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Management of Immune related

toxicitiesLuis H. Camacho, MD, MPH

St. Luke’s Episcopal Hospital Cancer Center

1Sunday, December 9, 12

Kinetics of toxicities

Weber J et al: J Clin Oncol 20122Sunday, December 9, 12

Select Important Safety Information: Adverse Reactions

Selected Adverse Reactions in the Pivotal Phase 3 Study

Patients, %a

YERVOY 3 mg/kg (n = 131)

YERVOY 3 mg/kg + gp100 (n = 380)

gp100 (n = 132)

System Organ Class/ Preferred Term Any Grade Grade 3-5 Any Grade Grade 3-5 Any Grade Grade 3-5

Gastrointestinal Disorders

Diarrhea 32 5 37 4 20 1

Colitis 8 5 5 3 2 0

Skin and Subcutaneous Tissue Disorders Pruritus 31 0 21 <1 11 0

Rash 29 2 25 2 8 0

General Disorders and Administration Site Conditions Fatigue 41 7 34 5 31 3

aIncidences presented in this table are based on reports of adverse events regardless of causality.

•  The data on this slide reflect selected adverse reactions from the pivotal phase 3 study, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3-5 events


Severe, life-threatening, or fatal (Grade 3-5)

Moderate (Grade 2)

•  Diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs

•  Diarrhea of ≤6 stools above baseline, abdominal pain, mucus or blood in stool

7% n = 34

5% n = 28

Immune-mediated enterocolitis in YERVOY-treated patients (N = 511)

Immune-Mediated Enterocolitis in the Pivotal Phase 3 Study


Colitis


CTLA4 blockade in MelanomaGastrointestinal Toxicity

Ribas A: J Clin Oncol 2005


Enterocolitis - Management

Permanently discontinue YERVOY™ (ipilimumab) in patients with severe enterocolitis

Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent

Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month

In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients

Withhold YERVOY dosing for moderate enterocolitis

Administer antidiarrheal treatment and If moderate enterocolitis persists for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent


Immune-mediated hepatitis in YERVOY-treated patients (N = 511)


Moderate (Grade 2)

•  AST or ALT elevations of >5 × ULN or total bilirubin elevations >3 × ULN

•  LFT abnormalities (AST or ALT elevations of >2.5 × but ≤5 × ULN or total bilirubin elevation of >1.5 × but ≤3 × ULN)

2% n = 8

2.5% n = 13

Immune-Mediated Hepatitis in the Pivotal Phase 3 Study


Immune-Mediated Hepatitis in the Pivotal Phase 3 Study (cont�d)

Immune-Mediated Hepatitis in YERVOY-Treated Patients (n = 21 of 511) Immune-Mediated Adverse Reaction Additional Information

Severe, life-threatening, or fatal (Grade 3-5) • AST or ALT elevations of >5 × ULN or

total bilirubin elevations >3 × ULN • n = 8 (2%)

• The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis

• There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event

Moderate (Grade 2) • LFT abnormalities (AST or ALT elevations

of >2.5 × but ≤5 × ULN or total bilirubin elevation of >1.5 × but ≤3 × ULN)

• n = 13 (2.5%)

2% n = 8

2.5% n = 13

•  0.2% of the 511 YERVOY-treated patients experienced fatal hepatic failure. •  0.4% of the 511 YERVOY-treated patients were hospitalized for hepatotoxicity.


Immune-mediated dermatitis in YERVOY-treated patients (N = 511)

2.5% n = 13

12% n = 63


Moderate (Grade 2)

•  Eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

Immune-Mediated Dermatitis in the Pivotal Phase 3 Study


Dermatitis


CTLA4 blockade in MelanomaSkin Toxicity



CTLA4 blockade in MelanomaSkin Toxicity


CD3 H & E

CD15


Immune-Mediated Dermatitis in the Pivotal Phase 3 Study (cont�d)

Immune-Mediated Dermatitis in YERVOY-Treated Patients (n = 76 of 511)

Treatment for Immune-Mediated Adverse Reaction

Patient Outcomes Following Treatment for

Immune-Mediated Adverse Reaction


• Eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

•  n = 13 (2.5%)

n = 13 •  7 (54%) received high-dose

corticosteroidsa for up to 14.9 weeks followed by corticosteroid taper

•  6 of the 7 patients had complete resolution; time to resolution ranged up to 15.6 weeks

aMedian dose = 60 mg/day prednisone or equivalent.

2.5% n = 13

12% n = 63 Moderate (Grade 2)

•  n = 63 (12%) n = 63

•  25 (40%) were treated with systemic corticosteroidsa for a median of 2.1 weeks

•  7 (11%) were treated with only topical corticosteroids

•  31 (49%) did not receive systemic or topical corticosteroids

n = 63 •  44 (70%) were reported to

have complete resolution •  7 (11%) improved to mild

(Grade 1) severity •  12 (19%) had no reported

improvement

• Across all YERVOY-treated patients, the median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY.

•  0.2% of the 511 YERVOY-treated patients died as a result of toxic epidermal necrolysis. •  1 of the 511 YERVOY-treated patients required hospitalization for severe dermatitis.


Immune-mediated endocrinopathies in YERVOY-treated patients (N = 511)

1.8% n = 9

2.3% n = 12

Severe to life-threatening (Grade 3-4)

Moderate (Grade 2)

•  Requiring hospitalization or urgent medical intervention, or interfering with activities of daily living

•  Requiring hormone replacement or medical intervention

Immune-Mediated Endocrinopathies in the Pivotal Phase 3 Study


Hypophysitis01/30/03 05/09/03 09/10/03


Immune-Mediated Endocrinopathies in the Pivotal Phase 3 Study (cont�d)

Immune-Mediated Endocrinopathies in YERVOY-Treated Patients (n = 21 of 511)

Immune-Mediated Adverse Reaction

Median Time to Onset After Initiation

of YERVOY

Treatment for Immune-Mediated Adverse Reaction

Severe to life-threatening (Grade 3-4) • Requiring hospitalization or urgent medical

intervention, or interfering with activities of daily living

• n = 9 (1.8%) –  All 9 had hypopituitarism, and some

had additional concomitant endocrinopathies, such as adrenal insufficiency, hypogonadism, and hypothyroidism

–  6 of the 9 were hospitalized for severe endocrinopathies

For moderate to severe • 11 weeks (ranged up

to 19.3 weeks)

• Of the 21 patients with moderate to life-threatening endocrinopathy, 17 required long-term hormone replacement therapy, including, most commonly, adrenal hormones (n = 10) and thyroid hormones (n = 13)

Moderate (Grade 2) • Requiring hormone replacement or

medical intervention • n = 12 (2.3%)

–  Consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome

1.8% n = 9

2.3% n = 12


Select Important Safety Information: When to Withhold YERVOY™ (ipilimumab)

•  Withhold scheduled dose of YERVOY for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy

•  For patients with complete or partial resolution of adverse reactions (Grade 0-1) who are receiving less than 7.5 mg/day prednisone or equivalent, resume YERVOY at a dose of 3 mg/kg every 3 weeks until whichever occurs earlier:

– Administration of all 4 planned doses OR

– 16 weeks from first dose


Select Important Safety Information: When to Permanently Discontinue YERVOY™ (ipilimumab) •  Permanently discontinue YERVOY for

–  Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg/day prednisone or equivalent

–  Failure to complete full treatment course within 16 weeks from administration of first dose –  Severe or life-threatening adverse reactions, including any of the following

Severe or Life-Threatening Adverse Reactions

Gastrointestinal

•  Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, or gastrointestinal perforation

Hepatic

•  AST or ALT >5 times the ULN or total bilirubin >3 times the ULN Skin-related •  Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or

necrotic, bullous, or hemorrhagic manifestations Neurologic •  Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis Other Adverse Reactions, including ocular manifestations •  Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis,

non-infectious myocarditis) •  Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy


Anti-PD1 AntibodiesNephritis Pancytopenia

Pneumonitis HyperthyroidismHypothyroidism Abdominal pain

Hepatitis EndophthalmitisSarcoidosis Myasthenia GravisPneumonitis Diabetes

Vitiligo ColitisHypophysitis Thyroiditis

Brahmer JR: N Eng J Med 2012Merck - Investigator’s Meeting (Los Angeles CA - Nov 17/2012)


Summary• CTLA4 IRAE include dermatitis,

enterocolitis, enteropathy, neuropathy, and hepatitis.

• Toxicities are commonly a spectrum of severity.

• Prompt recognition and treatment with steroids alleviate the symptoms in a majority of patients.

• Anti-PD1 and PD1-L1 antibodies exhibit smilar toxicites.


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