CHECKPOINT INHIBITOR-ASSOCIATED RENAL AND CARDIAC TOXICITIES. Ben SPRANGERS

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1 CHECKPOINT INHIBITOR-ASSOCIATED RENAL AND CARDIAC TOXICITIES Ben SPRANGERS

2 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

3 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

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8 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

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13 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

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23 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

24 64y, male Malignant melanoma -2003: lower back, surgery, pt2an1a stage IIIa -> lymph node resection -2013: relapse in axial lymph node right, BRAF mutation (p.gln61arg (p.q61r) NRAS mutation), pt2an3 stage IIIc -> total lymph node resection -Early 2015: diffuse abdominal/peritoneal metastasis with AKI due to postrenal obstruction -> stenting and start DTIC -3/2015: progressive disease -> switch DTIC to ipilimumab -6/2015: progressive disease -> pembrolizumab -7/2015: AKI Lab 4/2015 7/2015 scr mg/dl egfr ml/min/1,73 m² urbc 10 /µl uwbc 58 /µl upr 0.54 g/g creat (concommitant hepatitis started earlier than renal insufficiency) US kidney Stable findings, kidney size right 139 mm and left 126 mm

25 Treatment Replacementof the DJ stent on the right side (w/o effect on renal function) Renal biopsy - Glomeruli: normal - Vessels: normal - Interstitium: inflammatoryinfiltratepredominant mononuclearcellsbut alsopmn andeosinophils. Marked tubulitis and 1 granuloma Treatment - Stop pembrolizumab - Start methylprednisolone (in total 3 months) - Stop PPI

26 Outcome -Checkpoint inhibitors were not restarted -Kidney function remains stable (partial recovery) -MM remained stable until 9/2016 (metastasis left ear for which a resection was performed) Lab 4/2015 7/ /2016 scr mg/dl egfr ml/min/1,73 m² urbc 10 1 /µl uwbc /µl upr g/g creat

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34 The estimated incidence of any-grade acute kidney injury was 1 to 2 percent in patients treated with a single agent and approximately 5 percent in those treated with the combination of nivolumab plus ipilimumab. The incidence of grade 3 or 4 acute kidney injury was less than 1 percent with single agents and 1.7 percent with the combination of nivolumab plus ipilimumab. Renal toxicity was diagnosed a median of 91 days (range 21 to 245 days). The median peak serum creatinine was 4.5 mg/dl. Two patients required transient hemodialysis, and two patients remained on hemodialysis at the time of publication. Pathology from the renal biopsies revealed acute tubulointerstitial nephritis (n=12) and thrombotic microangiography (n=1). Checkpoint inhibitor immunotherapy was discontinued in all 13 patients. Eleven patients were treated with corticosteroids, and among these 11, nine patients improved. One patient with thrombotic microangiopathy did not improve, despite glucocorticoids, and another patient transiently improved but then worsened. Two additional patients did not receive immunosuppression and did not recover renal function. Cortazar FB et al. Kideny Int 2016;90(3):

35 Shirali A et al. Am J Kidney Dis 2016;68(2):

36 Renal toxicity was diagnosed between 3 and 18 months after initiation of checkpoint inhibitor. All patients took medications known to be associated with AIN (PPI, NSAIDS). One patient continued checkpoint inhibitor while stopping the PPI: kidney function remained stable over time. No dialysis required. Treatment: all received corticosteroids (recovery in 5/6). Rechallenge in 1 patients -> development of CS-responsive AIN. Shirali A et al. Am J Kidney Dis 2016;68(2):

37 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

38 Zimmer L et al. Eur J Cancer 2016;60:

39 8 cases of patients with malignant melanoma treated with ipilimumab and/or nivolumab/pembrolizumab Wide variety of cardiac events Heart failure Cardiomyopathy Rythm disorders: heart block Myocardial fibrosis Myocarditis Variable outcomes Resolution with steroids Fatal Only discovered on autopsy in 3 cases Heinzerling L et al J ImmunoTher Cancer 2016;4:50.

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42 Introduction Mechanisms of action of checkpoint inhibitors Immune-related adverse event Checkpoint inhibitor-associated renal toxicity Checkpoint inhibitor-associated cardiac toxicity Management of checkpoint inhibitor-associated toxicity Conclusion

43 Champiat S et al. Ann Oncol 2016;27:

44 Boutros C et al. Nat Rev Clin Oncol 2016;13:

45 The onset of checkpoint inhibitor-associated renal toxicity is variable so clinicians should be vigilant. Although severe AKI has been described the incidence is limited (5% with combination therapy) and AKI seems to be manageable with discontinuation of checkpoint inhibitors and administration of corticosteroids. Diagnosis: monitor kidney function and urinary parameters scr is a bad measure of kidney function (although still used in CTCAE) Urine is easy to obtain; check for proteinuria (g/g creatinine) and sediment abnormalities No recommendations regarding frequency of laboratory evaluation can be made Treatment: Early recognition and treatment are essential to allow for full recovery Steroids are effective: route of administration dose duration? Is discontinuation necessary? most likely yes and definitely so in grade 3 and 4 CTCAE Can checkpoint inhibitors be given again at a later time point Conflicting results regarding same checkpoint inhibitor other checkpoint inhibitor might be safe (nivo after ipi); although number of renal toxicities was small in this study THERE IS A NEED FOR THE DEVELOPMENT OF REGISTRY/GUIDELINES/RECOMMENDATION Weber J et al. Cancer Immunol Res 2016;4: