Immune-Mediated Adverse Reactions Management Guide

Transcription

1 Immune-Mediated Adverse Reactions Management Guide Please see Important Safety Information for OPDIVO on pages and US Full Prescribing Information for OPDIVO. Please refer to the end of the Important

2 OPDIVO is approved in 9 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 metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. 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 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 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 immunemediated reactions. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 2

3 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 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, as a single agent, 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. 1 OPDIVO, in combination with YERVOY, is indicated for the treatment of adults and pediatric patients 12 years and older with MSI-H or dmmr metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. 1 These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications 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 3

4 Considerations when managing immune-mediated adverse reactions 1,3-10 Early recognition of potential IMARs Close monitoring of signs/symptoms Use of corticosteroids, withholding, or discontinuing therapy While some side effects of immunotherapy may appear similar to chemotherapy, they may need to be managed differently HSCT=hematopoietic stem cell transplantation; 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 additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 4

5 Organ systems potentially impacted by immune-mediated adverse reactions 1 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. 5

6 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 agent 1 OPDIVO can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials 1 Please see pages for respective management of immune-mediated adverse reactions in patients treated with OPDIVO Incidence and onset of immune-mediated adverse reactions 1 Incidence all grades n Pneumonitis* 61 (3.1) 3.5 OPDIVO as a single agent (N=1994) Median time to onset (months) 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 Adrenal insufficiency Hypothyroidism/thyroiditis Hyperthyroidism Type 1 diabetes mellitus 12 (0.6) 20 (1) 171 (9) 54 (2.7) 17 (0.9) range: 1.4 to 11 months range: 15 days to 21 months range: 1 day to 16.6 months range: 1 day to 14.2 months range: 15 days to 22 months Nephritis, renal dysfunction 23 (1.2) 4.6 range: 23 days to 12.3 months Skin 171 (9) 2.8 range: <1 day to 25.8 months Encephalitis 3 (0.2) Time (months) *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. Incidence and onset of infusion reactions/hypersensitivity 1 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 reactions 1 OPDIVO can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY (ipilimumab), 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 and US Full Prescribing Information for OPDIVO. Please refer to the end of the Important 6

7 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 agent 1 N=1994 Permanently discontinued OPDIVO Withheld OPDIVO Corticosteroid use Median duration (range) Pneumonitis (n=61) ~89 26 days (1 day to 6 months) Colitis (n=58) ~91 23 days (1 day to 9.3 months) Hepatitis (n=35) days (1 day to 2 months) Endocrinopathies Hypophysitis (n=12) days (5 days to 26 days) Adrenal insufficiency (n=20) Hypothyroidism/ thyroiditis (n=171) Hyperthyroidism (n=54) Type 1 diabetes mellitus (n=17) Nephritis, renal dysfunction (n=23) days (1 day to 1 month) 4 9 Other treatments Resolution* Recurrence after re-initiation of OPDIVO 67 ~8 4 patients received infliximab in addition to high-dose CS 2 patients received mycophenolic acid in addition to high-dose CS 74 ~16 74 ~29 ~67% received HRT ~85% received HRT ~79% received levothyroxine ~26% received methimazole; 9% received carbimazole; 4% received propylthiouracil days (1 day to 15.4 months) Skin (n=171) ~16 12 days (1 day to 8.9 months) % received 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 and US Full Prescribing Information for OPDIVO. Please refer to the end of the Important 7

8 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 trials 1 Please see pages for respective management of immune-mediated adverse reactions in patients treated with OPDIVO + YERVOY Incidence and onset of immune-mediated adverse reactions 1 OPDIVO 1 mg/kg with YERVOY 3 mg/kg q3w followed by OPDIVO as a single agent (N=407) All grades n Induction Median time to onset (months) OPDIVO maintenance 3 mg/kg q2w* Pneumonitis 25 (6) 1.6 range: 24 days to 10.1 months Colitis 107 (26) 1.6 range: 3 days 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, renal dysfunction 9 (2.2) 2.7 range: 9 days to 7.9 months Skin 92 (22.6) 0.6 range: 1 day to 9.7 months Encephalitis 1 (0.2) Time (months) *After completing 4 doses of the combination, the recommended dose of OPDIVO in the single-agent phase is either 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. Encephalitis occurred in 1 patient receiving OPDIVO + YERVOY (0.2%) after 1.7 months of exposure. 1 mmelanoma=metastatic melanoma; q2w=every 2 weeks; q3w=every 3 weeks. Incidence and onset of infusion reactions/hypersensitivity 1 Hypersensitivity/infusion reactions occurred in 10 (2.5%) patients Other immune-mediated adverse reactions 1 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 8

9 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 trials 1 N=407 Permanently discontinued OPDIVO with YERVOY Withheld OPDIVO with YERVOY Corticosteroid use Median duration (range) Pneumonitis (n=25) ~84 30 days (5 days to 11.8 months) Colitis (n=107) 16 7 ~ months (1 day to 12 months) Hepatitis (n=51) 6 5 ~ months (1 day to 13.2 months) Other treatments Resolution * Recurrence after re-initiation of OPDIVO with YERVOY 68 ~13 ~23% received infliximab in addition to high-dose CS 75 ~28 75 ~11 Endocrinopathies Hypophysitis (n=36) days (1 day to 2.0 months) ~75% received HRT Adrenal insufficiency (n=21) days (1 day to 2.7 months) ~57% received HRT Hypothyroidism/ thyroiditis (n=89) ~73% received levothyroxine 45 Hyperthyroidism (n=34) ~29% received methimazole ; ~24% received carbimazole 94 Type 1 diabetes mellitus (n=6) 1 patient 1 patient Nephritis, renal dysfunction (n=9) ~ days (1 day to 1.1 months) II Skin (n=92) ~17 14 days (2 days to 4.7 months) 47 ~6 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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1 Includes 3 fatal cases. 1 II Two 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. 9

10 Summary of immune-mediated adverse reactions with OPDIVO + YERVOY in patients with 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 Please see pages for respective management of immune-mediated adverse reactions in patients treated with OPDIVO + YERVOY Incidence and onset of immune-mediated adverse reactions 1,12 OPDIVO 3 mg/kg with YERVOY 1 mg/kg q3w followed by OPDIVO as a single agent (N=547) Incidence all grades n Induction Median time to onset (months) OPDIVO maintenance 3 mg/kg q2w* 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 Endocrinopathies Hypophysitis 25 (4.6) 2.8 range: 1.3 to 7.3 months Adrenal insufficiency 41 (7) 3.4 range: 14 days to 26.8 months range: 2.0 to 22.3 months 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 90 (16) 1.5 range: 1 day to 20.9 months Encephalitis 1 (0.2) Time (months) *After completing 4 doses of the combination, the recommended dose of OPDIVO in the single-agent phase is either 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. 1 Fatal 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; q2w=every 2 weeks; q3w=every 3 weeks. Incidence and onset of infusion reactions/hypersensitivity 1,12 Infusion-related reactions occurred in 5.1% (28/547) of patients. Median time to onset not available Other immune-mediated adverse reactions 1 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 10

11 Summary of immune-mediated adverse reactions management and outcomes 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 (OPDIVO 3 mg/kg followed by YERVOY 1 mg/kg on the same day every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks) were evaluated in the first-line treatment of 547 patients with arcc enrolled in Checkmate 214 1,11-15 N=547 Permanently discontinued OPDIVO with YERVOY Withheld OPDIVO with YERVOY Corticosteroid use Median duration (range) Pneumonitis (n=24) ~92 19 days (4 days to 3.2 months) Colitis (n=52) ~83 21 days (1 day to 27 months) Other treatments ~8% of patients received infliximab in addition to high-dose CS ~23% of patients received infliximab in addition to high-dose CS Resolution* Recurrence after re-initiation of OPDIVO with YERVOY patients Hepatitis (n=38) ~92 1 month (1 day to 4 months) Endocrinopathies ~16% received mycophenolic acid 87 0 Hypophysitis (n=25) days (1 day to 1.6 months) 72% received HRT 60 Adrenal insufficiency (n=41) days (2 days to 5.6 months) ~93% received HRT 24 Hypothyroidism/ thyroiditis (n=119) ~9 22 days (12 days to 2.1 months) ~81% received levothyroxine; ~10% received HRT Hyperthyroidism (n=66) ~18 15 days (1 day to 1.5 months) ~23% received HRT Type 1 diabetes mellitus (n=15) ~7% received HRT 27 Nephritis, renal dysfunction (n=25) ~76 15 days (1 day to 5.9 months) 64 1 patient Skin (n=91) ~19 25 days (1 day to 23.1 months) 64 Encephalitis (n=1) * Resolution was defined in the context of the IMAE time-to-resolution analyses; the 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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1 arcc=advanced renal cell carcinoma; CS=corticosteroid; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event. 11

12 Summary of immune-mediated adverse reactions with OPDIVO + YERVOY in patients with MSI-H/dMMR mcrc In adult and pediatric patients 12 years and older with MSI-H/dMMR metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan Clinically significant adverse reactions of OPDIVO in combination with YERVOY were evaluated in 119 patients with MSI-H or dmmr mcrc enrolled in Checkmate Please see pages for respective management of immune-mediated adverse reactions in patients treated with OPDIVO + YERVOY Incidence and onset of immune-mediated adverse reactions 1,16 OPDIVO 3 mg/kg with YERVOY 1 mg/kg q3w followed by OPDIVO as a single agent (N=119) Incidence all grades n Induction Median time to onset (months) OPDIVO maintenance 3 mg/kg q2w* Pneumonitis 2 (1.7) 1.9 range: 27 days to 3 months Colitis 8 (6.7) 2.4 range: 22 days to 5.2 months Hepatitis 10 (8.4) 2.2 range: 22 days to 10.5 months Endocrinopathies Hypophysitis 4 (3.4) 3.7 range: 2.8 to 5.5 months Adrenal insufficiency 7 (5.9) 3.7 range: 2.5 to 13.4 months Hypothyroidism/thyroiditis 18 (15.1) 2.3 range: 22 days to 9.8 months Hyperthyroidism 14 (11.8) 1.1 range: 21 days to 5.4 months Type 1 diabetes mellitus Nephritis, renal dysfunction 2 (1.7) 3.6 range: 1.6 to 5.5 months Skin 17 (14.3) 0.9 range: 5 days to 9.8 months Encephalitis ll 1 (0.8) Time (months) * After completing 4 doses of the combination, the recommended dose of OPDIVO in the single-agent phase is 240 mg every 2 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. Time to onset for one patient was 27 days and for the other 3 months. 16 Time to onset for one patient was 1.6 months and for the other 5.5 months. 16 OPDIVO can cause skin immune-mediated adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. ll Time to onset for the one patient was after 15 days of exposure. dmmr=mismatch repair deficient; mcrc=metastatic colorectal cancer; MSI-H=microsatellite instability-high; q2w=every 2 weeks; q3w=every 3 weeks. Incidence and onset of infusion reactions/hypersensitivity 1,16 Hypersensitivity/infusion reaction events occurred in 5 (4.2%) patients, of which 3 (2.5%) required treatment with immune-modulating medication. Median time to onset was 2.1 months (range: 22 days to 12.2 months) Other immune-mediated adverse reactions 1 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 12

13 Summary of immune-mediated adverse reactions management and outcomes with OPDIVO + YERVOY in MSI-H/dMMR mcrc In adult and pediatric patients 12 years and older with MSI-H/dMMR metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan Clinically significant adverse reactions of OPDIVO in combination with YERVOY (OPDIVO 3 mg/kg followed by YERVOY 1 mg/kg on the same day every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks) were evaluated in 119 patients with previously treated mcrc enrolled in Checkmate 142 1,16,17 N=119 Permanently discontinued OPDIVO with YERVOY Withheld OPDIVO with YERVOY Corticosteroid use Median duration (range) Other treatments Resolution* Recurrence after re-initiation of OPDIVO with YERVOY Pneumonitis (n=2) 1 patient months (12 days to 2.8 months) 100% received HRT patient Colitis (n=8) ~63 22 days (14 days to 1.4 months) Hepatitis (n=10) months (11 days to 7.5 months) Endocrinopathies 25% of patients received infliximab in addition to high-dose CS 30% of patients received mycophenolic acid in addition to high-dose CS Hypophysitis (n=4) 1 patient days in 1 patient 75% received HRT 50 0 Adrenal insufficiency (n=7) Hypothyroidism/ thyroiditis (n=18) Hyperthyroidism (n=14) Type 1 diabetes mellitus (n=0) Nephritis, renal dysfunction (n=2) 1 patient days (2 days to 16 days) % received HRT % received levothyroxine; ~6% received HRT days in 1 patient ~7% received HRT months (1 month to 2.4 months) Skin (n=17) 0 1 patient days (11 days to 23 days) Encephalitis (n=1) patient received infliximab in addition to high-dose CS * Resolution was 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 At least 40 mg prednisone equivalents per day. 1,16 Complete resolution following CS use. 16 CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; MSI-H=microsatellite instability-high. 13

14 Signs, symptoms, and management of immune-mediated adverse reactions This section contains guidance for the management of select immune-mediated adverse reactions, which includes adverse reaction management algorithms from the clinical trials of OPDIVO and OPDIVO + YERVOY. 1,18 For ease of use, this guidance is organized by body system and contains both management and follow-up information. A general principle is that differential diagnoses should be diligently evaluated according to standard medical practice. n-inflammatory etiologies should be considered and appropriately treated 18 Corticosteroids are a primary treatment for immunotherapy-related adverse events. The oral equivalent of the recommended intravenous doses may be considered for ambulatory patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids 18 Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is recommended 18 The frequency and severity of the related adverse events covered by these algorithms will depend on the immunotherapeutic agent or regimen being used 18 14

15 Immune-mediated pneumonitis 1 OPDIVO can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology Fatal cases have been reported Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 OPDIVO as a single agent (n=61) mmelanoma (n=25) Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) ~89 26 days (1 day to 6 months) ~84 30 days (5 days to 11.8 months) Other treatments Resolution* Recurrence after re-initiation of treatment 67 ~8 68 ~13 arcc (n=24) ~92 19 days (4 days to 3.2 months) ~8% of patients received infliximab in addition to high-dose CS 79 0 MSI-H/dMMR mcrc (n=2) 1 patient months (12 days to 2.8 months) 100% received HRT patient *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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS taper. 1 Complete resolution following CS use. 1,12,16 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. Signs and symptoms may include 1 Radiographic changes New or worsening cough Chest pain Shortness of breath 15

16 Management of immune-mediated pulmonary adverse reactions Immune-mediated pulmonary adverse reactions 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Grade 1* (Radiographic changes only) Grade 2* (Mild to moderate new symptoms) Grade 3 4* (Severe new symptoms; new/worsening hypoxia; life-threatening) Monitoring Every 2 to 3 days Daily Hospitalize Treatment with OPDIVO or OPDIVO + YERVOY Consult Continue treatment Withhold dose Permanently discontinue Consider pulmonary and infectious disease Pulmonary and infectious disease Pulmonary and infectious disease Steroids 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 6 weeks Pulmonary tests Consider bronchoscopy, lung biopsy Consider bronchoscopy, lung biopsy Follow-up 1,18 Re-image at least every 3 weeks If worsens Treat as Grade 2 or 3 4 Re-image every 1 3 days If improved to baseline Taper steroids over at least 1 month before resuming treatment II If not improving after 2 weeks or worsening Treat as Grade 3 4 If improved to baseline Taper steroids over at least 6 weeks If persists or worsens after 2 days Add non-corticosteroid immunosuppressive medication *Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at the start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Add prophylactic antibiotics for opportunistic infections. 18 II Consider adding prophylactic antibiotics. 18 IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. 16

17 Immune-mediated colitis 1 OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology Monitor patients for signs and symptoms of colitis Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) Other treatments Resolution* Recurrence after re-initiation of treatment OPDIVO as a single agent (n=58) ~91 23 days (1 day to 9.3 months) 4 patients received infliximab in addition to high-dose CS 74 ~16 mmelanoma (n=107) 16 7 ~ months (1 day to 12 months) ~23% of patients received infliximab in addition to high-dose CS 75 ~28 arcc (n=52) ~83 21 days (1 day to 27 months) ~23% of patients received infliximab in addition to high-dose CS 89 2 patients MSI-H/dMMR mcrc (n=8) ~63 22 days (14 days to 1.4 months) 25% of patients received infliximab in addition to high-dose CS 88 0 *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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1,12,16 Includes 3 fatal cases. 1 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. Signs and symptoms may include 1 Diarrhea (loose stools) or more bowel movements than usual Blood in stools or dark, tarry, sticky stools Severe stomach-area (abdomen) pain or tenderness 17

18 Management of immune-mediated gastrointestinal adverse reactions Immune-mediated gastrointestinal adverse reactions 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Grade 1* (Diarrhea: <4 stools per day over baseline; colitis: asymptomatic) Grade 2* (Diarrhea: 4 6 stools per day over baseline; IV fluids indicated <24 hours; not interfering with ADL; colitis: abdominal pain, mucus or blood in stool) Grade 3 4* (Diarrhea [G3]: 7 stools per day over baseline; incontinence; IV fluids 24 hours; interfering with ADL; colitis [G3]: severe abdominal pain, medical intervention indicated, peritoneal signs; [G4]: life-threatening, perforation) Treatment with OPDIVO Grade 3: withhold dose Continue treatment Withhold dose Grade 4: permanently discontinue Treatment with OPDIVO + YERVOY Continue treatment Withhold dose Permanently discontinue Symptomatic treatment Administer Administer Steroids For Grade 2 colitis of >5 days 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month 1 to 2 mg/kg/day prednisone equivalents II followed by corticosteroid taper over at least 1 month GI tests Consider lower-gi endoscopy Follow-up 1,18 Close monitoring for worsening symptoms Educate patient to report worsening immediately If symptoms worsen Treat as Grade 2 or 3 4 If improved to Grade 1 Resume treatment If steroids have been administered, taper steroids over at least 1 month before resuming treatment Permanently discontinue for recurrent colitis upon re-initiation of OPDIVO or OPDIVO + YERVOY If worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents If improved from Grade 3 while administering single-agent OPDIVO When at Grade 1, taper steroids over at least 1 month before resuming treatment Permanently discontinue for recurrent colitis upon re-initiation of OPDIVO or OPDIVO + YERVOY If symptoms persist >3 to 5 days or recur after improvement Add non-corticosteroid immunosuppressive medication * Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Consider prophylactic antibiotics for opportunistic infections. 18 Add prophylactic antibiotics for opportunistic infections. 18 ADL=activities of daily living; G3=Grade 3; G4=Grade 4; GI=gastrointestinal; IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of 7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 18

19 Immune-mediated hepatitis 1 OPDIVO can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology Monitor patients for abnormal liver tests prior to and periodically during treatment For patients with hepatocellular carcinoma in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) Other treatments Resolution* Recurrence after re-initiation of treatment OPDIVO as a single agent (n=35) days (1 day to 2 months) 2 patients received mycophenolic acid in addition to high-dose CS 74 ~29 mmelanoma (n=51) 6 5 ~ months (1 day to 13.2 months) 75 ~11 arcc (n=38) ~92 1 month (1 day to 4 months) ~16% received mycophenolic acid 87 0 MSI-H/dMMR mcrc (n=10) months (11 days to 7.5 months) 30% of patients received mycophenolic acid in addition to high-dose CS 70 0 *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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1,12,16 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. 19

20 Immune-mediated hepatitis 1 Signs and symptoms may include 1 Transaminase elevation Total bilirubin elevation Yellowing of the skin or the whites of the eyes Severe nausea or vomiting Pain on the right side of the stomach area (abdomen) Drowsiness Dark urine (tea colored) Bleeding or bruising more easily than normal Feeling less hungry than usual Decreased energy Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 20

21 Management of immune-mediated hepatic adverse reactions for patients with HCC 1 Management of immune-mediated hepatic adverse reactions for patients with HCC For patients with HCC, permanently discontinue, withhold, or continue OPDIVO based on severity of immune-mediated hepatitis and baseline AST and ALT levels as described below In addition, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper when OPDIVO is withheld or discontinued due to immune-mediated hepatitis For HCC patients: recommended dose modifications 1 Severity* If AST/ALT is within normal limits at baseline and increases to >3 5x the ULN If AST/ALT is >1 3x ULN at baseline and increases to >5 10x the ULN If AST/ALT is >3 5x ULN at baseline and increases to >8 10x the ULN If AST or ALT increases to >10x the ULN or total bilirubin increases to >3x the ULN Dose modification Withhold dose Permanently discontinue * Toxicity was graded per NCI CTCAE Version Resume treatment when AST/ALT returns to baseline. 1 ALT=alanine aminotransferase; AST=aspartate aminotransferase; HCC=hepatocellular carcinoma; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit of normal. For non-hcc patients, please see page 22 for management of immune-mediated hepatic adverse reactions. Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 21

22 Management of immune-mediated hepatic adverse reactions for non-hcc patients Immune-mediated hepatic adverse reactions 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Treatment with OPDIVO or OPDIVO + YERVOY Monitoring Grade 1* (AST/ALT >1 3x ULN and/or T. bili >1 1.5x ULN) Grade 2* (AST/ALT >3 5x ULN or T. bili >1.5 3x ULN) Grade 3 4* (AST/ALT >5x ULN or T. bili >3x ULN) Continue treatment Withhold dose Permanently discontinue Monitor LFTs prior to and periodically during treatment Increase frequency of monitoring to every 3 days Increase frequency of monitoring to every 1 to 2 days Consult Gastroenterology Steroids For moderate (Grade 2) transaminase elevations 0.5 to 1 mg/kg/day prednisone equivalents For severe (Grade 3) or life-threatening (Grade 4) transaminase elevations with or without concomitant T. bili elevations 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month Follow-up 1,18 Continue monitoring LFTs If symptoms worsen Treat as Grade 2 or 3 4 If improved to Grade 1 or baseline Resume treatment If steroids have been administered, taper steroids over at least 1 month before resuming treatment ll Resume routine LFT monitoring If AST/ALT >5x and/or T. bili >3x ULN Treat as Grade 3 4 If improved to Grade 2 Taper steroids over at least 1 month If no improvement in 3 5 days, worsens, or rebounds Add non-corticosteroid immunosuppressive medication * Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Add prophylactic antibiotics for opportunistic infections. 18 ll Consider prophylactic antibiotics for opportunistic infections and resume immunotherapy per protocol. 18 ALT=alanine aminotransferase; AST=aspartate aminotransferase; HCC=hepatocellular carcinoma; IV=intravenous; LFT=liver function test; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; T. bili=total bilirubin; ULN=upper limit of normal. For HCC patients, please see page 21 for management of immune-mediated hepatic adverse reactions. 22

23 Immune-mediated endocrinopathies 1 OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and type 1 diabetes mellitus Monitor patients for signs and symptoms of hypophysitis and adrenal insufficiency and for hyperglycemia Monitor thyroid function prior to and periodically during treatment Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 Hypophysitis OPDIVO as a single agent (n=12) mmelanoma (n=36) arcc (n=25) MSI-H/dMMR mcrc (n=4) Adrenal insufficiency OPDIVO as a single agent (n=20) mmelanoma (n=21) arcc (n=41) Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) 14 days (5 days to 26 days) 19 days (1 day to 2 months) 10 days (1 day to 1.6 months) Other treatments Resolution* Recurrence after re-initiation of treatment ~67% received HRT ~75% received HRT 72% received HRT 60 1 patient days in 1 patient 75% received HRT days (1 day to 1 month) 9 days (1 day to 2.7 months) 12 days (1 day to 5.6 months) MSI-H/dMMR mcrc 1 patient days (2 days to 16 days) (n=7) Hypothyroidism/thyroiditis OPDIVO as a single agent (n=171) 4 mmelanoma (n=89) arcc (n=119) MSI-H/dMMR mcrc (n=18) ~9 22 days (12 days to 2.1 months) ~85% received HRT ~57% received HRT ~93% received HRT % received HRT 57 0 ~79% received levothyroxine ~73% received levothyroxine ~81% received levothyroxine; ~10% received HRT 78% received levothyroxine; ~6% received HRT *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 At least 40 mg prednisone equivalents per day. 1 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. 23

24 Immune-mediated endocrinopathies 1 Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 Hyperthyroidism OPDIVO as a single agent (n=54) mmelanoma (n=34) arcc (n=66) MSI-H/dMMR mcrc (n=14) Type 1 diabetes mellitus OPDIVO as a single agent (n=17) mmelanoma (n=6) arcc (n=15) MSI-H/dMMR mcrc (n=0) Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) ~18 15 days (1 day to 1.5 months) days in 1 patient Other treatments ~26% received methimazole; 9% received carbimazole; 4% received propylthiouracil ~29% received methimazole; 24% received carbimazole Resolution* Recurrence after re-initiation of treatment ~23% received HRT ~7% received HRT 0 1 patient 1 patient ~7% received HRT 27 * 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 At least 40 mg prednisone equivalent per day. 1 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. Signs and symptoms may include 1 Headaches that will not go away or unusual headaches Extreme tiredness Weight gain or weight loss Dizziness or fainting Changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness Hair loss Feeling cold Constipation Voice gets deeper Excessive thirst or lots of urine Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 24

25 Grading of immune-mediated endocrinopathies NCI CTCAE grading of immune-mediated endocrinopathies 19 * Grade 1 Grade 2 Grade 3 Grade 4 Hypophysitis 20 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Moderate; minimal, local, or noninvasive intervention indicated; limiting ageappropriate instrumental ADL Severe or medically significant but not immediately lifethreatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Adrenal insufficiency Asymptomatic; clinical or diagnostic observations only; intervention not indicated Moderate symptoms; medical intervention indicated Severe symptoms; hospitalization indicated Life-threatening consequences; urgent intervention indicated Hyperglycemia Fasting glucose value >ULN 160 mg/dl; fasting glucose value >ULN 8.9 mmol/l Fasting glucose value > mg/dl; fasting glucose value > mmol/l > mg/dl; > mmol/l; hospitalization indicated >500 mg/dl; >27.8 mmol/l; life-threatening consequences *Grades correspond to those listed in the NCI CTCAE Version ADL=activities of daily living; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit of normal. 25

26 Management of immune-mediated endocrinopathies Immune-mediated endocrinopathies 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Hypophysitis Adrenal insufficiency Hypothyroidism/thyroiditis or hyperthyroidism Type 1 diabetes mellitus Treatment with OPDIVO or OPDIVO + YERVOY Grade 2 or 3: withhold dose* Grade 4: permanently discontinue Grade 2: withhold dose* Grade 3 4: permanently discontinue There are no recommended dose modifications for hypothyroidism or hyperthyroidism Grade 3 hyperglycemia: withhold dose until metabolic control is achieved* Grade 4 hyperglycemia: permanently discontinue Monitoring Evaluate endocrine function Consider pituitary scan Repeat labs in 1 to 3 weeks/mri in 1 month if symptoms persist but normal lab/pituitary scan Monitor thyroid function prior to and periodically during treatment Monitor for hyperglycemia Consult Consider endocrinology Consider endocrinology Consider endocrinology Steroids Grade 2: 1 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month Grade 3 4: 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month Additional therapeutic management Administer hormone replacement therapy as clinically indicated Administer hormonereplacement therapy for hypothyroidism Initiate medical management for control of hyperthyroidism Follow-up 1,18 If improved (with or without hormone replacement) Taper steroids over at least 1 month before resuming treatment Continue standard monitoring Patients with adrenal insufficiency may need to continue steroids with mineralocorticoid component When Grade 3 hyperglycemia returns to Grade 0 or 1, resume treatment *Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Consider prophylactic antibiotics for opportunistic infections. 18 IV=intravenous; MRI=magnetic resonance imaging. 26

27 Immune-mediated nephritis and renal dysfunction 1 OPDIVO can cause immune-mediated nephritis, defined as renal dysfunction or Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology Monitor patients for elevated serum creatinine prior to and periodically during treatment Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 OPDIVO as a single agent (n=23) mmelanoma (n=9) arcc (n=25) MSI-H/dMMR mcrc (n=2) Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) days (1 day to 15.4 months) ~ days (1 day to 1.1 months) ~76 15 days (1 day to 5.9 months) months (1 month to 2.4 months) Other treatments Resolution* Recurrence after re-initiation of treatment (n) *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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1,12,16 Two patients resumed OPDIVO with YERVOY without recurrence of nephritis or renal dysfunction. 1 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. Signs and symptoms may include 1 Increase in serum creatinine Decrease in the amount of urine Blood in the urine Swelling in the ankles Loss of appetite 27

28 Management of immune-mediated renal adverse reactions Immune-mediated renal adverse reactions 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Grade 1* (Creatinine >ULN and >baseline but 1.5x baseline) Grade 2 3* (Creatinine >1.5x to 6x ULN) Grade 4* (Creatinine >6x ULN) Treatment with OPDIVO or OPDIVO + YERVOY Monitoring Continue treatment Withhold dose Permanently discontinue Monitor creatinine weekly Monitor creatinine every 2 to 3 days Consult Nephrology Steroids 0.5 to 1 mg/kg/day prednisone equivalents followed by a corticosteroid taper over at least 1 month Monitor creatinine daily 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper over at least 1 month Renal tests Consider renal biopsy Consider renal biopsy Follow-up 1,18 If improved to baseline Resume routine creatinine monitoring If worsens Treat as Grade 2 3 or 4 If improved to Grade 1 Taper steroids over at least 1 month before resuming treatment with routine creatinine monitoring If worsening or no improvement 1 to 2 mg/kg/day prednisone equivalents If improved to Grade 1 Taper steroids over at least 1 month II *Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Consider prophylactic antibiotics for opportunistic infections. 18 II Add prophylactic antibiotics for opportunistic infections. 18 IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit of normal. 28

29 Immune-mediated skin adverse reactions 1 OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome Dose modifications, management, and resolution rates in patients receiving OPDIVO and OPDIVO + YERVOY (% of patients) 1,12-17 OPDIVO as a single agent (n=171) mmelanoma (n=92) arcc (n=91) MSI-H/dMMR mcrc (n=17) Permanently discontinued treatment Withheld treatment Corticosteroid use Median duration (range) ~16 12 days (1 day to 8.9 months) ~17 14 days (2 days to 4.7 months) ~19 25 days (1 day to 23.1 months) 0 1 patient days (11 days to 23 days) Other treatments 85% received topical CS Resolution* Recurrence after re-initiation of treatment ~ *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 At least 40 mg prednisone equivalents per day. 1 Complete resolution following CS use. 1,12,16 arcc=advanced renal cell carcinoma; CS=corticosteroid; dmmr=mismatch repair deficient; HRT=hormone replacement therapy; IMAE=immune-mediated adverse event; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. Signs and symptoms may include 1 Rash Itching Skin blistering Ulcers in the mouth or other mucous membranes 29

30 Management of immune-mediated skin adverse reactions Immune-mediated skin adverse reactions 1,18 When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Treatment with OPDIVO or OPDIVO + YERVOY Symptomatic treatment Grade 1 2* (Covering 30% BSA) Continue treatment Administer (eg, antihistamines and topical steroids) Grade 3 4* (Covering >30% BSA; life-threatening consequences) Grade 3 rash or symptoms/signs of SJS or TEN: withhold dose Grade 4 rash or confirmed SJS or TEN: permanently discontinue For symptoms or signs of SJS or TEN Refer the patient for specialized care for assessment and treatment Consult Dermatology Steroids Administer symptomatic treatment (eg, topical steroids) For immune-mediated rash 1 to 2 mg/kg/day of prednisone or equivalent followed by corticosteroid taper over at least 1 month Skin test Consider skin biopsy Follow-up 1,18 If symptoms persist >1 2 weeks or recur Consider skin biopsy Withhold dose If symptoms worsen Treat as Grade 3 4 If improved to Grade 1 Taper steroids over at least 1 month before resuming treatment *Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Add prophylactic antibiotics for opportunistic infections. 18 BSA=body surface area; IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SJS=Stevens-Johnson syndrome; TEN=toxic epidermal necrolysis. Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 30

31 Immune-mediated encephalitis 1 OPDIVO can cause immune-mediated encephalitis with no clear alternate etiology OPDIVO as a single agent 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 HSCT OPDIVO 1 mg/kg with YERVOY 3 mg/kg in mmelanoma Encephalitis occurred in 1 patient receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks (0.2%) after 1.7 months of exposure OPDIVO 3 mg/kg with YERVOY 1 mg/kg in arcc Encephalitis occurred in 1 patient receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks (0.2%) after approximately 4 months of exposure OPDIVO 3 mg/kg with YERVOY 1 mg/kg in MSI-H/dMMR mcrc Encephalitis occurred in 1 patient receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks (0.8%) after 15 days of exposure Signs and symptoms may include 1 Headache Fever Tiredness or weakness Confusion Memory problems Sleepiness Seeing or hearing things that are not really there (hallucinations) Seizures Stiff neck arcc=advanced renal cell carcinoma; dmmr=mismatch repair deficient; HSCT=hematopoietic stem cell transplantation; mcrc=metastatic colorectal cancer; mmelanoma=metastatic melanoma; MSI-H=microsatellite instability-high. 31

32 Management of immune-mediated neurologic adverse reactions Immune-mediated neurologic adverse reactions 1,18 Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld, YERVOY should also be withheld. Grade 1* (Asymptomatic or mild symptoms) Grade 2* (New-onset moderate to severe neurologic signs or symptoms) Grade 3 4* (Severe symptoms; life-threatening) Immunemediated encephalitis Treatment with OPDIVO or OPDIVO + YERVOY Continue treatment Withhold dose Permanently discontinue Consult Consider consulting neurology Neurology Steroids Treat symptoms per local guidelines 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month Follow-up 1,18 If worsens Treat as Grade 2 or 3 4 If improved to baseline Resume treatment If worsens or no improvement Treat as Grade 3 4 If improved to Grade 2 Taper steroids over at least 1 month If worsens or atypical presentation Consider other immunosuppressive therapies *Grades correspond to those listed in the NCI CTCAE Version ,19 Resume treatment when adverse reaction returns to Grade 0 or 1. 1 Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 18 Add prophylactic antibiotics for opportunistic infections. 18 IV=intravenous; MRI=magnetic resonance imaging; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. Important Safety Information About YERVOY In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 32

33 Management of other immune-mediated adverse reactions 1 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 The eye disorder Vogt-Koyanagi-Harada (VKH) syndrome is an adverse reaction that was identified during post approval use of OPDIVO. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy For any suspected immune-mediated adverse reactions, exclude other causes Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event Signs and symptoms may include 1 Changes in eyesight Severe or persistent muscle or joint pains Severe muscle weakness Chest pain 33

34 Signs, symptoms, and management of infusion reactions 1,21 OPDIVO can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials 1 Infusion reactions were graded according to the NCI CTCAE Version ,21 Mild/moderate symptoms (Grade 1 or 2) 1,21 Interrupt or slow the rate of infusion in patients Monitor patients until recovery Severe/life threatening (Grade 3 or 4) 1,21 Discontinue OPDIVO in such patients To manage anaphylaxis, follow institutional protocol Patient should be monitored until the treating physician is comfortable that the symptoms will not recur NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. Signs and symptoms may include 1 Chills or shaking Itching or rash Flushing Difficulty breathing Dizziness Fever Feeling like passing out 34

35 Important Safety Information 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. Immune-Mediated Pneumonitis OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients. In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12). Immune-Mediated Colitis OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immunemediated colitis occurred in 7% (8/119) of patients. In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of 7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOYtreated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Immune-Mediated Hepatitis OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immunemediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immunemediated hepatitis occurred in 8% (10/119) of patients. In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO. In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%. (continued on next page) Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 35

36 Important Safety Information (cont d) Immune-Mediated Neuropathies In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Immune-Mediated Endocrinopathies OPDIVO can cause immune-mediated hypophysitis, immunemediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia. In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immunemediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients. In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Immune-Mediated Nephritis and Renal Dysfunction OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immunemediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients. Immune-Mediated Skin Adverse Reactions and Dermatitis OPDIVO can cause immune-mediated rash, including Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients. (continued on next page) Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 36

37 Important Safety Information (cont d) Immune-Mediated Skin Adverse Reactions and Dermatitis (cont d) In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis. Immune-Mediated Encephalitis OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mcrc patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure. Other Immune-Mediated Adverse Reactions Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and if appropriate, initiate hormonereplacement therapy. 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. 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 may require treatment with systemic steroids to reduce the risk of permanent vision loss. Infusion Reactions OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute 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. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mcrc patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusionrelated reactions occurred in 4.2% (5/119) of patients. Complications of Allogeneic HSCT after OPDIVO Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reducedintensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reducedintensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly. (continued on next page) Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 37

38 Important Safety Information (cont d) Embryo-Fetal Toxicity Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY-containing regimen and for at least 5 months after the last dose of OPDIVO. Lactation It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose. Serious Adverse Reactions In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent ( 10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. 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; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mcrc patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVOtreated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients. Common Adverse Reactions In Checkmate 037, the most common adverse reaction ( 20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions ( 20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), (continued on next page) Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 38

39 Important Safety Information (cont d) Common Adverse Reactions (cont d) rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common ( 20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common ( 20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions ( 20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions ( 20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions ( 20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions ( 20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions ( 20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%), and pruritus (20%). In Checkmate 141, the most common adverse reactions ( 10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator s choice. In Checkmate 275, the most common adverse reactions ( 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mcrc patients receiving OPDIVO as a single agent, the most common adverse reactions ( 20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mcrc patients receiving OPDIVO with YERVOY, the most common adverse reactions ( 20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions ( 20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions ( 20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions ( 5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). Checkmate Trials and Patient Populations Checkmate 067 advanced melanoma alone or in combination with YERVOY Checkmate 214 intermediate or poor risk advanced renal cell carcinoma in combination with YERVOY Checkmate 142 MSI-H/dMMR metastatic colorectal cancer alone or in combination with YERVOY Checkmate 205/039 classical Hodgkin lymphoma Checkmate 040 hepatocellular carcinoma Checkmate 037/066 advanced melanoma Checkmate 017 squamous non-small cell lung cancer (NSCLC) Checkmate 057 non-squamous NSCLC Checkmate 025 previously treated renal cell carcinoma Checkmate 141 squamous cell carcinoma of the head and neck Checkmate 275 urothelial carcinoma Checkmate 238 adjuvant treatment of melanoma Checkmate 032 previously treated small cell lung cancer Please see additional Important Safety Information for OPDIVO and YERVOY on pages and US Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important 39

40 References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34 [protocol]. 4. American Cancer Society. Chemotherapy Side Effects. chemotherapy/chemotherapy-side-effects.html. Updated February 15, Accessed January 23, National Cancer Institute. Immunotherapy to Treat Cancer. Updated May 4, Accessed January 23, Yu DP, Cheng X, Liu ZD, Xu SF. Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: meta-analysis and systematic review. Oncol Lett. 2017;14(2): Kornblau S, Benson AB, Catalano R, et al. Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage. 2000;19(2) Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015;4(5): Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21(10): Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (iraes) induced by immune checkpoint inhibitor therapy. Front Pharmacol doi: /fphar Data on file. NIVO 252. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 361. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 406. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 407. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 408. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 376. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 409. Princeton, NJ: Bristol-Myers Squibb Company; Data on file. NIVO 158. Princeton, NJ: Bristol-Myers Squibb Company; National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v Published June 14, Accessed January 23, Torino F, Barnabei A, De Vecchis L, Salvatori R, Corsello SM. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17(4): Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17): [protocol]. 40

41 Bristol-Myers Squibb is dedicated to offering resources to support you and your patients Responses provided between 8:00 am and 8:00 pm ET, Monday Friday For healthcare professionals The following resources are available to download at Patient Monitoring Checklist A tool to help nurses identify the signs and symptoms of immune-mediated adverse reactions (IMARs). Contacting the patient and reviewing this checklist once weekly is recommended. Patient Monitoring Checklist Patient name Date This checklist is intended for nurses or other healthcare professionals (HCPs) to use prior to dosing each patient and at any follow-up visits or calls with the patient to identify some of the signs and symptoms associated with adverse reactions related to treatment with OPDIVO or the OPDIVO + YERVOY Regimen. Early identification of adverse reactions and intervention are important parts of the safe use of OPDIVO and the OPDIVO + YERVOY Regimen. OPDIVO (10 mg/ml) and YERVOY (5 mg/ml) are injections for intravenous (IV) use. Please note: this checklist is not meant to be all inclusive. If the patient responds to any of these questions, consult with the patient s HCP before administering OPDIVO. QUESTION RESPONSE NOTES GENERAL Are you having difficulty performing your normal activities? Have you had constant or unusual headaches? Have you felt drowsy or extremely tired? Have you felt dizzy or fainted? Have you had changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness? Have you felt cold? Have you gained or lost weight? Have you had hair loss? Has your voice gotten deeper? Have you noticed your skin or eyes turning yellow? Are you experiencing increased thirst? Are you urinating more or less often than usual? Is your urine bloody, dark, or tea-colored? Do you bleed or bruise more easily than normal? Do you have swelling in your ankles? Have you had severe or constant muscle or joint pain? Have you had severe muscle weakness? Have you been running a fever? Have you had changes in your eyesight? Have you started taking any new medications (prescription, nonprescription, or herbal)? If yes, which and how often? Have you experienced any weakness? PULMONARY Do you have a new cough or one that has worsened? Are you having chest pain? Are you having trouble breathing or shortness of breath? GASTROINTESTINAL Are you severely nauseous and/or vomiting? Do you have a loss of appetite or have you felt less hungry than usual? How many bowel movements are you having each day? Is this different than normal? If yes, how? Are your stools loose or watery, or do they have a foul smell? Have you seen blood or mucous in your stools? Are your stools dark, tarry, or sticky? Are you having painful bowel movements? Are you having pain or tenderness around your belly? If yes, where? Questions pertaining to OPDIVO as a single agent and the OPDIVO + YERVOY Regimen continue on the next page. Please see Important Safety Information, including Boxed WARNING regarding Immune-Mediated Adverse Reactions for YERVOY, on pages 3 5 and accompanying US Full Prescribing Information for OPDIVO and YERVOY. Please refer to the end of the Important 1 The OPDIVO Safety Tool A quick reference for the IMARs associated with OPDIVO treatment. You may access this app from your cellular phone, tablet, or computer. For patients and caregivers The following resources are available to download at Resources for personalized assistance A patient support program designed to help patients and their caregivers better understand their therapy, including live support with a care counselor for patients who have been prescribed OPDIVO or OPDIVO + YERVOY (ipilimumab). Available at Important Safety Information about OPDIVO (nivolumab) Important Safety Information for OPDIVO (nivolumab) OPDIVO is a medicine that may treat your melanoma, lung cancer, kidney cancer, blood cancer, head and neck cancer, bladder cancer, liver cancer, by working with your immune system. OPDIVO can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. Serious side effects may include: Lung problems (pneumonitis). Symptoms of pneumonitis may include: new or worsening cough; chest pain; and shortness of breath. Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include: diarrhea (loose stools) or more bowel movements than usual; blood in your stools or dark, tarry, sticky stools; and severe stomach area (abdomen) pain or tenderness. Liver problems (hepatitis). Signs and symptoms of hepatitis may include: yellowing of your skin or the whites of your eyes; severe nausea or vomiting; pain on the right side of your stomach area (abdomen); drowsiness; dark urine (tea colored); bleeding or bruising more easily than normal; and feeling less hungry than usual. Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include: headaches that will not go away or unusual headaches; extreme tiredness; weight gain or weight loss; dizziness or fainting; changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness; hair loss; feeling cold; constipation; voice gets deeper; and excessive thirst or lots of urine. Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include: decrease in the amount of urine; blood in your urine; swelling in your ankles; and loss of appetite. Skin Problems. Signs of these problems may include: rash; itching; skin blistering; and ulcers in the mouth or other mucous membranes. Inflammation of the brain (encephalitis). Signs and symptoms of encephalitis may include: headache; fever; tiredness or weakness; confusion; memory problems; sleepiness; seeing or hearing things that are not really there (hallucinations); seizures; and stiff neck. Problems in other organs. Signs of these problems may include: changes in eyesight; severe or persistent muscle or joint pains; and severe muscle weakness. Getting medical treatment right away may keep these problems from becoming more serious. Your healthcare provider will check you for these problems during treatment. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider IMPORTANT Reminders for Patients If you experience any symptoms listed on this Signs and Symptoms Checklist, or they get worse, please notify your oncologist immediately. Getting medical treatment right away may keep the problem from becoming more serious Your oncologist may decide to delay or completely stop OPDIVO or give you other medicines to treat your symptoms OPDIVO and the related logo are trademarks of Bristol-Myers Squibb Company Bristol-Myers Squibb Company. All rights reserved. 1506US may also need to delay or completely stop treatment, if you have severe side effects. OPDIVO can cause serious side effects, including: Severe infusion reactions. Tell your doctor or nurse right away if you get these symptoms during an infusion of OPDIVO: chills or shaking; itching or rash; flushing; difficulty breathing; dizziness; fever; and feeling like passing out. Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with OPDIVO. These complications can be severe and can lead to death. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant. Pregnancy and Nursing: Tell your healthcare provider if you are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby. Females who are able to become pregnant should use an effective method of birth control during and for at least 5 months after the last dose of OPDIVO. Talk to your healthcare provider about birth control methods that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment. Before receiving treatment, tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if OPDIVO passes into your breast milk. Do not breastfeed during treatment. Tell your healthcare provider about: Your health problems or concerns if you have immune system problems such as Crohn s disease, ulcerative colitis, or lupus; have had an organ transplant; have lung or breathing problems; have liver problems; or have any other medical conditions. All the medicines you take, including prescription and overthe-counter medicines, vitamins, and herbal supplements. The most common side effects of OPDIVO when used alone include: feeling tired; pain in muscles, bones, and joints; diarrhea; cough; constipation; back pain; fever; rash; itchy skin; nausea; shortness of breath; decreased appetite; upper respiratory tract infection; and weakness. These are not all the possible side effects. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call FDA You may also report side effects to Bristol-Myers Squibb at Please see US Full Prescribing Information and Medication Guide for OPDIVO in the pocket. Patient Pocket Guide 3 Read the information inside and use the Signs and Symptoms Checklist to recognize and report symptoms Call your treating doctor right away if you experience anything unusual while on OPDIVO therapy If you experience any of the symptoms listed on the Signs and Symptoms Checklist or they get worse, please notify your treating doctor immediately. Getting medical treatment right away may keep the problem from becoming more serious Show this wallet card during any urgent care/emergency room visit Tell the urgent care/emergency room staff that you are being treated with OPDIVO and show them the doctor/nurse section this wallet card I am receiving OPDIVO (nivolumab) Please contact my doctor immediately. Name: Treating Doctor: Contact Number: 1506US Card_v9.indd 1 The Patient Pocket Guide Patient resource containing OPDIVO and OPDIVO + YERVOY IMAR symptoms and healthcare provider contact information. SELECT IMPORTANT SAFETY INFORMATION Present this card every time you see a doctor or nurse Bristol-Myers Squibb Company. All rights reserved. OPDIVO is a prescription medicine used to treat: a type of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced melanoma). OPDIVO is approved for both BRAF+ and BRAF- patients. OPDIVO was approved for BRAF+ metastatic melanoma patients based on the amount of time patients lived without their tumors worsening. There is ongoing evaluation of clinical benefit of OPDIVO for this use. a type of advanced stage lung cancer (called non-small cell lung cancer) that has spread or grown and you have tried chemotherapy that contains platinum, and it did not work or is no longer working. If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDAapproved therapy for tumors with these abnormal genes, and it did not work or is no longer working. kidney cancer (renal cell carcinoma) when your cancer has spread or grown after treatment with other cancer medications adults with a type of blood cancer called classical Hodgkin lymphoma if your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells (autologous), and you used the drug brentuximab vedotin (Adcetris ) before or after your stem cell transplant, or if you received at least 3 kinds of treatment including an autologous stem cell transplant. OPDIVO was approved based on response rate. There is ongoing evaluation of clinical benefit of OPDIVO for this use. head and neck cancer that has come back or spread and you have tried chemotherapy that contains platinum and it did not work or is no longer working. bladder cancer (urothelial carcinoma) that has spread or grown and you have tried chemotherapy that contains platinum, and it did not work or is no longer working. OPDIVO was approved based on response rate and how long patients responses lasted. There is ongoing evaluation of clinical benefit of OPDIVO for this use. OPDIVO is a prescription medicine used to treat hepatocellular carcinoma (liver cancer) that has spread or grown after treatment with Nexavar (sorafenib). OPDIVO was approved based on response rate and how long patients responses lasted. There is ongoing evaluation of clinical benefit of OPDIVO for this use. It is not known if OPDIVO is safe and effective in children less than 18 years of age. Detach the wallet card and keep on your person at all times Fill out the treating doctor s contact information OPDIVO can cause problems that can sometimes become serious or life-threatening and can lead to death. Serious side effects may include lung problems (pneumonitis); intestinal problems (colitis) that can lead to tears or holes in your intestine; liver problems (hepatitis); hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas); kidney problems, including nephritis and kidney failure; skin problems; inflammation of the brain (encephalitis); problems in other organs; severe infusion reactions; and complications of stem-cell transplant that uses donor stem cells (allogeneic) after treatment with OPDIVO. 08/17 8/29/17 1:30 PM Please see additional Important Safety Information on reverse side and US Full Prescribing Information and Medication Guide for OPDIVO in the pocket. 08/ US _01_01_OPD_MONO_PAT_ALERT_RES_REDESIGN_ _v9_RS.indd US _01_01_OPD_MONO_PAT_ALERT_RES_REDESIGN_ _v9.indd 1 Flip Open for Information to Monitor Your Signs and Symptoms A guide to identifying possible signs and symptoms, including immune-mediated side effects 1 2 8/29/17 2:42 PM 8/29/17 2:38 PM YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials Bristol-Myers Squibb Company. All rights reserved. OPDIVO, YERVOY, and the related logos are trademarks of Bristol-Myers Squibb Company. 1506US /18