Adverse Events with immune checkpoint inhibitors how to manage patients in clinical practice ? Stéphane Champiat , MD, MSc Inserm U981 & Drug Development Department Gustave Roussy Cancer Campus, Grand Paris
Clinical development of immune checkpoint inhibitors (ICIs) Target drug name company development stage FDA approved (Melanoma) Ipilimumab BMS Phase I-II multiple tumors CTLA4 Tremelimumab MedImmune Phase I-III multiple tumors Phase III multiple tumors Nivolumab BMS (melanoma, RCC, NSCLC, HNSCC) Phase I-II multiple tumors PD1 Pembrolizumab Merck Phase III NSCLC/melanoma Pidilizumab CureTech Phase II multiple tumors Phase I-II multiple tumors MPDL3280A Genentech-Roche Phase III NSCLC PD-L1 MEDI-4736 Astra-Zeneca Phase I-II multiple tumors BMS-936559 BMS Phase I solid tumors
Toxicity with ICIs ICIs activation of the immune system against tumors cytokine release by activated T-cells a novel spectrum of AEs : immune related AEs = irAEs
Immune checkpoint inhibitors treatment schedule treatment phase ICI ICI ICI initiation continuation discontinuation months 1 2 3 4 5 6 adverse early delayed off treatment events generally progression well tolerated +++
Kinetic of T-cell responses effector T-cells population memory size T-cells days immune CD8 checkpoint CD8 CD8 CD8 blockade CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 Tumor polyclonal tumor CD8 CD8 anti-tumor CD8 CD8 CD8 CD8 specific Control CD8 immune response CD8 T-cells CD8 CD8 CD8 CD8 CD8 CD8
Kinetic of T-cell responses effector T-cells auto-reactive clone population memory size T-cells days immune CD8 checkpoint CD8 CD8 CD8 blockade CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 polyclonal tumor CD8 CD8 anti-tumor CD8 CD8 CD8 CD8 specific CD8 immune response CD8 T-cells CD8 CD8 CD8 CD8 CD8 CD8 Auto auto CD8 auto-immune CD8 reactive Immunity CD8 CD8 response CD8 clone
Kinetics of appearance of immune-related adverse events Rash, pruritis Diarrhea, colitis Liver toxicity Hypophysitis Toxicity grade 0 2 4 6 10 12 14 8 weeks after treatment initiation adapted from Weber, et al., Management of immune-related adverse events and kinetics of response with ipilimumab. Journal of Clinical Oncology, 2012.
Hypothetical model of ICIs immune-related toxicity Immune system activation by immune checkpoint blockade opportunistic co pathogens medications disease genetic & tumoral background environment TOXICITY
immune-related AEs = new adverse events > new type of AEs may involve any organ system > new kinetic of AEs The majority occur during treatment however, a minority happen weeks to months after discontinuation Recognize and address symptoms early Educate patients to identify signs and symptoms associated with immune-mediated adverse reactions
Risk management Action Anticipation Detection Prevention
Risk management Treat & refer Inform patients when needed & physicians Action Anticipation Detection Prevention Get information Diagnose AEs about risk factors
Anticipation Inform patients & physicians promptly report any new, persistent, or worsening symptoms Getting medical treatment right away may help keep these problems from becoming more serious
Prevention Get information about risk factors > personal and family history: -immune system diseases (Crohn’s disease, ulcerative colitis, lupus, … ) -organ transplantation - lung or liver conditions -severe infections -any other medical conditions -pregnancy > concomitant medications
Risk management Inform patients & physicians Action Anticipation Detection Prevention Get information Diagnose AEs about risk factors
Detection Diagnose AEs = any new, persistent, or worsening symptoms
GASTRO ENDOCRINE INTESTINAL Fatigue Diarrhea Headache Abdominal pain Mental status changes Blood or mucus in stool Abdominal pain Bowel perforation Unusual bowel habits Peritoneal signs Hypotension Ileus Abnormal thyroid function tests and/or serum chemistries LIVER NEUROLOGIC Abnormal liver function tests (AST, ALT) Unilateral or bilateral weakness or total bilirubin elevation Sensory alterations Paresthesia SKIN Pruritus Rash OTHER ADVERSE REACTIONS … adapted from YERVOY FDA-approved Risk Evaluation and Mitigation Strategy (REMS)
OTHER ADVERSE REACTIONS … Gastrointestinal Blood and lymphatic pancreatitis hemolytic anemia Infectious Cardiovascular meningitis angiopathy myocarditis Musculoskeletal pericarditis arthritis temporal arteritis polymyalgia rheumatica vasculitis Renal and urinary Endocrine nephritis autoimmune thyroiditis Respiratory Eye pneumonitis blepharitis, conjunctivitis episcleritis, iritis Skin scleritis, uveitis psoriasis leukocytoclastic vasculitis adapted from YERVOY FDA-approved Risk Evaluation and Mitigation Strategy (REMS)
reported irAEs in melanoma Ipilimumab Pembrolizumab Nivolumab N=131 N=135 N=107 Grade Grade Grade % of patients Total Total Total 3/4 3/4 3/4 any, drug related 80,2 22,9 79,3 12,6 54,2 4,7 skin 43,5 1,5 20,7 2,2 35,5 0 gastrointestinal 29 7,6 20 0,7 17,8 1,9 endocrinopathies 7,6 3,8 8,1 0,7 13,1 1,9 hepatic 3,8 0 9,6 1,5 6,5 0,9 infusion reaction ND ND 0,7 0 5,6 0 pulmonary 14,5 3,9 8,1 0 3,7 0 renal ND 0,7 2,2 1,5 1,9 0,9 Hodi et al., NEJM 2010, "Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. » Hamid et al., NEJM 2013, « Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. » Topalian et al., JCO 2014 : « Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab »
reported irAEs in melanoma Ipilimumab Pembrolizumab Nivolumab N=131 N=135 N=107 Grade Grade Grade % of patients Total Total Total 3/4 3/4 3/4 any, drug related 80,2 22,9 79,3 12,6 54,2 4,7 skin 43,5 1,5 20,7 2,2 35,5 0 gastrointestinal 29 7,6 20 0,7 17,8 1,9 endocrinopathies 7,6 3,8 8,1 0,7 13,1 1,9 hepatic 3,8 0 9,6 1,5 6,5 0,9 infusion reaction ND ND 0,7 0 5,6 0 pulmonary 14,5 3,9 8,1 0 3,7 0 renal ND 0,7 2,2 1,5 1,9 0,9 Hodi et al., NEJM 2010, "Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. » Hamid et al., NEJM 2013, « Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. » Topalian et al., JCO 2014 : « Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab »
Detection Diagnose AEs Most common adverse reactions (in ≥ 20% of patients) : fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea What toxicity should we focus on ? colitis pneumonitis infusion reaction neurological renal skin ocular hepatic endocrine
Risk management Treat & refer Inform patients when needed & physicians Action Anticipation Detection Prevention Get information Diagnose AEs about risk factors
Action physical examination lab tests disease fortuitous events, irAEs not directly related progression GRADE Treat
GRADE = CTCAE version 4.0 How does this AE affect the daily life ? //sleep, daily activities, …
Action Treating irAEs follow Guidelines symptomatic ttt steroids or other immunosuppressants withhold or permanently discontinue ICI remain vigilant : potential AE relapse and new AE know when to refer patients with severe AE
Kähler et al., Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. JDDG, 2011
Kähler et al., Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. JDDG, 2011
Action Dose Modifications > Withhold + /- Resume when AE recover to Grade 0-1 > Permanently discontinue for ✔ any life-threatening adverse reaction ✔ ✔ ✔ and : -Grade ≥ 3 pneumonitis -Grade ≥ 3 nephritis -AST or ALT > 5 N or total bilirubin > 3 N -Grade ≥ 3 infusion-related reactions ✔ inability to reduce steroid dose to ≤ 10 mg/day within 12 weeks ✔ persistent Grade 2 or 3 that do not recover to Grade 0-1 within 12 weeks after last dose of ICIs ✔ ✔ any severe or Grade 3 that recurs ✔ ✔ adapted from Keytruda FDA-approved prescribing information
Action When do we need help ? refer patients with severe AE or AE difficult to manage
Action Who is my dream team ? a multidisciplinary approach Dermatologist Endocrinologist Oncologist prescriber Gastro Chest enterologist specialist Neurologist
Action Why we need a dream team ? a multidisciplinary approach define your team +++ educate organ specialist improve mechanistic knowledge of side effects and improve toxicity management late effects managements and monitoring frequency of AEs across tumor types ?
in clinical practice . . .
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