Adjuvant Treatment of UC

OPDIVO Qvantig® offers a chance to change
the future for patients with high-risk
urothelial carcinoma1-5*†

In the adjuvant treatment of adult patients with UC at high risk of recurrence after radical resection of UC, OPDIVO Qvantig and OPDIVO® IV: The only FDA-approved options regardless of prior neoadjuvant chemotherapy, nodal involvement, and PD-L1 status.

PD-L1=programmed death-ligand 1; UC=urothelial carcinoma.

*OPDIVO Qvantig was not evaluated in Checkmate 274. The use of OPDIVO Qvantig is supported by the pivotal trials of OPDIVO IV and Checkmate 67T. In Checkmate 67T, OPDIVO Qvantig demonstrated non-inferiority to OPDIVO IV with a comparable PK and ORR profile.1,6

Please see Checkmate 67T trial data below

See Safety Page >
  • mDFS in all randomized patients (minimum follow‑up time of 5.9 months; median follow‑up time of 20.9 months for OPDIVO IV and 19.5 months for placebo): 20.8 months (95% CI: 16.5–27.6) for OPDIVO IV and 10.8 months (95% CI: 8.3–13.9) for placebo; HR=0.70 (95% CI: 0.57–0.86); P=0.00083.2,7
  • mDFS in patients with PD‑L1 ≥1% (minimum follow‑up time of 6.3 months; median follow‑up time of 22.1 months for OPDIVO IV and 18.7 months for placebo): NR (95% CI: 21.2–NE) for OPDIVO IV and 8.4 months (95% CI: 5.6–21.2) for placebo; HR=0.55 (95% CI: 0.39–0.77); P=0.0005278.2,7

INDICATIONS

  • OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.
  • OPDIVO Qvantig® (nivolumab + hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

Scroll down for the latest overall survival data

There is a need for approved adjuvant options to help extend DFS

In a retrospective, observational cohort study† of patients 65 years and older with UC at high risk‡ of recurrence after radical resection, the mDFS§ was 13.5 months.8||
Patients who received neoadjuvant chemotherapy were also included.8

†This study included 665 patients from the SEER-Medicare database who had UC of the bladder or upper tract at a high risk of recurrence after radical resection.8
‡Prior neoadjuvant chemotherapy: AJCC stage T2–T4a or N+ and M0 for bladder site and AJCC stage T2–T4 or N+ and M0 for other sites; no neoadjuvant chemotherapy: AJCC stage T3–T4a or N+ and M0 for bladder site and AJCC stage T3–T4 or N+ and M0 for other sites.8
§DFS was defined as the first occurrence of surgery, radiotherapy, ≥1 administration of systemic chemotherapy, or palliative TURBT after 120 days of primary surgical resection. Those who received adjuvant treatment within 120 days of radical resection were excluded from the study.8
||mDFS was 13.5 months (95% CI: 11.3–16.8).8

AJCC=American Joint Committee on Cancer; CI=confidence interval; DFS=disease-free survival; IV=intravenous, mDFS=median disease-free survival; PK=pharmacokinetics; SEER=Surveillance, Epidemiology, and End Results Program; TURBT=transurethral resection of bladder tumor.

Scroll down to learn more about Checkmate 274

CHECKMATE 274:  FOR ADULT PATIENTS WITH UC AT HIGH RISK OF RECURRENCE AFTER RADICAL RESECTION OF UC

First and only phase 3, placebo-controlled adjuvant trial in patients with UC2,3,9

Checkmate 274 study design, graphic

Checkmate 274 includes data from an extended follow-up analysis at a minimum follow-up time of 31.6 months.10¶

  • This trial excluded patients with any condition requiring systemic treatment with immunosuppressants (eg, glucocorticoids) within 2 weeks of treatment11
  • DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death2
  • Minimum follow-up time in all randomized patients was 5.9 months. Median follow-up time in all randomized patients was 20.9 months for OPDIVO® (nivolumab) and 19.5 months for placebo3

*Urothelial carcinoma originating in the bladder or upper urinary tract (renal pelvis or ureter).2
†AJCC tumor stage.12
‡Using the PD-L1 IHC 28-8 pharmDx assay.2
§Approved dosing for OPDIVO is 240 mg IV q2w or 480 mg IV q4w.2
||OS data are immature at the time of the planned interim analysis.2,3
Based on extended follow-up analysis in all randomized patients at a minimum follow-up time of 31.6 months and a median follow-up time of 37.4 months for OPDIVO and 33.9 months for placebo.12

ECOG PS=Eastern Cooperative Oncology Group Performance Status; ICH=immunohistochemistry; IV=intravenous; OS=overall survival; q2w=every 2 weeks; q4w=every 4 weeks.

Select Important Safety Information
Serious Adverse Reactions

In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

Common Adverse Reactions

In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

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

Patient eligibility criteria

CHECKMATE 274 DEFINED PATIENTS AT HIGH RISK OF RECURRENCE
ACCORDING TO THE FOLLOWING CRITERIA2:
Patient eligibility criteria for Checkmate 274 clinical trial, graphic

OPDIVO Qvantig and OPDIVO IV are the only FDA-approved adjuvant options for these patients, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status1,2

*Cisplatin-based.2
†Are not eligible for or refused cisplatin-based chemotherapy.2

Checkmate 274 baseline characteristics9

BASELINE CHARACTERISTICS OPDIVO IV
(n=353)		 PLACEBO 
(n=356)
Median age (range), years 65.3 (30–92) 65.9 (42–88)
Male, % 75.1 77.2

Region, %

United States
Europe
Asia
Rest of the world

 

13.9
48.2
22.7
15.3

 

14.9
48.0
20.8
16.3

ECOG PS,* %

0
1
2†

 

63.5
34.6
2.0

 

62.1
35.1
2.5

Tumor origin at initial diagnosis, %

Urinary bladder
Upper tract disease

 


79.0
21.0

 


78.9
21.1
Minor histological variants present, % 41.1 39.6
PD-L1 ≥1% (IVRS), % 39.7 39.9
Prior neoadjuvant cisplatin, % 43.3 43.5

Pathologic T stage at resection,‡§ %

pTO–2
pT3
pT4a
Other
22.7
58.4
16.1
2.5
24.2
57.3
17.4
0.8

Nodal status at resection,§ %

N+
N0/x with <10 nodes removed
N0 with ≥10 nodes removed

 

47.3
26.6
25.8

 

47.2
27.8
24.7 

In the OPDIVO IV arm:

  • ~40% of patients expressed PD-L1 ≥1%9
  • ~43% of patients received prior neoadjuvant chemotherapy9
  • ~47% of patients had nodal involvement9

*Not reported for 1 patient in the placebo arm.9
†ECOG PS of 2 was permitted only for patients who did not receive cisplatin-based neoadjuvant chemotherapy and were ineligible for adjuvant cisplatin-based chemotherapy.8
‡The AJCC tumor staging included patients with N+, N0, or Nx.9,12
§Not reported for 1 patient in each arm.9

IVRS=Interactive Voice-Response System.

Continued disease-free survival with OPDIVO IV at 31.6-month minimum follow-up10*†

DISEASE-FREE SURVIVAL IN ALL RANDOMIZED PATIENTS
(31.6-MONTH MINIMUM FOLLOW-UP)10
OPDIVO® (nivolumab) DFS for patients in Checkmate 274 clinical trial at minimum follow-up of 31.6 months, Kaplan-Meier Curve

Limitation: Checkmate 274 was not powered to detect differences in the treatment effect at extended follow-up analysis; therefore, results from this exploratory analysis should be interpreted with caution.

Primary analysis:
mDFS in all randomized patients (minimum follow-up time of 5.9 months; median follow-up time of 20.9 months for OPDIVO IV and 19.5 months for placebo)2,3

  • OPDIVO IV: 20.8 months (95% CI: 16.5–27.6)2,3
  • Placebo: 10.8 months (95% CI: 8.3–13.9)2,3
  • HR=0.70 (95% CI: 0.57–0.86); P=0.00082,3

mDFS in patients with PD-L1 ≥1% (minimum follow-up time of 6.3 months; median follow-up time of 22.1 months for OPDIVO IV and 18.7 months for placebo)2,12

  • OPDIVO IV: NR (95% CI: 21.2–NE)2
  • Placebo: 8.4 months (95% CI: 5.6–21.2)2
  • HR=0.55 (95% CI: 0.39–0.77); P=0.00052

Extended follow-up analysis:
mDFS in patients with PD-L1 ≥1% (median follow-up time of 39.8 months for OPDIVO IV and 33.3 months for placebo)10

  • OPDIVO IV: 52.6 months (95% CI: 25.8–NE)10
  • Placebo: 8.4 months (95% CI: 5.6–17.9)10
  • HR=0.52 (95% CI: 0.37–0.72)10

Primary analysis exploratory and secondary endpoint information

  • In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74–1.80)2
  • In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64–1.08)2
  • OS data are immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm)2

*Based on extended follow-up analysis in all randomized patients at a minimum follow-up time of 31.6 months and a median follow-up time of 37.4 months for OPDIVO and 33.9 months for placebo.10
†Vs placebo.10

HR=hazard ratio; NE=not estimable; NR=not reached; UTUC=upper tract urothelial carcinoma.

Overall survival with OPDIVO IV14*

OVERALL SURVIVAL IN ALL RANDOMIZED PATIENTS
(INTERIM ANALYSIS AT 31.6-MONTH MINIMUM FOLLOW-UP; 36.1-MONTH MEDIAN FOLLOW-UP)14
OPDIVO® (nivolumab) Overall survival for patients in Checkmate 274 clinical trial at minimum follow-up of 31.6 months, Kaplan-Meier Curve

Limitation: OS data are immature and follow-up is ongoing as the prespecified statistical boundary for significance was not met at the time of this analysis. Results are descriptive and should be interpreted with caution.

Primary analysis secondary endpoint information (minimum follow-up time of 5.9 months; median follow-up time of 20.9 months for OPDIVO IV and 19.5 months for placebo)3

  • OS data are immature with 33% of deaths in overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm)2

Median OS in patients with PD-L1 ≥1% (interim analysis at minimum follow-up time of 11.4 months; median follow-up time of 23.4 months)14

  • OPDIVO IV (n=140): NR (95% CI: NE)14
  • Placebo (n=142): NR (95% CI: 29.0–NE)14
  • HR=0.56 (95% CI: 0.36–0.86)14

*Based on pre-planned interim analysis in all randomized patients at a minimum follow-up time of 31.6 months and a median follow-up time of 36.1 months.14

Disease-free survival and interim OS data with OPDIVO IV15*†‡

Checkmate 274
Primary endpoint in all randomized patients

DFS at the 59.6-month minimum follow-up

26%

reduced risk of recurrence or death
HR=0.74 (95% CI: 0.61-0.90)

• mDFS: 21.9 months (95% Cl: 18.8-36.9) for OPDIVO IV and 11.0 months (95% CI: 8.3-16.6) for placebo

Secondary endpoint in all randomized patients

Interim OS data at the 59.6-month minimum follow-up

54.6%

of patients still alive at 5 years with OPDIVO IV vs 47.1% with placebo

    • mOS: 75.0 months (95% CI: 56.7-NE) for OPDIVO IV and 50.1 months (95% CI: 38.0-72.1) for placebo; HR=0.83 (95% CI: 0.67-1.02)

Limitations: Analyses of the follow-up data were not prespecified within the study protocol and were not powered to detect differences between treatment arms; therefore, the results should be interpreted with caution. OS data are immature and follow-up is ongoing as the pre-specified statistical boundary for significance was not met at the time of this analysis. Results are descriptive and should be interpreted with caution.

Extended follow-up analysis results for OPDIVO IV vs placebo from Checkmate 27415§
  • mDFS in patients with PD-L1 ≥1% (minimum follow-up time of 60.0 months): 55.5 months (95% CI: 25.8–66.5) for OPDIVO IV and 8.4 months (95% Cl: 5.6-20.0) for placebo; HR=0.58 (95% CI: 0.42–0.79)
Primary analysis results for OPDIVO IV vs placebo from Checkmate 274
  • mDFS in all randomized patients (minimum follow-up time of 5.9 months; median follow-up time of 20.9 months for OPDIVO IV and 19.5 months for placebo): 20.8 months (95% CI: 16.5–27.6) for OPDIVO IV and 10.8 months (95% CI: 8.3–13.9) for placebo; HR=0.70 (95% CI: 0.57–0.86); P=0.00082,3,15
  • mDFS in patients with PD-L1 ≥1% (minimum follow-up time of 6.3 months; median follow-up time of 22.1 months for OPDIVO IV and 18.7 months for placebo): NR (95% CI: 21.2–NE) for OPDIVO IV and 8.4 months (95% CI: 5.6–21.2) for placebo; HR=0.55 (95% CI: 0.39–0.77); P=0.00052,13,15
  • In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the OPDIVO IV arm compared with the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74–1.80)1
  • OS in all randomized patients (minimum follow-up time of 5.9 months; median follow-up time of 20.9 months for OPDIVO IV and 19.5 months for placebo): OS data were immature with 33% of deaths. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm)2,3

*vs placebo.15
†Based on extended follow-up analysis in all randomized patients who received OPDIVO IV or placebo at a minimum follow-up time of 59.6 months and a median follow-up time of 43.4 months.15
‡See study design for additional information on Checkmate 274.
§Based on extended follow-up analysis in patients with tumor expression PD-L1 expression ≥1% who received OPDIVO IV or placebo at a minimum follow-up of 60.0 months and a median follow-up of 52.9 months.2

Checkmate 67T Study Information

Study design: Checkmate 67T was a phase 3, randomized (1:1), open-label, non-inferiority trial evaluating OPDIVO Qvantig (1,200 mg of nivolumab and 20,000 units of hyaluronidase) compared with OPDIVO IV, in adult patients with advanced or metastatic ccRCC who received prior systemic therapy. Patients were stratified by weight (<80 kg versus ≥80 kg) and IMDC risk score (favorable vs intermediate vs poor risk). A total of 495 patients were randomized to receive either OPDIVO Qvantig every 4 weeks subcutaneously (n=248) or OPDIVO 3 mg/kg every 2 weeks intravenously (n=247). The co-primary endpoints were time-averaged serum concentration over 28 days (Cavgd28) and minimum serum concentration at steady state (Cminss). The key powered secondary endpoint was ORR, as assessed by BICR. The minimum follow-up time was 8 months.1,6

Results: Co-primary PK endpoints: Cavgd28 GMR of 2.10 (90% CI: 2.00–2.20) and Cminss GMR of 1.77 (90% CI: 1.63–1.93). ORR was 24% (95% CI: 19–30) for OPDIVO Qvantig (n=248) and 28% (95% CI: 14–24) for OPDIVO IV (n=247) with a risk ratio of 1.33 (95% CI: 0.94–1.87). Both PK and ORR met the predefined acceptance margin for non-inferiority. The most common adverse reactions (≥10%) in patients treated with OPDIVO Qvantig were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. Serious adverse reactions occurred in 28% of patients who received OPDIVO Qvantig. Serious adverse reactions in >1% of patients included pleural effusion, pneumonitis, hyperglycemia, hyperkalemia, hemorrhage, and diarrhea.1,6

OPDIVO Qvantig dosing options1

OPDIVO is still available as an IV infusion. View OPDIVO IV dosing schedule >

OPDIVO Qvantig® (nivolumab+hyaluronidase-nvhy) Dosing Options

INDICATION OPDIVO Qvantig (nivolumab + hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

  • OPDIVO Qvantig is administered as a 3- to 5-minute subcutaneous injection1
  • Review the Full US Prescribing Information for recommended dosage information for OPDIVO Qvantig
  • No premedication required1
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Safety Data

View a selected safety profile of adverse reactions seen in clinical trials.

See Data

OPDIVO® (nivolumab) vial with timer icon
Dosing Schedules

Find dosing information to get patients started on therapy. 

View Schedule

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More UC Indications

Learn about another urothelial carcinoma indication.

Choose Another Indication

Learn more about how OPDIVO is approved for use in earlier stages of cancer

See Indications

References:

  1. OPDIVO Qvantig® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. OPDIVO® (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  3. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
  4. Jodon G, Fischer SM, Kessler ER. Treatment of urothelial cancer in elderly patients: focus on immune checkpoint inhibitors. Drugs Aging. 2018;35(5):409-421.
  5. Duplisea JJ, Dinney CPN. Should chemotherapy still be used to treat all muscle invasive bladder cancer in the "era of immunotherapy"? Expert Rev Anticancer Ther. 2019;19(7):543-545.
  6. Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol. 2025;36(1):99-107.
  7. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
  8. Drakaki A, Pantuck A, Mhatre SK, et al. "Real-world" outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma. Urol Oncol. 2021;39(1):76.e15-76.e22.
  9. Bajorin DF, Witjes JA, Gschwend JE, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at ASCO GU 2021. Abstract 391.
  10. Galsky MD, Witjes JA, Gschwend JE, et al. Extended follow-up results from the CheckMate 274 trial. Oral presentation at ASCO GU 2021. Abstract LBA443.
  11. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. [supplementary appendix]
  12. Bladder cancer early detection, diagnosis, and staging. American Cancer Society. Accessed March 15, 2026. https://www.cancer.org/content/dam/CRC/PDF/Public/8559.00.pdf
  13. Data on file. NIVO 639. Princeton, NJ: Bristol-Myers Squibb Company.
  14. Galsky MD, Witjes JA, Gschwend JE, et al. Extended follow-up from CheckMate 274 including the first report of overall survival outcomes. Oral presentation at EAU 2024.
  15. Galsky MD, Gschwend JE, Milowsky MI, et al. Adjuvant nivolumab vs placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274. Oral presentation at ESMO 2025. Presentation 30680.
foot note heading
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 QVANTIG, OPDIVO, or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO QVANTIG, 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 QVANTIG, 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 QVANTIG, OPDIVO, and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO QVANTIG, 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 QVANTIG, OPDIVO, and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions. 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%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). 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%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

Immune-Mediated Colitis

OPDIVO QVANTIG, 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. Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions. 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%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). 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 QVANTIG, OPDIVO, and YERVOY can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. 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%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). 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% (35/320) of patients.

Immune-Mediated Endocrinopathies

OPDIVO QVANTIG, 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 QVANTIG, 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.

Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456) of patients, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). 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 monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456) of patients, including Grade 3 (2.4%) and Grade 2 (6%). 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%).

Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade 1 (0.4%) adverse reaction. In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). 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%).

Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (0.4%) adverse reactions. 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). 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%).

Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (5.7%) adverse reactions. 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). 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%).

Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG. 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. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO QVANTIG, OPDIVO and YERVOY can cause immune-mediated nephritis. Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG. 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%). 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 QVANTIG, OPDIVO, and YERVOY can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (drug rash with eosinophilia and systemic symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue OPDIVO QVANTIG, OPDIVO, and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 7% (17/247) of patients taking OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.8%) adverse reactions. 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%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). 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 QVANTIG or OPDIVO monotherapy or in combination with YERVOY, chemotherapy or immunotherapy, 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; 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, other transplant (including corneal graft) rejection; other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reporting as the co-occurrence of either two or all three adverse reactions.

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 QVANTIG, 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 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. In melanoma 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 HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, 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 every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) 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 QVANTIG or 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 QVANTIG or 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 QVANTIG, 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 QVANTIG, 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. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG, 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 QVANTIG, 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 of OPDIVO QVANTIG, OPDIVO, or YERVOY.

Serious Adverse Reactions

In Checkmate 67T, serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG (n=247). Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications. 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 (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) 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 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated 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. In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=524). Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). The most frequent Grade 3-4 lab abnormalities reported in ≥1% of OPDIVO-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%). In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. In Checkmate 77T, serious adverse reactions occurred in 21% of patients who received OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228). The most frequent (≥2%) serious adverse reaction was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). In the adjuvant phase of Checkmate 77T, 22% of patients experienced serious adverse reactions (n=142). The most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. 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 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. 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 48% 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. In Study CA209-8UT (SWOG 1826), serious adverse reactions occurred in 39% of patients receiving OPDIVO in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (n=490). The most frequent serious adverse reactions reported in ≥5% patients who received OPDIVO in combination with AVD were neutropenia (7%), pyrexia (7%), febrile neutropenia (6%), and nausea (6%). Fatal adverse reactions occurred in 3 patients (0.6%), all from sepsis. 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 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 8HW, serious adverse reactions occurred in 46% of patients receiving OPDIVO in combination with YERVOY. The most frequent serious adverse reactions reported in ≥1% of patients who received OPDIVO with YERVOY were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). Fatal adverse reactions occurred in 2 (0.6%) patients who received OPDIVO in combination with YERVOY; these included myocarditis and pneumonitis (1 each). In Checkmate 8HW, serious adverse reactions occurred in 39% of patients receiving OPDIVO alone. The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO as a single agent were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%). Fatal adverse reactions occurring in 3 (0.9%) patients who received OPDIVO as a single agent; these included pneumonitis (n=2) and myasthenia gravis. In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reporting in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; this included sepsis (1%). OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction. In Checkmate 9DW, serious adverse reactions occurred in 53% of patients receiving OPDIVO with YERVOY (n=332). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with YERVOY were diarrhea/colitis (4.5%), immune-mediated hepatitis (3%), gastrointestinal hemorrhage (2.4%), and hepatic failure (2.4%). Fatal adverse reactions occurred in 12 (3.6%) patients who received OPDIVO with YERVOY; these included 4 (1.2%) subjects who died due to immune-mediated or autoimmune hepatitis. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO. In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving OPDIVO in combination with YERVOY (n=322). The most frequent serious adverse reactions reported in ≥2% who received OPDIVO in combination with YERVOY were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with YERVOY; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. 

Common Adverse Reactions

In Checkmate 67T, the most common adverse reactions (≥10%) in patients treated with OPDIVO QVANTIG (n=247) were musculoskeletal pain (31%), fatigue (20%), pruritus (16%), rash (15%), hypothyroidism (12%), diarrhea (11%), cough (11%), and abdominal pain (10%). 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%), 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 (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). 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 Checkmate 76K, the most common adverse reactions (≥20%) reported with OPDIVO (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritus (20%). In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 77T, the most common adverse reactions (reported in ≥20%) in patients receiving OPDIVO in combination with chemotherapy (n=228) were anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%). In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). 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 743, the most common adverse reactions (≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). 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%). 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 Study CA209-8UT (SWOG 1826), the most common adverse reactions (≥30%) in the OPDIVO plus AVD arm (n=490) were nausea (70%), neutropenia (61%), fatigue (59%), anemia (51%), constipation (49%), leukopenia (44%), musculoskeletal pain (42%), peripheral neuropathy (41%), transaminases increase (41%), vomiting (33%), and stomatitis (30%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) 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 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%). In Checkmate 8HW, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with YERVOY were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. In Checkmate 8HW, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. In Checkmate 901, the most common adverse reactions (≥20%) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. In Checkmate 9DW, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=332) were rash (36%), pruritus (34%), fatigue (33%), and diarrhea (22%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Attraction-3, the most common adverse reactions (≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with YERVOY (n=322) were rash (31%), fatigue (28%), pyrexia (23%), nausea (22%), diarrhea (22%), and constipation (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Surgery Related Adverse Reactions

In Checkmate 77T, 5.3% (n=12) of the OPDIVO-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in OPDIVO-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).

Please see US Full Prescribing Information for OPDIVO, YERVOY, and OPDIVO QVANTIG.

Clinical Trials and Patient Populations

Checkmate 67T–previously treated advanced or metastatic clear cell renal cell carcinoma with OPDIVO QVANTIG; Checkmate 037–previously treated metastatic melanoma; Checkmate 066—previously untreated unresectable or metastatic melanoma; Checkmate 067–previously untreated unresectable or metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 238–adjuvant treatment of patients with completely resected Stage III B/C or Stage IV melanoma; Checkmate 76K–adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 77T–Neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent OPDIVO as adjuvant treatment after surgery; Checkmate 227—previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025–previously treated renal cell carcinoma; Study CA209-8UT (SWOG 1826)—previously untreated Classical Hodgkin Lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 8HW–Previously Checkmate 142–MSI-H or dMMR unresectable or metastatic colorectal cancer in combination with YERVOY; Checkmate 8HW: Previously Checkmate 142–previously treated MSI-H or dMMR metastatic colorectal cancer; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 9DW–hepatocellular carcinoma, in combination with YERVOY; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY, after prior treatment with sorafenib; Attraction-3–esophageal squamous cell carcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma in combination with chemotherapy; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma combination with YERVOY; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma

 

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