Adverse Events with immune checkpoint inhibitors how to manage - - PowerPoint PPT Presentation

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

Target drug name company development stage CTLA4 Ipilimumab BMS

FDA approved (Melanoma) Phase I-II multiple tumors

Tremelimumab MedImmune

Phase I-III multiple tumors

PD1 Nivolumab BMS

Phase III multiple tumors (melanoma, RCC, NSCLC, HNSCC)

Pembrolizumab Merck

Phase I-II multiple tumors Phase III NSCLC/melanoma

Pidilizumab CureTech

Phase II multiple tumors

PD-L1 MPDL3280A

Genentech-Roche

Phase I-II multiple tumors Phase III NSCLC

MEDI-4736 Astra-Zeneca

Phase I-II multiple tumors

BMS-936559 BMS

Phase I solid tumors

Clinical development

• f immune checkpoint inhibitors

(ICIs)

Toxicity with ICIs

cytokine release by activated T-cells activation of the immune system against tumors a novel spectrum of AEs : immune related AEs = irAEs

ICIs

ICI initiation ICI discontinuation ICI continuation

treatment phase

generally well tolerated +++ early delayed

• ff treatment

progression

adverse events

months 1 2 3 4 5 6

Immune checkpoint inhibitors treatment schedule

Kinetic of T-cell responses

population size effector T-cells memory T-cells days

CD8 CD8 CD8 CD8 CD8 CD8

tumor specific T-cells polyclonal anti-tumor immune response immune checkpoint blockade

Tumor Control

CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8

Kinetic of T-cell responses

population size effector T-cells memory T-cells auto-reactive clone days

CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8

tumor specific T-cells auto reactive clone polyclonal anti-tumor immune response auto-immune response immune checkpoint blockade

Auto Immunity

CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8 CD8

Liver toxicity

Toxicity grade

weeks after treatment initiation

2 4 6 8 10 12 14

Rash, pruritis Diarrhea, colitis Hypophysitis

Kinetics of appearance

• f immune-related adverse events

adapted from Weber, et al., Management of immune-related adverse events and kinetics of response with ipilimumab. Journal of Clinical Oncology, 2012.

TOXICITY Immune system activation by immune checkpoint blockade disease & tumoral environment

• pportunistic

pathogens co medications genetic background

Hypothetical model

• f ICIs immune-related 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

Action Anticipation Prevention Detection Risk management

Action Anticipation Prevention Detection

Inform patients & physicians

Risk management

Get information about risk factors Diagnose AEs Treat & refer when needed

Anticipation

Inform patients & physicians

Getting medical treatment right away may help keep these problems from becoming more serious promptly report any new, persistent, or worsening symptoms

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

Action Anticipation Prevention Detection

Inform patients & physicians

Risk management

Get information about risk factors Diagnose AEs

Detection

Diagnose AEs

= any new, persistent, or worsening symptoms

GASTRO INTESTINAL

Diarrhea Abdominal pain Blood or mucus in stool Bowel perforation Peritoneal signs Ileus

LIVER

Abnormal liver function tests (AST, ALT)

• r total bilirubin elevation

SKIN

Pruritus Rash

NEUROLOGIC

Unilateral or bilateral weakness Sensory alterations Paresthesia

ENDOCRINE

Fatigue Headache Mental status changes Abdominal pain Unusual bowel habits Hypotension Abnormal thyroid function tests and/or serum chemistries

OTHER ADVERSE REACTIONS …

adapted from YERVOY FDA-approved Risk Evaluation and Mitigation Strategy (REMS)

OTHER ADVERSE REACTIONS …

Blood and lymphatic

hemolytic anemia

Cardiovascular

angiopathy myocarditis pericarditis temporal arteritis vasculitis

Endocrine

autoimmune thyroiditis

Eye

blepharitis, conjunctivitis episcleritis, iritis scleritis, uveitis

Gastrointestinal

pancreatitis

Infectious

meningitis

Musculoskeletal

arthritis polymyalgia rheumatica

Renal and urinary

nephritis

Respiratory

pneumonitis

Skin

psoriasis leukocytoclastic vasculitis

adapted from YERVOY FDA-approved Risk Evaluation and Mitigation Strategy (REMS)

Ipilimumab

N=131

Pembrolizumab

N=135

Nivolumab

N=107 % of patients

Total Grade 3/4 Total Grade 3/4 Total Grade 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 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 9,6 1,5 6,5 0,9 infusion reaction ND ND 0,7 5,6 pulmonary 14,5 3,9 8,1 3,7 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

N=131

Pembrolizumab

N=135

Nivolumab

N=107 % of patients

Total Grade 3/4 Total Grade 3/4 Total Grade 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 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 9,6 1,5 6,5 0,9 infusion reaction ND ND 0,7 5,6 pulmonary 14,5 3,9 8,1 3,7 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

Most common adverse reactions (in ≥20% of patients) : fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea

Detection

Diagnose AEs

What toxicity should we focus on ? colitis pneumonitis neurological skin hepatic endocrine infusion reaction renal

• cular

Action Anticipation Prevention Detection

Inform patients & physicians

Risk management

Get information about risk factors Diagnose AEs Treat & refer when needed

physical examination lab tests

GRADE disease progression irAEs

fortuitous events, not directly related

Action Treat

GRADE = CTCAE version 4.0 How does this AE affect the daily life ? //sleep, daily activities, …

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

Action

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

> Withhold +/- Resume when AE recover to Grade 0-1

adapted from Keytruda FDA-approved prescribing information

Dose Modifications Action

> 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

When do we need help ? Action

refer patients with severe AE

• r AE difficult to manage

Oncologist prescriber Dermatologist Endocrinologist Chest specialist Gastro enterologist Neurologist

Action Who is my dream team ?

a multidisciplinary approach

Why we need a dream team ?

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 ?

Action

a multidisciplinary approach

in clinical practice . . .

AE presentation clinical confirmatory explorations treatments

• ptions

Skin rash, pruritus +/- skin biopsy topical ttt Colitis diarrhea, blood in stools, pain

stool diagnostics

colonoscopy +/- CT scan steroids

budenoside?

+/- infliximab Endocrine fatigue, frilosity, headache hormonal blood tests +/- MRI hormone replacement ttt Hepatitis abnormal liver function tests

(AST/ALT, bilirubin)

hepatitis serology auto-antibodies +/- biopsy steroids +/- tacrolimus, cellcept or infliximab ?

in clinical practice . . .

AE presentation clinical confirmatory explorations treatments

• ptions

Pneumonitis dyspnea, cough CT-scan bronchoscopy + lavage steroids

+/- infliximab ? +/- antibiotics ? +/- antifungal ?

Neurological weakness sensory alterations MRI lumbar puncture steroids +/- infliximab ? +/- Ig IV

in clinical practice . . .

> initiate steroids early, taper slowly > monitor closely ++ // potential secondary relapse of irAEs > infliximab if no improval or worsening within 48-72 hours > antimicrobial prophylaxis (Bactrim)? in clinical practice . . .

Conclusion

Toxicity with ICIs are a novel spectrum of AEs : immune related AEs = irAEs may be unfamiliar to clinicians requires multidisciplinary approach can be serious requires prompt recognition requires patient & health care providers education Conclusion

so …Think different. not all toxicities are immune-related : but immune-related toxicities have ALWAYS to be considered

ICIs are bringing Internal Medicine BACK to the Oncology practice

• disease progression
• fortuitous

toxicity profile reported in melanoma may be different in NSCLC, HNSCC, RCC …

Agent (mg/kg) Grade 3-4 % Nivo 0,3 5 Nivo 2 17 Nivo 10 13 MPDL3280A 13 NIVO 3 + IPI 1 29 NIVO 1 + IPI 3 61 Sutent + NIVO 82 PAZ + NIVO 70

Toxicity and combination regimens

Motzer ASCO 2014, Cho ASCO 2013, Hammers ASCO 2014, Amin ASCO 2014

yervoy : 4 cycles treatment duration with PD1/PD-L1 inhibitors ??? until progression unacceptable toxicity ? intermittent treatment / maintenance re-induction

• ff treatment responses possible ?

Brahmer J Clin Oncol 2010 Jul1; 28(19):3167-75 Lipson Clin Cancer Res; 19(2); 462-8 2012 Disease worsening vs pseudo-progression : should we introduce steroids ?

Key questions

reported irAEs Ipilimumab in melanoma

Hodi et al., NEJM 2010, "Improved Survival with Ipilimumab in Patients with Metastatic Melanoma."

Ipilimumab Alone (N=131)

Adverse events, % of patients Total Grade 3 /4 Any event 96,9 45,8 Any drug-related event 80,2 22,9 Gastrointestinal disorders Diarrhea 32,8 5,3 Nausea 35,1 2,3 Constipation 20,6 2,3 Vomiting 23,7 2,3 Abdominal pain 15,3 1,5 Other Fatigue 42 6,9 Decreased appetite 26,7 1,5 Pyrexia 12,2 Headache 14,5 2,3 Cough 16 Dyspnea 14,5 3,9 Anemia 11,5 3,1 Adverse events, % of patients Total Grade 3 /4 Any immune-related event 61,1 14,5 Dermatologic 43,5 1,5 Pruritus 24,4 Rash 19,1 0,8 Vitiligo 2,3 Gastrointestinal 29 7,6 Diarrhea 27,5 4,6 Colitis 7,6 5,3 Endocrine 7,6 3,8 Hypothyroidism 1,5 Hypopituitarism 2,3 1,5 Hypophysitis 1,5 1,5 Adrenal insufficiency 1,5 Hepatic 3,8 Increase in alanine aminotransferase 1,5 Increase in aspartate aminotransferase 0,8 Hepatitis 0,8 Other 4,6 2,3

reported irAEs

No treatment-related deaths

Ribas et al., ASCO 2014 : « Efficacy and Safety of the Anti-PD-1 Monoclonal Antibody MK-3475 in 411 Patients With Melanoma »

Pembrolizumab in melanoma

reported irAEs

Ribas et al., ASCO 2014 : « Efficacy and Safety of the Anti-PD-1 Monoclonal Antibody MK-3475 in 411 Patients With Melanoma »

Pembrolizumab in melanoma

g potentially immune-mediated AEs were reported in <1% of patients: nephritis, hypophysiti

reported irAEs

Topalian et al. , JCO 2014 : « Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab »

Nivolumab in melanoma

Selected drug-related AEs (≥ 1%) all patients have ≥ 1 year of follow-up

Category Any Grade % (n) Grade 3-4 % (n) Any selected AE 54 (58) 5 (5) Skin 36 (38) Gastrointestinal 18 (19) 2 (2) Endocrinopathies 13 (14) 2 (2) Hepatic 7 (7) 1 (1) Infusion reaction 6 (6) Pulmonary 4 (4) Renal 2 (2) 1 (1)