immunotherapy Supportive Care Management Normal Results Continue None Abnormal Results Moderate Symptoms Abnormal Results Severe Symptoms Hold Resume only if symptoms improve and patient taking <7.5 mg/day prednisone equivalents Permanently discontinue Endocrine consult Replace appropriate hormones as indicated Oral: 1 mg/kg/day prednisone After symptoms improve, taper over >4 weeks Hospitalization indicated Endocrine consult Replace appropriate hormones as indicated IV: 2 mg/kg/day methylprednisolone After symptoms improve, taper over >4 weeks Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. Fecher LA, et al. Oncologist [Internet]. 2013; 18(6):733-43. 37 Summary Immune-related adverse events from checkpoint inhibitors can affect any organ system Organ systems particularly susceptible to toxicity include: Skin Gastrointestinal tract Lungs Toxicity can occur at any time during or after treatment Naidoo J, et al. Ann Oncol [Internet]. 2015; 26(12):2375-91. 38 13
Conclusions Use of checkpoint inhibitors will continue to expand More indications More patients Pharmacists have a key role in the care of patients on checkpoint inhibitors Patient education on early reporting Early identification of adverse effects Frequent follow-up Treatment modifications 39 Checkpoint inhibitors: Strategies to checkmate T-cell mediated toxicity Adam J. DiPippo, PharmD Clinical Pharmacy Specialist Leukemia Texas Society of Health-System Pharmacists 2017 Annual Seminar April 29, 2017 Post-Assessment Question 1 1. Which immune-related adverse event is correctly matched with an associated sign or symptom from checkpoint inhibitors? A. Hypotension due to cytokine release syndrome B. Irregular heart rate due to QTc prolongation C. Visual changes due to hypophysitis D. Hand foot syndrome due to dermatitis 14
Post-Assessment Question 2 2. Which immune-related adverse event is more frequently associated with nivolumab compared to ipilimumab? A. Rash B. Pneumonitis C. Diarrhea D. Colitis Post-Assessment Question 4 3. CT is a 64 year old male receiving ipilimumab for metastatic melanoma. He presents to clinic for Cycle 3 clearance and is experiencing 3 gastrointestinal toxicity Which of the following is the most appropriate supportive care measure for CT s symptoms? A. Fluid replacement orally B. Methylprednisolone 2 mg/kg/day IV C. Budesonide 3 mg PO TID D. Prednisone 1 mg/kg/day PO Questions 15