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Full Indications

For Patients With Previously Untreated Intermediate
or Poor Risk Advanced Renal Cell Carcinoma

Two 1L aRCC combinations
based on OPDIVO® (nivolumab)1

Select an OPDIVO-based treatment option to view clinical information

WHEN LOOKING FOR A CHANCE FOR LONG-TERM, DURABLE SURVIVAL2
THE ONLY APPROVED I-O + TKI COMBINATION TO DOUBLE MEDIAN PFS1,3*

Please see OPDIVO + CABOMETYX data below.

*vs sunitinib in the ITT population.

BICR assessed.1

1L=first-line; aRCC=advanced renal cell carcinoma; CI=confidence interval; HR=hazard ratio; I-O=immuno-oncology; ITT=intent to treat; mPFS=median progression-free survival; TKI=tyrosine kinase inhibitor.

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

  • mOS:
    • The 48-month OS rate for OPDIVO + YERVOY was 50.0% vs 35.8% for sunitinib. OPDIVO + YERVOY: 48.1 months (95% CI: 35.6-NE)2
    • Sunitinib: 26.6 months (95% CI: 22.1-33.5)2
    • HR=0.65 (95% CI: 0.54-0.78)2

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

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

Checkmate 214 Study Design1,4

Checkmate 214 was a phase 3, randomized (1:1), open-label study of OPDIVO 3 mg/kg IV and YERVOY 1 mg/kg IV (n=425) every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg IV every 2 weeks vs sunitinib (n=422) 50 mg administered orally once daily for 4 weeks, followed by 2 weeks off every cycle, in patients with previously untreated intermediate/poor risk aRCC. Patients were stratified by IMDC prognostic score and region, and treatment was continued until disease progression or unacceptable toxicity. The co-primary endpoints in IMDC intermediate/poor risk patients were OS, ORR, and PFS.1,4†

In the primary analysis of Checkmate 9ER (median follow-up of 18.1 months [range: 10.6–30.6 months]):

  • mPFS was 16.6 months (95% CI: 12.5–24.9) with OPDIVO + CABOMETYX vs 8.3 months (95% CI: 7.0–9.7) with sunitinib (HR=0.51; 95% CI: 0.41–0.64; P<0.0001).1

In the extended follow-up analysis of Checkmate 9ER (median follow-up of 23.5 months):

  • mPFS was 17.0 months (95% CI: 12.6–19.4) with OPDIVO + CABOMETYX vs 8.3 months (95% CI: 6.9–9.7) with sunitinib (HR=0.52; 95% CI: 0.43–0.64).4

Checkmate 9ER Study Design

Checkmate 9ER was a phase 3, randomized (1:1), open-label study of OPDIVO 240 mg/kg IV every 2 weeks|| and CABOMETYX 40 mg orally once daily (n=323) vs sunitinib 50 mg administered orally once daily (n=328) for the first 4 weeks of a 6-week cycle (4 weeks of treatment followed by 2 weeks off) in patients with previously untreated aRCC. Patients were stratified by IMDC prognostic score, PD-L1 tumor expression, and region, and treatment was continued until disease progression or unacceptable toxicity. Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter. The primary endpoint was PFS (BICR assessed). Secondary endpoints were OS and ORR (BICR assessed).1,3

Checkmate 214 Study Design1,4

Checkmate 214 was a phase 3, randomized (1:1), open-label study of OPDIVO 3 mg/kg IV and YERVOY 1 mg/kg IV (n=425) every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg IV every 2 weeks vs sunitinib (n=422) 50 mg administered orally once daily for 4 weeks, followed by 2 weeks off every cycle, in patients with previously untreated intermediate/poor risk aRCC. Patients were stratified by IMDC prognostic score and region, and treatment was continued until disease progression or unacceptable toxicity. The co-primary endpoints in IMDC intermediate/poor risk patients were OS, ORR,§ and PFS.1,4§

BICR assessed.1

The recommended dose of OPDIVO in combination with YERVOY is OPDIVO 3 mg/kg administered as an IV infusion over 30 minutes, followed by YERVOY 1 mg/kg administered as an IV infusion over 30 minutes on the same day, every 3 weeks for 4 doses. The recommended subsequent dose of OPDIVO as a single agent is either 240 mg or 480 mg administered as an IV infusion over 30 minutes every 2 weeks or 4 weeks, respectively, until disease progression or unacceptable toxicity.1

||Approved dosing: OPDIVO 240 mg IV q2w or OPDIVO 480 mg IV q4w, in combination with CABOMETYX 40 mg PO qd without food. Continue OPDIVO until disease progression, unacceptable toxicity, or up to 2 years. Continue CABOMETYX until disease progression or unacceptable toxicity.1

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

CR=complete response; IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; IV=intravenous; mOS=median OS; NE=not evaluable; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors.

Select Important Safety Information

Serious Adverse Reactions

In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 46% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Common Adverse Reactions

Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%).

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

More Important Safety Information Collapse

Important Safety 
Information

Important Safety Information

Severe and Fatal Immune-Mediated Adverse Reactions

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

Immune-Mediated Pneumonitis

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

Immune-Mediated Colitis

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

Immune-Mediated Hepatitis and Hepatotoxicity

  • OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).
  • OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

  • OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis and Renal Dysfunction

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

Immune-Mediated Dermatologic Adverse Reactions

  • OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
  • YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.
  • Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
  • In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

Other Immune-Mediated Adverse Reactions

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

Infusion-Related Reactions

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

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

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

Embryo-Fetal Toxicity

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

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

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

Lactation

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

Serious Adverse Reactions

  • In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 46% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Common Adverse Reactions

  • In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%).

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

Checkmate Trials and Patient Populations

Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib.

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company.
  2. Albiges L, Tannir NM, Burrotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma in Checkmate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Poster presentation at ESMO 2020. Abstract 711P.
  3. Choueiri TK, Powles T, Burroto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 Checkmate 9ER trial. Slide presentation at ESMO 2020. Presentation 6960.
  4. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. Poster presentation at ASCO GU 2021. Abstract 308.