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Full Indication

Combining 2 proven agents* in aRCC1,2

OPDIVO® (nivolumab)
  CABOMETYX® (cabozantinib)

Superior efficacy vs sunitinib across 3 key endpoints1†

  Scroll to see data below  

Primary analysis results (median follow-up time of 18.1 months; range: 10.6–30.6 months).1,3

Overall response rate

Secondary endpoint1,3†‡

  • ORR: 55.7% (n=180/323) (95% CI: 50.1–61.2) with OPDIVO + CABOMETYX vs 27.1% (n=89/328) (95% CI: 22.4–32.3) with sunitinib (P<0.0001)
    • 8% (n=26/323) CR and 47.7% (n=154/323) PR for OPDIVO + CABOMETYX vs 4.6% (n=15/328) CR and 22.6% (n=74/328) PR for sunitinib3

Progression-free survival

Primary endpoint1,3†‡

  • mPFS: 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)1,3

Overall survival

Secondary endpoint1†

  • mOS: NR (95% CI: NR) with OPDIVO + CABOMETYX and NR (95% CI: 22.6–NR) with sunitinib (HR=0.60; 98.89% CI: 0.40–0.89; P=0.0010)1,3

Select Important Safety Information

Serious adverse reactions in Checkmate 9ER occurred in 46% of patients receiving OPDIVO and CABOMETYX (n=320). 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.

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%), upper respiratory tract infection (20%), and cough (20%).

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

VIEW BASELINE CHARACTERISTICS

Extended follow-up analysis results (median follow-up time of 23.5 months; range: 16.0–36.0 months)4:

ORR‡: 54.8% (n=177/323 [95% CI: 49.2–60.3]) with OPDIVO + CABOMETYX vs 28.4% (n=93/328) [95% CI: 23.5–33.6]) with sunitinib; CR: 9.3% (n=30/323) with OPDIVO + CABOMETYX vs 4.3% (n=14/328) with sunitinib; PR: 45.5% (n=147/323) with OPDIVO + CABOMETYX vs 24.1% (n=79/328) with sunitinib; mPFS‡: 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); mOS‡: NR (95% CI: NE) with OPDIVO + CABOMETYX and 29.5 months (95% CI: 28.4–NE) with sunitinib (HR=0.66; 95% CI: 0.50–0.87).

*OPDIVO as a single agent is indicated for the treatment of patients with advanced renal cell carcinoma (aRCC) who have received prior anti-angiogenic therapy.1 CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (aRCC).2

†Based on primary analysis results at a median follow-up of 18.1 months (range: 10.6–30.6 months).3

‡BICR assessed.1

aRCC=advanced renal cell carcinoma; BICR=blinded independent central review; CI=confidence interval; CR=complete response; HR=hazard ratio; mOS=median OS; mPFS=median PFS; NE=not estimable; NR=not reached; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PR=partial response.

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Study Design

When choosing I-O + TKI therapy in aRCC OPDIVO® + CABOMETYX® (cabozantinib) was studied in a phase 3, head-to-head trial vs sunitinib1,3

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) study design OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) study design

Checkmate 9ER includes data from an extended follow-up analysis at a median follow-up time of 23.5 months (range: 16.0–36.0 months)4

  • Median follow-up time of the primary analysis was 18.1 months (range: 10.6–30.6 months)3
  • Patients with autoimmune disease or other medical conditions requiring systemic immunosuppression were excluded from the trial1
  • OPDIVO dosing was not to exceed a total of 2 years (from Cycle 1); CABOMETYX and sunitinib treatment was allowed to continue beyond 2 years in the absence of progression or unacceptable toxicity1,3
  • Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator1
  • Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter1

†BICR assessed.3

‡Defined as the percent of positive tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry 28-8 pharmDx assay.3

§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

IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; I-O=immuno-oncology; IV=intravenous; PD-L1=programmed death-ligand 1; PO=by mouth; q2w=every 2 weeks; qd=every day; RECIST=Response Evaluation Criteria In Solid Tumors; TKI=tyrosine kinase inhibitor.

 

Overall Response Rate

When choosing I-O + TKI therapy in aRCC OPDIVO® + CABOMETYX® (cabozantinib): ORR vs sunitinib1,3,4*†‡

Primary analysis ORR: 55.7% (n=180/323) with OPDIVO® + CABOMETYX® (95% CI: 50.1–61.2) vs 27.1% (n=89/328) with sunitinib (95% CI: 22.4–32.3); P<0.0001*

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) overall response rate bar chart OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) overall response rate bar chart

OPDIVO + CABOMETYX: ~90% DCR4†

  • The FDA does not consider SD to be a valid endpoint for the measurement of response because it may reflect the natural history of disease rather than any effect of the drug5
  • DCR was not pre-specified1

Median follow-up time of primary analysis was 18.1 months (range: 10.6–30.6 months)3

Complete and partial response rates

  • 8% (n=26/323) CR and 47.7% (n=154/323) PR for OPDIVO + CABOMETYX vs 4.6%

Median follow-up time of extended follow-up analysis was 23.5 months (range: 16.0–36.0 months)4

Overall response rate‡

  • 54.8% (n=177/323) ORR for OPDIVO + CABOMETYX (95% CI: 49.2–60.3) and 28.4% (n=93/328) for sunitinib (95% CI: 23.5–33.6)

Complete and partial response rates

  • 9.3% (n=30/323) CR and 45.5% (n=147/323) PR for OPDIVO + CABOMETYX vs 4.3% (n=14/328) CR and 24.1% (n=79/328) PR for sunitinib

*Based on primary analysis results at a median follow-up of 18.1 months (range: 10.6–30.6 months).3

†Based on extended follow-up analysis results at a median follow-up of 23.5 months (range: 16.0–36.0 months).4

‡BICR assessed.1

DCR=disease control rate; SD=stable disease.

 

Progression-Free Survival

When choosing I-O + TKI therapy in aRCC OPDIVO® + CABOMETYX® (cabozantinib): The Only Approved I-O + TKI Combination to Double Median PFS1,3,4*†‡§

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) progression-free survival Kaplan-Meier curve OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) progression-free survival Kaplan-Meier curve

Median PFS§ at primary analysis (median follow-up time of 18 months; range 10.6–30.6 months)1,3

  • OPDIVO + CABOMETYX: 16.6 months (95% CI: 12.5–24.9)
  • Sunitinib: 8.3 months (95% CI: 7.0–9.7)
  • HR=0.51 (95% CI: 0.41–0.64); P<0.0001

Median PFS§ at extended follow-up analysis (median follow-up time of 23.5 months; range: 16.0–36.0 months)4

  • OPDIVO + CABOMETYX: 17.0 months (95% CI: 12.6–19.4)
  • Sunitinib: 8.3 months (95% CI: 6.9–9.7)
  • HR=0.52 (95% CI: 0.43–0.64)

*Based on primary analysis results at a median follow-up of 18.1 months (range: 10.6–30.6–months).3

†Based on extended follow-up analysis results at a median follow-up of 23.5 months (range: 16.0–36.0–months).4

‡vs sunitinib in the ITT population.1

§BICR assessed.1

ITT=intent to treat.

 

Overall Survival

When choosing I-O + TKI therapy in aRCC OPDIVO® + CABOMETYX® (cabozantinib): OS at ~2-year median follow-up1,3,4*

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) overall survival Kaplan-Meier curve OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) overall survival Kaplan-Meier curve
34% reduction in the risk of death was observed at nearly 2 years.4

Median OS at primary analysis (median follow-up time of 18.1 months; range: 10.6–30.6 months)1,3

  • OPDIVO + CABOMETYX: NR (95% CI: NR)
  • Sunitinib: NR (95% CI: 22.6–NR)
  • HR=0.60 (98.89% CI: 0.40–0.89); P=0.0010

Median OS at extended follow-up analysis (median follow-up time of 23.5 months; range: 16.0–36.0 months)4

  • OPDIVO + CABOMETYX: NR (95% CI: NE)
  • Sunitinib: 29.5 months (95% CI: 28.4–NE)
  • HR=0.66 (95% CI: 0.50–0.87)

*Based on extended follow-up analysis results at a median follow-up of 23.5 months (range: 16.0–36.0 months).4

 

Dosing

OPDIVO + CABOMETYX: Flexible dosing options and a once-daily TKI1

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) dosing information OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) dosing information
  • Based on exploratory dose exposure-response relationships for efficacy and safety, OPDIVO 240 mg q2w and 480 mg q4w are predicted to be similar6
  • In combination with OPDIVO, the recommended starting dose for CABOMETYX is 40 mg. If needed, CABOMETYX may be interrupted or reduced to either 20 mg daily or
    20 mg every other day1
  • Review the Full Prescribing Information for both OPDIVO and CABOMETYX prior to initiation, including recommended dosage and dose modifications1
  • No premedication required with OPDIVO + CABOMETYX1

OPDIVO is administered as an IV infusion over 30 minutes.1

q4w=every 4 weeks.

 

Select Safety Information
 

Selected Safety Profile

When choosing I-O + TKI therapy in aRCC What are your safety expectations for I-O + TKI therapy?

Grade 3–5 adverse reactions were similar with OPDIVO + CABOMETYX vs sunitinib (75% vs 71%)3
OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) selected safety profile tornado diagram
Reactions, %#

Grade 1-4 adverse reactions occurring in ≥15% of patients receiving OPDIVO + CABOMETYX1		OPDIVO +
CABOMETYX
(n=320)1		Sunitinib

(n=320)1
Grades 1–5 (%)Grades 1–5 (%)
All-cause adverse reactions310099
General  
Fatigue**5150
Hepatobiliary  
Hepatotoxicity††4426
Skin and Subcutaneous Tissue  
Palmar-plantar
erythrodysesthesia syndrome		4041
Stomatitis‡‡3746
Rash§§3614
Pruritus194.4
Gastrointestinal  
Diarrhea6447
Nausea2731
Vomiting1721
Abdominal pain***2215
Dyspepsia§§§1522
Musculoskeletal and Connective Tissue  
Musculoskeletal pain##3329
Arthralgia189
Respiratory, Thoracic, and Mediastinal  
Cough†††2017
Dysphonia173.4
Infections and Infestations  
Upper respiratory tract infection‡‡‡208
Metabolism and Nutrition  
Decreased appetite2820
Nervous System  
Dysgeusia2422
Headache1612
Endocrine  
Hypothyroidism¶¶3430
Vascular  
Hypertension||||3639
Reactions, %#

Grade 1-4 adverse reactions in ≥15% of patients receiving OPDIVO + CABOMETYX1		OPDIVO +
CABOMETYX
(n=320)1		Sunitinib

(n=320)1
Grades 3–5 (%)Grades 3–5 (%)
All-cause adverse reactions37571
General  
Fatigue**88
Hepatobiliary  
Hepatotoxicity††115
Skin and Subcutaneous Tissue  
Palmar-plantar
erythrodysesthesia syndrome		88
Stomatitis‡‡3.44.4
Rash§§3.10
Pruritus0.30
Gastrointestinal  
Diarrhea74.4
Nausea0.60.3
Vomiting1.90.3
Abdominal pain***1.90.3
Dyspepsia§§§00.3
Musculoskeletal and Connective Tissue  
Musculoskeletal pain##3.83.1
Arthralgia0.30.3
Respiratory, Thoracic, and Mediastinal  
Cough†††0.30
Dysphonia0.30
Infections and Infestations  
Upper respiratory tract infection‡‡‡0.30.3
Metabolism and Nutrition  
Decreased appetite1.91.3
Nervous System  
Dysgeusia00
Headache00.6
Endocrine  
Hypothyroidism¶¶0.30.3
Vascular  
Hypertension||||1314

Toxicity was graded per NCI CTCAE v4.1

#Includes events that occurred on therapy or within 30 days after the end of the treatment period of all treated patients.3

**Includes asthenia.1

††Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure.1

‡‡Includes mucosal inflammation, aphthous ulcer, mouth ulceration.1

§§Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.1

||||Includes blood pressure increased, blood pressure systolic increased.1

¶¶Includes primary hypothyroidism.1

##Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.1

***Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.1

†††Includes productive cough.1

‡‡‡Includes nasopharyngitis, pharyngitis, rhinitis.1

§§§Includes gastroesophageal reflux disease.1

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Discontinuation rate 
due to the same adverse reaction occurring at the same time1,8:
OPDIVO AND CABOMETYX 5.6%
  • Adverse reactions leading to discontinuation of either OPDIVO or CABOMETYX occurred in 19.7% of patients: 6.6% OPDIVO only, 7.5% CABOMETYX only, and 5.6% OPDIVO + CABOMETYX due to same adverse reaction at the same time1,8
  • Adverse reactions leading to dose interruption or reduction of either OPDIVO or CABOMETYX occurred in 83% of patients: 3% OPDIVO only, 46% CABOMETYX only, 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially1
  • Serious adverse reactions in Checkmate 9ER occurred in 48% of patients receiving OPDIVO and CABOMETYX. 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%) patients1
  • The most common adverse reactions (>20%) reported in patients receiving OPDIVO + CABOMETYX 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%), upper respiratory tract infection (20%), and cough (20%)1

Laboratory values worsening from baseline in >20% of patients on OPDIVO and CABOMETYX1

Percentage of patients with worsening laboratory tests from baseline1||||||

Laboratory 
abnormality		OPDIVO +
CABOMETYX		Sunitinib
Grades 1–4 (%)Grades 3–4 (%)Grades 1–4 (%)Grades 3–4 (%)
Chemistry    
Increased ALT799.8393.5
Increased AST777.9572.6
Hypophosphatemia69284810
Hypocalcemia541.9240.6
Hypermagnesemia471.3250.3
Hyperglycemia443.5441.7
Hyponatremia43113612
Increased lipase41143813
Increased amylase4110286
Increased alkaline phosphatase412.837
1.6
Increased creatinine391.3420.6
Hyperkalemia354.7271
Hypoglycemia260.8140.4
Hematology    
Lymphopenia426.64510
Thrombocytopenia410.3709.7
Anemia372.5314.8
Leukopenia370.3665.1
Neutropenia353.26712
Laboratory 
abnormality		OPDIVO +
CABOMETYX		Sunitinib
Grades 1–4 (%)Grades 1–4 (%)
Chemistry  
Increased ALT7939
Increased AST7757
Hypophosphatemia6948
Hypocalcemia5424
Hypermagnesemia4725
Hyperglycemia4444
Hyponatremia4336
Increased lipase4138
Increased amylase4128
Increased
alkaline
phosphatase		4137
Increased creatinine3942
Hyperkalemia3527
Hypoglycemia2614
Hematology  
Lymphopenia4245
Thrombocytopenia4170
Anemia3731
Leukopenia3766
Neutropenia3567
Laboratory 
abnormality		OPDIVO +
CABOMETYX		Sunitinib
Grades 3–4 (%)Grades 3–4 (%)
Chemistry  
Increased ALT9.83.5
Increased AST7.92.6
Hypophosphatemia2810
Hypocalcemia1.90.6
Hypermagnesemia1.30.3
Hyperglycemia3.51.7
Hyponatremia1112
Increased lipase1413
Increased amylase106
Increased
alkaline
phosphatase		2.81.6
Increased creatinine1.30.6
Hyperkalemia4.71
Hypoglycemia0.80.4
Hematology  
Lymphopenia6.610
Thrombocytopenia0.39.7
Anemia2.54.8
Leukopenia0.35.1
Neutropenia3.212

||||||Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO + CABOMETYX group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).1

  • In the 23.5-month extended follow-up analysis, all-cause laboratory abnormalities occurring in >20% of patients receiving OPDIVO + CABOMETYX and not previously included in the primary analysis include: hypokalemia (OPDIVO + CABOMETYX: 21.8% Grades 1-4, 3.2% Grades 3-4; sunitinib: 12.6% Grades 1-4, 1.6% Grades 3–4)1,7
 

IMAR Safety Management Resources

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

View the OPDIVO Safety Tool

OPDIVO
OPDIVO
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. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. 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 depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO 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 can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis

  • OPDIVO can cause immune-mediated colitis . 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 monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

  • OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), 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 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 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 monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). 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 monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).
  • In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).
  • In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).
  • In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).
  • In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

  • OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

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.
  • Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
  • In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

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 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.
  • 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, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
  • Infusion-Related Reactions
  • OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO 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 patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial 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.

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. 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 and allogeneic HSCT.
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

  • Based on its mechanism of action and findings from animal studies, OPDIVO 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 OPDIVO 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 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 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. 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.

Common Adverse Reactions

  • 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%). 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%).

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

Checkmate Trials and Patient Populations

Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025–previously treated renal cell carcinoma.

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. CABOMETYX [package insert]. Alameda, CA: Exelixis, Inc.
  3. Choueiri TK, Powles T, Burotto 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.
  5. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics. Published December 2018. Accessed October 21, 2020.
  6. Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018;29(11):2208-2213.
  7. Data on File. NIVO 55447. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
  8. Data on File. NIVO 54859. Princeton, NJ: Bristol-Myers Squibb Company; 2020.

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