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Contact us at 1-855-OPDIVO-1

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Full Indication

In the 1L treatment of patients with intermediate or poor risk advanced renal cell carcinoma1,2

A CHANCE TO GO 4 FOR 4 WITH OPDIVO® (nivolumab)
+ YERVOY®
(ipilimumab)3*

The only I-O combination with durable survival
and durable response data at 4 years1,3*

4 years of extended follow-up data.3

*Based on results from an extended follow-up
analysis at a minimum of 48 months.3

In a phase 3 trial.3

4 years of extended follow-up data.3

Checkmate 214 Primary and Follow-Up Analyses

Scroll to see additional information, including extended follow-up data below

In the primary analysis of Checkmate 214 (median follow-up time of 25.2 months):

  • Median OS not yet reached (95% CI: 28.2–NE) for OPDIVO + YERVOY vs 25.9 months (95% CI: 22.1–NE) for sunitinib; HR=0.63 (99.8% CI: 0.44–0.89); P<0.00011,4
  • Confirmed ORR: 41.6% (n=177/425) (95% CI: 36.9–46.5) for OPDIVO + YERVOY vs 26.5% (n=112/422) (95% CI: 22.4–31.0) for sunitinib (P<0.0001)1,4
    • CR: 9.4% (n=40) for OPDIVO + YERVOY vs 1.2% (n=5) for sunitinib1,4
    • PR: 32.2% (n=137) for OPDIVO + YERVOY vs 25.4% (n=107) for sunitinib1,4
    • Among responders, median DOR was not evaluable (NE) (95% CI: 21.8–NE) for OPDIVO + YERVOY vs 18.2 months (95% CI: 14.8–NE) for sunitinib1,4
  • Median PFS: 11.6 months (95% CI: 8.7–15.5) for OPDIVO + YERVOY vs 8.4 months (95% CI: 7.0–10.8) for sunitinib; HR=0.82 (99.1% CI: 0.64–1.05)1,4
    • Per pre-specified analysis, progression-free survival did not meet statistical significance1,4

In the extended analysis of Checkmate 214 (minimum follow-up time of 48 months):

  • mOS:
    • The 48-month OS rate for OPDIVO + YERVOY was 50.0% vs 35.8% for sunitinib. OPDIVO + YERVOY: 48.1 months (95% CI: 35.6–NE)3
    • Sunitinib: 26.6 months (95% CI: 22.1–33.5)3
    • HR=0.65 (95% CI: 0.54–0.78)3
  • ORR:
    • OPDIVO + YERVOY: ORR: 41.9% (n=178/425 [95% CI: 37–47]; CR: 10.4% [n=44/425]; PR: 31.5% [n=134/425])3
    • Sunitinib: ORR: 26.8% (n=113/422 [95% CI: 23–31]; CR: 1.4% [n=6/422]; PR: 25.4% [n=107/422]3
  • mDOR:
    • Among responders, median DOR was not yet reached (95% CI: 45.8–NE) for OPDIVO + YERVOY vs 19.7 months (95% CI: 15.4–25.0) for sunitinib3
    • HR=0.45 (95% CI: 0.31–0.65)3

PFS and ORR were assessed by an independent radiographic review committee per RECIST v1.1.1,4

Scroll to see additional information,
including extended follow-up data below

Select Important Safety Information

Serious Adverse Reactions

  • In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis.  

Common Adverse Reactions

  • In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%).

Please see additional Important Safety Information below and U.S. Full Prescribing Information for OPDIVO and YERVOY.


Click or tap the tabs to view
additional data.
expand allclose all
 
 

Baseline Characteristics

Checkmate 214 baseline characteristics1,4,5 IMDC intermediate or poor risk patients.

CharacteristicOPDIVO + YERVOY
(n=425)
Sunitinib
(n=422)

Median age, years4,5

≥65 years, %
≥75 years, %

62
38
8
61
39
7

Male, %4

7471

IMDC prognostic score, %4

Intermediate (1–2)
Poor (3–6)

79
21
79
21

No. of sites with ≥1 target/non-target lesion, %4

1
≥2

21
79
20
80

Quantifiable tumor PD-L1 expression, %4

<1%
≥1%

(n=384)
74
26
(n=392)
71
29

Most common site of metastasis, %4

Lung
Lymph node
Bone
Liver

69
45
22
21
70
51
23
21
CharacteristicOPDIVO + YERVOY
(n=425)
Sunitinib
(n=422)

Median age, years4,5

≥65 years, %
≥75 years, %

62
38
8
61
39
7

Male, %4

7471

IMDC prognostic score, %4

Intermediate (1–2)
Poor (3–6)

79
21
79
21

No. of sites with ≥1 target/
non-target lesion, %4

1
≥2

21
79
20
80

Quantifiable tumor PD-L1 expression, %4

<1%
≥1%

(n=384)
74
26
(n=392)
71
29

Most common site of metastasis, %4

Lung
Lymph node
Bone
Liver

69
45
22
21
70
51
23
21
An overview of the Checkmate 214 patient baseline characteristics, a phase 3 study for IMDC intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus IMDC intermediate or poor risk patients taking sunitinib An overview of the Checkmate 214 patient baseline characteristics, a phase 3 study for IMDC intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus IMDC intermediate or poor risk patients taking sunitinib

§Of evaluable patients (n=284/384).4

Approximately 75%-80% of
1L aRCC patients qualify as
intermediate or poor risk4,6-8||

||Based on large, retrospective, population-based studies.6-8

 

IMDC Risk Factors

Up to 80% of 1L aRCC patients qualify as intermediate or poor risk4,6-8||

Intermediate or poor risk patients have ≥1 prognostic risk factor per the IMDC criteria4,6

Risk factors from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Risk factors from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)

||Based on large, retrospective, population-based studies.6-8

Extended Follow-Up Data
 

Overall Survival

In an extended follow-up analysis at a minimum of 48 months in 1L intermediate/poor risk aRCC patients

OPDIVO + YERVOY: The only I-O combination with 50% of patients alive at 4 years

Checkmate 214: Overall survival in intermediate or poor risk patients1,3,4,9#

Kaplan-Meier Curve of overall survival in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib Kaplan-Meier Curve of overall survival in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib

The 48-month overall survival rate analyses was not pre-specified within the study protocol.10 In the primary analysis, the pre-specified 12-month overall survival rate was 80% (95% CI: 76–84) with OPDIVO + YERVOY vs 72% (95% CI: 67–76) with sunitinib. The median follow-up time was 25.2 months.4,10

mOS at primary analysis (median follow-up time of 25.2 months)1,4

  • OPDIVO + YERVOY: Not yet reached (95% CI: 28.2–NE)1,4
  • Sunitinib: 25.9 months (95% CI: 22.1–NE)1,4
  • HR=0.63 (99.8% CI: 0.44–0.89); P<0.00011,4

mOS at extended follow-up (minimum follow-up time of 48 months)3

  • OPDIVO + YERVOY: 48.1 months (95% CI: 35.6–NE)3
  • Sunitinib: 26.6 months (95% CI: 22.1–33.5)3
  • HR=0.65 (95% CI: 0.54–0.78)3

In a phase 3 trial.3,4

#Performance status is based on IMDC prognostic score (0=favorable, 1-2=intermediate, 3+=poor).4

 

Progression-Free Survival

In an extended follow-up analysis at 48 months in 1L intermediate/poor risk aRCC patients

Progression-free survival data at 4 years3**

Checkmate 214:
Progression-free survival data in intermediate or poor risk patients1,3,4,9

Kaplan-Meier Curve of progression free survival in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib Kaplan-Meier Curve of progression free survival in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib

mPFS** at primary analysis (median follow-up time of 25.2 months)1,4

  • OPDIVO + YERVOY: 11.6 months (95% CI: 8.7–15.5)1,4
  • Sunitinib: 8.4 months (95% CI: 7.0–10.8)1,4
  • HR=0.82 (99.1% CI: 0.64–1.05)1,4
  • Per a pre-specified analysis, PFS did not meet statistical significance1,4

mPFS** at extended follow-up (minimum follow-up time of 48 months)3

  • OPDIVO + YERVOY: 11.2 months (95% CI: 8.4–16.1)3
  • Sunitinib: 8.3 months (95% CI: 7.0–10.8)3
  • HR=0.74 (95% CI: 0.62–0.88)3

**In both the primary analysis and the extended follow-up analysis, PFS was assessed by an independent radiographic review committee per RECIST v1.1.1,3,4,9

 

Overall Response Rate
(DOR, CR)

In an extended follow-up analysis at 48 months in 1L intermediate/poor risk aRCC patients

With OPDIVO + YERVOY, there was ~60% chance for responses to last 4 years3,11

Checkmate 214: Median duration of response in intermediate or poor risk patients1,3,4,11

Kaplan-Meier Curve of duration of response in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib Kaplan-Meier Curve of duration of response in intermediate or poor risk advanced renal cell carcinoma patients taking OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus patients taking sunitinib

ORR†† at primary analysis (median follow-up time of 25.2 months)1,4

  • OPDIVO + YERVOY: ORR: 41.6% (n=177/425) (95% CI: 36.9–46.5%); CR: 9.4% (n=40); PR: 32.2% (n=137)1,4
  • Sunitinib: ORR: 26.5% (n=112/422) (95% CI: 22.4–31.0); CR: 1.2% (n=5); PR=25.4% (n=107)1,4
  • P<0.0001 for ORR1

mDOR at primary analysis (minimum follow-up time of 25.2 months)1,4

  • Not yet reached (95% CI: 21.8–NE) for OPDIVO + YERVOY vs 18.2 months (95% CI: 14.8–NE) for sunitinib1,4

ORR†† at extended follow-up analysis (minimum follow-up time of 48 months)3

  • OPDIVO + YERVOY: ORR: 41.9% (n=178/425 [95% CI: 37–47]; CR: 10.4% [n=44/425]; PR: 31.5% [n=134/425])3
  • Sunitinib: ORR: 26.8% (n=113/422 [95% CI: 23–31]; CR: 1.4% [n=6/422]; PR: 25.4% [n=107/422]3

mDOR†† at extended follow-up analysis (minimum follow-up time of 48 months)3

  • Not yet reached (95% CI: 45.8–NE) for OPDIVO + YERVOY vs 19.7 months (95% CI: 15.4–25.0) for sunitinib3
  • HR=0.45 (95% CI: 0.31–0.65)3

In an extended follow-up analysis at a minimum of 48 months in 1L intermediate/poor risk aRCC patients

~86% of complete responses to OPDIVO + YERVOY were ongoing at 4 years3,12

Ongoing complete responses for the phase 3 Checkmate 214 trial of first-line OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus sunitinib in patients with intermediate or poor risk advanced renal cell carcinoma Ongoing complete responses for the phase 3 Checkmate 214 trial of first-line OPDIVO® (nivolumab) + YERVOY® (ipilimumab) versus sunitinib in patients with intermediate or poor risk advanced renal cell carcinoma

ORR†† at primary analysis (median follow-up time of 25.2 months)1,4

  • OPDIVO + YERVOY: ORR: 41.6% (n=177/425 [95% CI: 36.9–46.5]; CR: 9.4% [n=40]; PR: 32.2% [n=137])1,4
  • Sunitinib: ORR: 26.5% (n=112/422 (95% CI: 22.4–31.0); CR: 1.2% [n=5]; PR: 25.4% [n=107])1,4
  • P<0.0001 for ORR1

ORR‡‡ at extended follow-up analysis (minimum follow-up time of 48 months)3

  • OPDIVO + YERVOY: ORR: 41.9% (n=178/425) (95% CI: 34–47); CR: 10.4% (n=44/425); PR: 31.5% (n=134/425)3
  • Sunitinib: ORR: 26.8% (n=113/422) (95% CI: 23–31); CR: 1.4% (n=6/422); PR: 25.4% (n=107/422)3

††At both the primary analysis and the extended follow-up analysis, ORR was assessed by an independent radiographic review committee per RECIST v1.1.1,3,4

SELECT Safety Information
 

Selected Safety Profile

Checkmate 214: Selected safety profile1

Optimized dosing resulted in fewer overall Grade 3-4 adverse reactions in
the OPDIVO + YERVOY arm vs sunitinib (65% vs 76%)1

 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Adverse reactionsGrades 1-4Grades 3-4Grades 1-4Grades 3-4

Adverse reactions, %

All causes

99659976

General disorders and
administration site
conditions, %

Fatigue‡‡
Pyrexia
Edema§§

58
25
16
8
0.7
0.5
69
17
17
13
0.6
0.6

Respiratory, thoracic, and mediastinal disorders, %

Cough/productive cough Dyspnea/exertional dyspnea

28
20
0.2
2.4
25
21
0.4
2.1

Gastrointestinal disorders, %

Diarrhea
Nausea
Vomiting
Abdominal pain
Constipation

38
30
20
19
17
4.6
2.0
0.9
1.6
0.4
58
43
28
24
18
6
1.5
2.1
1.9
0

Skin and subcutaneous
tissue disorders, %

Rash||||
Pruritus/generalized pruritus

39
33
3.7
0.5
25
11
1.1
0

Endocrine disorders, %

Hypothyroidism

180.4270.2

Nervous system disorders, %

Headache

190.9230.9

Metabolism and
nutrition disorders, %

Decreased appetite

211.8290.9

Musculoskeletal and connective tissue disorder, %

Musculoskeletal pain¶¶ Arthralgia

37
23
4.0
1.3
40
16
2.6
0
 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Adverse
reactions
Grades
1-4
Grades
1-4

Adverse
reactions, %

All causes

9999

General
disorders and
administration
site
conditions, %

Fatigue‡‡
Pyrexia
Edema§§

58
25
16
69
17
17

Respiratory, thoracic, and mediastinal disorders, %

Cough/
productive
cough
Dyspnea/
exertional dyspnea

28


20
25


21

Gastrointestinal disorders, %

Diarrhea
Nausea
Vomiting
Abdominal pain
Constipation

38
30
20
19
17
58
43
28
24
18

Skin and subcutaneous tissue
disorders, %

Rash||||
Pruritus/
generalized pruritus

39


33
25


11

Endocrine disorders, %

Hypothyroidism

1827

Nervous
system
disorders, %

Headache

1923

Metabolism
and nutrition
disorders, %

Decreased appetite

2129

Musculo-
skeletal and connective tissue
disorder, %

Musculo-
skeletal pain¶¶ Arthralgia

37
23
40
16
 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Adverse
reactions
Grades
3-4
Grades
3-4

Adverse
reactions, %

All causes

6576

General
disorders and
administration
site
conditions, %

Fatigue‡‡
Pyrexia
Edema§§

8
0.7
0.5
13
0.6
0.6

Respiratory, thoracic, and mediastinal disorders, %

Cough/
productive
cough
Dyspnea/
exertional dyspnea

0.2


2.4
0.4


2.1

Gastrointestinal disorders, %

Diarrhea
Nausea
Vomiting
Abdominal pain
Constipation

4.6
2.0
0.9
1.6
0.4
6
1.5
2.1
1.9
0

Skin and subcutaneous tissue
disorders, %

Rash||||
Pruritus/
generalized pruritus

3.7


0.5
1.1


0

Endocrine disorders, %

Hypothyroidism

0.40.2

Nervous
system
disorders, %

Headache

0.90.9

Metabolism
and nutrition
disorders, %

Decreased appetite

1.80.9

Musculo-
skeletal and connective tissue
disorder, %

Musculo-
skeletal pain¶¶ Arthralgia

4.0
1.3
2.6
0
  • In the 48-month follow-up analysis, all-cause adverse events occurring in >15% of patients receiving OPDIVO + YERVOY and not previously included in the primary analysis include: upper respiratory tract infection (OPDIVO + YERVOY: 21.4% Grades 1-4, 0.4% Grades 3-4; sunitinib: 14.8% Grades 1-4)1,13

Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.

‡‡Includes asthenia.

§§Includes peripheral edema, peripheral swelling.

||||Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative,
erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.

¶¶Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity,
spinal pain.

Checkmate 214: Grade 1-4 laboratory abnormalities that occurred
in >15% of patients on OPDIVO + YERVOY1

Percentage of patients with worsening laboratory test from baseline##

 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Laboratory abnormalitiesGrades 1-4Grades 3-4Grades 1-4Grades 3-4

Hematology

Anemia
Lymphopenia

43
36
3
5
64
63
9
14

Chemistry

Increased lipase
Increased creatinine
Increased ALT
Increased AST
Increased amylase
Hyponatremia
Increased alkaline phosphatase
Hyperkalemia
Hypocalcemia
Hypomagnesemia

48
42
41
40
39
39
29
29
21
16
20
2.1
7
4.8
12
10
2
2.4
0.4
0.4
51
46
44
60
33
36
32
28
35
26
20
1.7
2.7
2.1
7
7
1
2.9
0.6
1.6
 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Laboratory abnormalitiesGrades
1-4
Grades
1-4

Hematology

Anemia
Lymphopenia

43
36
64
63

Chemistry

Increased lipase
Increased creatinine
Increased ALT
Increased AST
Increased amylase
Hyponatremia
Increased
alkaline
phosphatase
Hyperkalemia
Hypocalcemia
Hypo-
magnesemia

48

42
41
40

39
39


29
29
21

16
51

46
44
60

33
36


32
28
35

26
 OPDIVO + YERVOY
(n=547)
Sunitinib
(n=535)
Laboratory abnormalitiesGrades
3-4
Grades
3-4

Hematology

Anemia
Lymphopenia

3
5
9
14

Chemistry

Increased lipase
Increased creatinine
Increased ALT
Increased AST
Increased amylase
Hyponatremia
Increased
alkaline
phosphatase
Hyperkalemia
Hypocalcemia
Hypo-
magnesemia

20

2.1
7
4.8

12
10


2
2.4
0.4

0.4
20

1.7
2.7
2.1

7
7


1
2.9
0.6

1.6

##Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: OPDIVO + YERVOY group (range: 490–538 patients) and sunitinib group (range: 485–523 patients).1

In addition, among patients with TSH less than or equal to the ULN at baseline, a lower proportion of patients experienced
a treatment-emergent elevation of TSH greater than the ULN in the OPDIVO + YERVOY group compared to the sunitinib
group (31% and 61%, respectively).1

  • A lower incidence of overall Grade 3-4 adverse reactions occurred with OPDIVO + YERVOY vs
    sunitinib (65% and 76%, respectively)1
  • Treatment discontinuation rate due to adverse reactions was 31% with OPDIVO + YERVOY vs 21%
    with sunitinib1,14
  • Dose interruption due to adverse reactions occurred in 54% of patients receiving OPDIVO +
    YERVOY and 43% receiving sunitinib1,15
    • In the sunitinib group, 53% of patients required a dose reduction; dose reductions were not
      permitted in the OPDIVO + YERVOY treatment group16
  • Serious adverse reactions occurred in 59% of patients receiving OPDIVO + YERVOY and in 43% of
    patients receiving sunitinib1,17
    • The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO +
      YERVOY were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury,
      dyspnea, adrenal insufficiency, and colitis; for sunitinib, they were pneumonia, pleural effusion,
      and dyspnea1
  • The most common adverse reactions (reported in at least 20% of OPDIVO + YERVOY-treated
    patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia,
    arthralgia, decreased appetite, dyspnea, and vomiting1
 

IMAR Safety Management Resources

The OPDIVO Safety Tool is a quick reference to the immune-mediated adverse reactions (IMARs) associated with OPDIVO treatment. You may access this web app from your phone, tablet, or computer.

Resources

1L=first-line; ALT=alanine aminotransferase; aRCC=advanced renal cell carcinoma; AST=aspartate aminotransferase;
CI=confidence interval; CR=complete response; DOR=duration of response; HR=hazard ratio; IMDC=International Metastatic
Renal Cell Carcinoma Database Consortium; I-O=immuno-oncology; IV=intravenous; LLN=lower limit of normal;
mDOR=median duration of response; NE=not evaluable; No.=number; ORR=overall response rate; OS=overall survival;
PD-L1=programmed death-ligand 1; PFS=progression-free survival; PR=partial response; PS=performance score;
RCC=renal cell carcinoma; RECIST=Response Evaluation Criteria In Solid Tumors; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.

More Important Safety Information Collapse

Important Safety
Information

Important Safety Information

Severe and Fatal Immune-Mediated Adverse Reactions

  • Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.
  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
  • Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

  • OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).

Immune-Mediated Colitis

  • OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

Immune-Mediated Hepatitis and Hepatotoxicity

  • OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO 3 mg/kg with YERVOY
    1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies

  • OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%).  
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%), and Grade 2 (4.5%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis with Renal Dysfunction

  • OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

  • OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
  • YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.
  • Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
  • In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.
  • Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

  • OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. 

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

  • Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

  • Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

  • In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

  • There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

  • In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. 

Common Adverse Reactions

  • In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). 

OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous (IV) use.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY.

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company 2021.
  2. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company 2020.
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  4. Motzer RJ, Tannir NM, McDermott DF, et al; for CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
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  9. Data on file. NIVO 54859. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
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  13. Data on file. NIVO 593. Princeton, NJ:
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  15. Data on file. NIVO 463. Princeton, NJ:
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  16. Data on file. NIVO 369. Princeton, NJ:
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