Immune-Mediated Adverse Reactions Management Guide

88 Pages·2017·4.41 MB·English

Immune-mediated adverse
reactions management guide
Please see Important Safety Information for OPDIVO on pages 33–37 and US Full Prescribing Information for OPDIVO®.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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OPDIVO® is approved in 8 tumor types
OPDIVO as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or
metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.1
OPDIVO as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.1
OPDIVO, in combination with YERVOY, is indicated for the treatment of patients with unresectable or metastatic melanoma.
This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication
may be contingent upon verification and description of clinical benefit in the confirmatory trials.1
OPDIVO is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic
disease who have undergone complete resection.1
OPDIVO is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or
after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.1
OPDIVO is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.1
OPDIVO in combination with YERVOY, is indicated for the treatment of patients with intermediate or poor risk, previously
untreated advanced renal cell carcinoma (RCC).1
OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines
of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in
confirmatory trials.1
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous use.1,2
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may
involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis,
hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months
after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate
clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid
function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-
mediated reactions.
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 2
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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OPDIVO® is approved in 8 tumor types (cont’d)
OPDIVO is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck
(SCCHN) with disease progression on or after a platinum-based therapy.1
OPDIVO is indicated for treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have
disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated
approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory trials.1
OPDIVO is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high
(MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with
a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response
rate and duration of response. Continued approval for this indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.1
OPDIVO is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of
response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the
confirmatory trials.1
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 3
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Considerations when managing immune-mediated
adverse reactions1,3-10
Use of corticosteroids,
Early recognition Close monitoring of
withholding, or
of potential IMARs signs/symptoms
discontinuing therapy
While some side effects of immunotherapy may appear similar to chemotherapy,
they may need to be managed differently
HSCT=hematopoietic stem cell transplant; IMAR=immune-mediated adverse reaction.
Select Important Safety Information
OPDIVO® is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis,
hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions;
infusion reactions; complications of allogeneic HSCT after OPDIVO; and embryo-fetal toxicity.
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 4
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Organ systems potentially impacted by immune-mediated
adverse reactions1
NEUROLOGIC ENDOCRINE
HEPATIC
PULMONARY
GASTROINTESTINAL
RENAL
SKIN
Additionally, infusion reactions have been reported
These are not all the possible organ systems that may be affected.
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 5
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Summary of immune-mediated adverse reactions with
OPDIVO® as a single agent
Clinically significant adverse reactions of OPDIVO as a single agent were evaluated in 1994 patients enrolled in Checkmate 037,
017, 057, 066, 025, 067, 205, and 039, or a single-arm trial in NSCLC (n=117), administering OPDIVO as a single agent1
OPDIVO can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials1
Please see pages 12–32 for respective management of immune-mediated adverse reactions in patients treated with OPDIVO
Frequency and onset of immune-mediated adverse reactions1
OPDIVO as a single agent (N=1994)
Incidence
all grades Median time to onset (months)
n (%)
Pneumonitis* 61 (3.1) 3.5 range: 1 day to 22.3 months
Colitis 58 (2.9) 5.3 range: 2 days to 20.9 months
Hepatitis 35 (1.8) 3.3 range: 6 days to 9 months
Endocrinopathies
Hypophysitis 12 (0.6) 4.9 range: 1.4 to 11 months
Adrenal insufficiency 20 (1) 4.3 range: 15 days to 21 months
Hypothyroidism/thyroiditis 171 (9) 2.9 range: 1 day to 16.6 months
Hyperthyroidism 54 (2.7) 1.5 range: 1 day to 14.2 months
Type 1 diabetes mellitus 17† (0.9) 4.4 range: 15 days to 22 months
Nephritis,
23 (1.2) 4.6 range: 23 days to 12.3 months
renal dysfunction
range:
Skin‡ 171 (9) 2.8 <1 day to 25.8 months
Encephalitis 3§ (0.2)
Months 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
* Fatal cases have been reported.1 †Two cases of diabetic ketoacidosis occurred.1 ‡OPDIVO can cause skin immune-mediated adverse reactions including Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN); some cases with fatal outcome.1 §Fatal limbic encephalitis occurred in 1 patient after 7.2 months of exposure despite discontinuation of OPDIVO and
administration of corticosteroids. In the other 2 patients, encephalitis occurred post-allogeneic hematopoietic stem cell transplantation.1
NSCLC=non-small cell lung cancer.
Frequency and onset of infusion reactions/hypersensitivity1
As a 60-minute intravenous infusion, hypersensitivity/infusion reactions occurred in 127 (6.4%) patients
In a study assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute
intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369)
of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within
48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of OPDIVO
Other immune-mediated adverse reactions1
OPDIVO can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Across clinical trials of
OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions,
some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome
Please see Important Safety Information for OPDIVO on pages 33–37 and US Full Prescribing Information for OPDIVO. 6
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Summary of immune-mediated adverse reactions
management and outcomes with OPDIVO® as a single agent
Clinically significant adverse reactions of OPDIVO as a single agent were evaluated in 1994 patients enrolled in Checkmate 037,
017, 057, 066, 025, 067, 205, and 039, or a single-arm trial in NSCLC (n=117), administering OPDIVO as a single agent1
Corticosteroid use Recurrence
Permanently after
discontinued Withheld re-initiation
OPDIVO OPDIVO Median duration Resolution* of OPDIVO
N=1994 (%) (%) (%) (range) Other treatments (%) (%)
26 days
Pneumonitis (n=61) 1.1 1.3 ~89† – 67‡ ~8
(1 day to 6 months)
4 patients received
23 days
Colitis (n=58) 0.7 1 ~91† infliximab in addition 74§ ~16
(1 day to 9.3 months)
to high-dose CS
2 patients received
23 days mycophenolic acid
Hepatitis (n=35) 0.7 1 100† 74§ ~29
(1 day to 2 months) in addition to
high-dose CS
Endocrinopathies
14 days
Hypophysitis (n=12) 0.1 0.2 33† ~67% received HRT – –
(5 to 26 days)
Adrenal insufficiency 11 days
0.1 0.5 25† ~85% received HRT – –
(n=20) (1 day to 1 month)
Hypothyroidism/ ~79% received
– – 4 – 35 –
thyroiditis (n=171) levothyroxine
~26% received
methimazole;
Hyperthyroidism ~9% received
– – 9 – 76 –
(n=54) carbimazole;
~4% received
propylthiouracil
Type 1 diabetes
– – – – – – –
mellitus (n=17)
Nephritis, 21 days
0.3 0.8 100† – 48§ 0
renal dysfunction (n=23) (1 day to 15.4 months)
12 days 85% received
Skin (n=171) 0.3 0.8 ~16† 48§ 1.4
(1 day to 8.9 months) topical CS
Encephalitis (n=3) – – – – – – –
* Resolution defined in the context of the IMAE time-to-resolution analyses; resolution date was defined as the investigator-assessed IMAE resolution date. In the analyses of complete
resolution, complete resolution was defined as improved to Grade 0 or baseline grade per investigator assessment with completion of corticosteroid treatment (or other medical
intervention).11 †At least 40 mg prednisone equivalents per day.1 ‡Complete resolution following CS taper.1 §Complete resolution following CS use.1
CS=corticosteroid; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; IMAR=immune-mediated adverse reaction; NSCLC=non-small cell lung cancer.
Please see Important Safety Information for OPDIVO on pages 33–37 and US Full Prescribing Information for OPDIVO. 7
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Summary of immune-mediated adverse reactions with
OPDIVO® + YERVOY in patients with mMelanoma
In patients with metastatic melanoma
Clinically significant adverse reactions of OPDIVO in combination with YERVOY were evaluated in 407 patients with melanoma
enrolled in Checkmate 067 (n=313) or a phase 2 randomized trial (n=94), administering OPDIVO with YERVOY, supplemented
by immune-mediated adverse reaction reports in ongoing clinical trials1
Please see pages 12-32 for respective management of immune-mediated adverse reactions in patients treated with
OPDIVO + YERVOY
Frequency and onset of immune-mediated adverse reactions1*
OPDIVO 1 mg/kg with YERVOY 3 mg/kg q3w followed by OPDIVO as a single agent (n=407)
All grades Median time to onset (months)
n (%) Combo OPDIVO monotherapy
Pneumonitis 25 (6) 1.6 range: 24 days to 10.1 months
range: 3 days
Colitis 107 (26) 1.6
to 15.2 months
Hepatitis, including liver
function test elevations 51 (13) 2.1 range: 15 days to 11 months
Endocrinopathies
Hypophysitis 36 (9) 2.7 range: 27 days to 5.5 months
Adrenal insufficiency 21 (5) 3.0 range: 21 days to 9.4 months
Hypothyroidism/thyroiditis 89 (22) 2.1 range: 1 day to 10.1 months
Hyperthyroidism 34 (8) 0.77 range: 3 days to 3.7 months
Type 1 diabetes mellitus 6 (1.5) 2.5 range: 1.3 to 4.4 months
Nephritis,
9 (2.2) 2.7 range: 9 days to 7.9 months
renal dysfunction
Skin 92 (22.6) 0.6 range: 1 day to 9.7 months
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Months
*E ncephalitis occurred in 1 patient receiving OPDIVO + YERVOY (0.2%) after 1.7 months of exposure.1
mMelanoma=metastatic melanoma; q3w=every 3 weeks.
Frequency and onset of infusion reactions/hypersensitivity1
Hypersensitivity/infusion reactions occurred in 10 (2.5%) patients
Other immune-mediated adverse reactions1
OPDIVO can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Across clinical trials of
OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions,
some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 8
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Summary of immune-mediated adverse reactions management
and outcomes with OPDIVO® + YERVOY in mMelanoma
In patients with metastatic melanoma
Clinically significant adverse reactions of OPDIVO in combination with YERVOY (OPDIVO 1 mg/kg followed by YERVOY 3 mg/kg
on the same day every 3 weeks for 4 doses, then OPDIVO 240 mg every 2 weeks) were evaluated in 407 patients with melanoma
enrolled in Checkmate 067 (n=313) or a phase 2 randomized trial (n=94), administering OPDIVO with YERVOY, supplemented
by immune-mediated adverse reaction reports in ongoing clinical trials1
Corticosteroid use Recurrence
Permanently Withheld after
discontinued OPDIVO re-initiation
OPDIVO with with of OPDIVO
YERVOY YERVOY Median duration Other Resolution with YERVOY
n=407 (%) (%) (%) (range) treatments (%)* (%)
30 days
Pneumonitis (n=25) 2.2 3.7 ~84† – 68‡ ~13
(5 days to 11.8 months)
~23% received
1.1 months infliximab in
Colitis (n=107)§ 16 7 ~96† 75‡ ~28
(1 day to 12 months) addition to
high-dose CS
1.1 months
Hepatitis (n=51) 6 5 ~92† – 75‡ ~11
(1 day to 13.2 months)
Endocrinopathies
19 days ~75% received
Hypophysitis (n=36) 1 3.9 56† – –
(1 day to 2.0 months) HRT
Adrenal insufficiency 9 days ~57% received
0.5 1.7 33† – –
(n=21) (1 day to 2.7 months) HRT
Hypothyroidism/ ~73% received
– – – – 45 –
thyroiditis (n=89) levothyroxine
~29% received
Hyperthyroidism methimazole
– – – – 94 –
(n=34) ~24% received
carbimazole
Type 1 diabetes
1 patient 1 patient – – – – –
mellitus (n=6)
Nephritis, 13.5 days
0.7 0.5 ~67† – 100‡ 0II
renal dysfunction (n=9) (1 day to 1.1 months)
14 days
Skin (n=92) 0.5 3.9 ~17† – 47‡ ~6
(2 days to 4.7 months)
Encephalitis (n=1) – – – – – – –
* Resolution defined in the context of the IMAE time-to-resolution analyses; resolution date was defined as the investigator-assessed IMAE resolution date. In the analyses of complete
resolution, complete resolution was defined as improved to Grade 0 or baseline grade per investigator assessment with completion of CS treatment (or other medical intervention).11
† A t least 40 mg prednisone equivalents per day.1 ‡Complete resolution following CS use.1 §Includes 3 fatal cases.1 IITwo patients resumed OPDIVO with YERVOY without recurrence of nephritis
or renal dysfunction.1
CS=corticosteroid; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mMelanoma=metastatic melanoma.
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 9
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
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Summary of immune-mediated adverse reactions with
OPDIVO® + YERVOY in aRCC
In patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma
Clinically significant adverse reactions of OPDIVO in combination with YERVOY were evaluated in the first-line treatment of
547 patients with aRCC enrolled in Checkmate 2141
Please see pages 12–32 for respective management of immune-mediated adverse reactions in patients treated with
OPDIVO + YERVOY
Frequency and onset of immune-mediated adverse reactions1
OPDIVO 3 mg/kg with YERVOY 1 mg/kg q3w followed by OPDIVO as a single agent (n=547)
Median time to onset (months)
Incidence
all grades
n (%) Combo OPDIVO monotherapy
Pneumonitis* 24 (4.4) 2.6 range: 8 days to 9.2 months
Diarrhea/colitis 52 (10) 1.7 range: 2 days to 19.2 months
Hepatitis 38 (7) 2.0 range:
14 days to 26.8 months
Endocrinopathies
Hypophysitis 25 (4.6) 2.8 range: 1.3 to 7.3
Adrenal insufficiency 41 (7) 3.4 range: 2.0 to 22.3
Hypothyroidism/thyroiditis 119 (22) 2.2 range: 1 day to 21.4 months
Hyperthyroidism 66 (12) 1.4 range: 6.0 days to 14.2 months
Type 1 diabetes mellitus 15 (2.7) 3.2 range: 19 days to 16.8 months
Nephritis, renal dysfunction 25 (4.6) 2.5 range: 1 day to 13.2 months
Skin† 91 (16.6) 1.5 range: 1 day to 20.9 months
Encephalitis 1 (0.2) 4.0
Time (months) 0 3 6 9 12 15 18 21 24 27 30
*F atal cases have been reported.1 †OPDIVO can cause skin immune-mediated adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN);
some cases with fatal outcome.1
aRCC=advanced renal cell carcinoma; q3w=every 3 weeks.
Frequency and onset of infusion reactions/hypersensitivity1
Infusion-related reactions occurred in 5.1% (28/547) of patients. Median time to onset not available
Other immune-mediated adverse reactions1
OPDIVO can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Across clinical trials of
OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions,
some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome
Please see Important Safety Information for OPDIVO and OPDIVO + YERVOY on pages 33–37 and US Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. 10
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
1506US1704575-02-01_IMAR_Guide_Redesign_Digital_172012169_v3.indd 10 5/8/18 10:33 AM