Drug Detail:Opdivo (Nivolumab [ nye-vol-ue-mab ])
Drug Class: Anti-PD-1 and PD-L1 monoclonal antibodies (immune checkpoint inhibitors)
Highlights of Prescribing Information
OPDIVO (nivolumab) injection, for intravenous use
Initial U.S. Approval: 2014
Recent Major Changes
Indications and Usage (1) |
2/2023 |
Dosage and Administration (2) |
2/2023 |
Indications and Usage for Opdivo
OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:
Melanoma
- •
- adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. (1.1)
- •
- adult and pediatric (12 years and older) patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. (1.2)
Non-Small Cell Lung Cancer (NSCLC)
- •
- adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.3)
- •
- adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab. (1.4)
- •
- adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy. (1.4)
- •
- adult patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. (1.4)
Malignant Pleural Mesothelioma
- •
- adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab. (1.5)
Renal Cell Carcinoma (RCC)
- •
- adult patients with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab. (1.6)
- •
- adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. (1.6)
- •
- adult patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.6)
Classical Hodgkin Lymphoma (cHL)
- •
- adult patients with classical Hodgkin lymphoma that has relapsed or progressed aftera: (1.7)
- •
- autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
- •
- 3 or more lines of systemic therapy that includes autologous HSCT.
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
- •
- adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. (1.8)
Urothelial Carcinoma
- •
- adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. (1.9)
- •
- adult patients with locally advanced or metastatic urothelial carcinoma who:
- •
- have disease progression during or following platinum-containing chemotherapy
- •
- have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.9)
Colorectal Cancer
- •
- adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab.a (1.10)
Hepatocellular Carcinoma (HCC)
- •
- adult patients with hepatocellular carcinoma who have been previously treated with sorafenib in combination with ipilimumab.a (1.11)
Esophageal Cancer
- •
- adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.12)
- •
- adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12)
- •
- adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab. (1.12)
- •
- adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. (1.12)
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
- •
- adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.13)
a This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Opdivo Dosage and Administration
- •
- Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2)
- •
- Unresectable or metastatic melanoma
- •
- Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2)
- •
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
- •
- Adult and pediatric patients weighing 40 kg or greater:1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2)
- •
- Pediatric patients weighing less than 40 kg: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
- •
- Adjuvant treatment of melanoma
- •
- Adult and pediatric patients weighing 40 kg or greater: 240 40 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2)
- •
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
- •
- Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer
- •
- 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles (2.2)
- •
- Metastatic non-small cell lung cancer
- •
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
- •
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2)
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Malignant pleural mesothelioma
- •
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
- •
- Advanced renal cell carcinoma
- •
- 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.2)
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Classical Hodgkin lymphoma
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Recurrent or metastatic squamous cell carcinoma of the head and neck
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Adjuvant treatment of urothelial carcinoma
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Locally advanced or metastatic urothelial carcinoma
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
- •
- Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks. (2.2)
- •
- Adult and pediatric patients weighing 40 kg or greater: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Hepatocellular carcinoma
- •
- 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Adjuvant treatment of resected esophageal or gastroesophageal cancer
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks for total treatment duration of 1 year. (2.2)
- •
- Esophageal squamous cell carcinoma
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks in combination with chemotherapy regimen of fluoropyrimidine- and platinum-containing chemotherapy. (2.2)
- •
- 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
- •
- 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
- •
- Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC, GEJC, or EAC)
- •
- 360 mg every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks. (2.2)
- •
- 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.2)
- •
- See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.
Dosage Forms and Strengths
- •
- Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) solution in a single-dose vial. (3)
Contraindications
- •
- None. (4)
Warnings and Precautions
- •
-
Immune-Mediated Adverse Reactions: (5.1)
- o
- Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.
- o
- Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
- o
- Withhold or permanently discontinue based on severity and type of reaction. (2.3)
- •
- Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction. (5.2)
- •
- Complications of allogeneic HSCT: Fatal and other serious complications can occur in patient who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3)
- •
- Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3)
- •
- 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. (5.5)
Adverse Reactions/Side Effects
Most common adverse reactions (incidence ≥20%) in patients were:
- •
- As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1)
- •
- In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (6.1)
- •
- In combination with platinum-doublet chemotherapy: nausea, constipation, fatigue, decreased appetite, and rash. (6.1)
- •
- In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1)
- •
- In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)
- •
- In combination with fluoropyrimidine- and platinum-containing chemotherapy: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use In Specific Populations
- •
- Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2023
Related/similar drugs
Yervoy, Retevmo, Keytruda, Rybrevant, Lumakras, methotrexate, AvastinFull Prescribing Information
1. Indications and Usage for Opdivo
1.1 Unresectable or Metastatic Melanoma
OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.
1.2 Adjuvant Treatment of Melanoma
OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
1.3 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
OPDIVO, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).
1.4 Metastatic Non-Small Cell Lung Cancer
- •
- OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.
- •
- OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.
- •
- OPDIVO is indicated for the treatment of adult patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
1.5 Malignant Pleural Mesothelioma
OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.
1.6 Advanced Renal Cell Carcinoma
- •
- OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced RCC.
- •
- OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.
- •
- OPDIVO as a single agent is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
1.7 Classical Hodgkin Lymphoma
OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:
- •
- autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
- •
- 3 or more lines of systemic therapy that includes autologous HSCT.
This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
1.8 Squamous Cell Carcinoma of the Head and Neck
OPDIVO is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.
1.9 Urothelial Carcinoma
OPDIVO 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 [see Clinical Studies (14.9)].
OPDIVO is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:
- •
- have disease progression during or following platinum-containing chemotherapy
- •
- have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
1.10 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
1.11 Hepatocellular Carcinoma
OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
1.12 Esophageal Cancer
- •
- OPDIVO is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).
- •
- OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
- •
- OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
- •
- OPDIVO is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.
1.13 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
2. Opdivo Dosage and Administration
2.1 Patient Selection
Select patients with metastatic NSCLC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.4)].
Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosage
The recommended dosages of OPDIVO as a single agent are presented in Table 1.
* 30-minute intravenous infusion. | ||
Indication |
Recommended OPDIVO Dosage |
Duration of Therapy |
Metastatic non-small cell lung cancer |
240 mg every 2 weeks* or 480 mg every 4 weeks* |
Until disease progression or unacceptable toxicity |
Advanced renal cell carcinoma |
||
Classical Hodgkin lymphoma |
||
Squamous cell carcinoma of the head and neck |
||
Locally advanced or metastatic urothelial carcinoma |
||
Esophageal squamous cell carcinoma |
||
Unresectable or metastatic melanoma |
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks* |
Until disease progression or unacceptable toxicity |
Pediatric patients age 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks* or 6 mg/kg every 4 weeks* |
||
Adjuvant treatment of melanoma |
240 mg every 2 weeks* or 480 mg every 4 weeks* |
Until disease recurrence or unacceptable toxicity for up to 1 year |
Adjuvant treatment of urothelial carcinoma (UC) |
||
Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer |
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks* |
Until disease progression or unacceptable toxicity |
Pediatric patients age 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks* |
||
Adjuvant treatment of resected esophageal or gastroesophageal junction cancer |
240 mg every 2 weeks* or 480 mg every 4 weeks* |
Until disease progression or unacceptable toxicity for a total treatment duration of 1 year |
The recommended dosages of OPDIVO in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO for the recommended dosage information, as appropriate.
* 30-minute intravenous infusion on the same day. | ||
Indication |
Recommended OPDIVO Dosage |
Duration of Therapy |
Unresectable or metastatic melanoma |
1 mg/kg every 3 weeks* with ipilimumab 3 mg/kg intravenously* |
In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier |
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks* |
After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity |
|
Pediatric patients age 12 years and older and weighing less than 40 kg: or 6 mg/kg every 4 weeks* |
||
Neoadjuvant treatment of resectable non-small cell lung cancer |
360 mg every 3 weeks* with platinum-doublet chemotherapy on the same day every 3 weeks |
In combination with platinum-doublet chemotherapy for 3 cycles |
Metastatic non-small cell lung cancer expressing PD-L1 |
360 mg every 3 weeks* with ipilimumab 1 mg/kg every 6 weeks* |
In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
Metastatic or recurrent non-small cell lung cancer |
360 mg every 3 weeks* with ipilimumab 1 mg/kg every 6 weeks* and histology-based platinum doublet chemotherapy every 3 weeks |
In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
2 cycles of histology-based platinum-doublet chemotherapy |
||
Malignant pleural mesothelioma |
360 mg every 3 weeks* with ipilimumab 1 mg/kg every 6 weeks* |
In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
Advanced renal cell carcinoma |
3 mg/kg every 3 weeks* with ipilimumab 1 mg/kg intravenously* |
In combination with ipilimumab |
240 mg every 2 weeks* or 480 mg every 4 weeks* Administer OPDIVO in combination with cabozantinib 40 mg orally once daily without food |
OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years |
|
Cabozantinib: Until disease progression or unacceptable toxicity |
||
240 mg every 2 weeks* or 480 mg every 4 weeks* |
After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity |
|
Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer |
3 mg/kg every 3 weeks* with ipilimumab 1 mg/kg intravenously* |
In combination with ipilimumab |
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks* |
After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity |
|
Pediatric patients age 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks* |
||
Hepatocellular carcinoma |
1 mg/kg every 3 weeks* with ipilimumab 3 mg/kg intravenously* |
In combination with ipilimumab |
240 mg every 2 weeks* or 480 mg every 4 weeks* |
After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity |
|
Esophageal squamous cell carcinoma |
240 mg every 2 weeks* or 480 mg every 4 weeks* Administer OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy |
OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years |
Chemotherapy: Until disease progression or unacceptable toxicity |
||
3 mg/kg every 2 weeks* or 360 mg every 3 weeks* with ipilimumab 1 mg/kg every 6 weeks* |
In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years |
|
Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma |
240 mg every 2 weeks* with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks or 360 mg every 3 weeks* with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks |
Until disease progression, unacceptable toxicity, or up to 2 years |
2.3 Dose Modifications
No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
Dosage modifications for OPDIVO or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.
When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines.
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal |
||
Adverse Reaction |
Severity |
Dosage Modification |
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] |
||
Pneumonitis |
Grade 2 |
Withholda |
Grades 3 or 4 |
Permanently discontinue |
|
Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. |
Grade 2 or 3 |
Withholda |
Grade 4 |
Permanently discontinue |
|
Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. |
AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. |
Withholda |
AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. |
Permanently discontinue |
|
Hepatitis with tumor involvement of the liverb For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. |
Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. |
Withholda |
AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. |
Permanently discontinue |
|
Endocrinopathiesc |
Grade 3 or 4 |
Withhold until clinically stable or permanently discontinue depending on severity |
Nephritis with Renal Dysfunction |
Grade 2 or 3 increased blood creatinine |
Withholda |
Grade 4 increased blood creatinine |
Permanently discontinue |
|
Exfoliative Dermatologic Conditions |
Suspected SJS, TEN, or DRESS |
Withhold |
Confirmed SJS, TEN, or DRESS |
Permanently discontinue |
|
Myocarditis |
Grades 2, 3, or 4 |
Permanently discontinue |
Neurological Toxicities |
Grade 2 |
Withholda |
Grade 3 or 4 |
Permanently discontinue |
|
Other Adverse Reactions |
||
Infusion-Related Reactions [see Warnings and Precautions (5.2)] |
Grade 1 or 2 |
Interrupt or slow the rate of infusion |
Grade 3 or 4 |
Permanently discontinue |
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement. c Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib. d After recovery, rechallenge with one or both of OPDIVO and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO, refer to cabozantinib Prescribing Information. |
|||
Treatment |
Adverse Reaction |
Severity |
Dosage Modification |
OPDIVO in combination with ipilimumab |
Colitis |
Grade 2 |
Withholda |
Grade 3 or 4 |
Permanently discontinue |
||
Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC |
AST/ALT increases to >3 times ULN and ≤5 times ULN or Total bilirubin increases to ≥1.5 and ≤3 times ULN. |
Withholda |
|
AST or ALT >5 times ULN or Total bilirubin >3 times ULN. |
Permanently discontinue |
||
Hepatitis with tumor involvement of the liverb/HCC |
Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. |
Withholda |
|
AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. |
Permanently discontinue |
||
OPDIVO in combination with cabozantinib |
Liver enzyme elevations |
ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN |
Withholdc both OPDIVO and cabozantinib until adverse reactions recoverd to Grades 0-1 |
ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN |
Permanently discontinuec both OPDIVO and cabozantinib |
2.4 Preparation and Administration
Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake.
Preparation
- •
- Withdraw the required volume of OPDIVO and transfer into an intravenous container.
- •
- Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.
• For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.
• For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight. - •
- Mix diluted solution by gentle inversion. Do not shake.
- •
- Discard partially used vials or empty vials of OPDIVO.
- •
- The product does not contain a preservative.
- •
- After preparation, store the diluted solution either:
• at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
• under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation. - •
- Do not freeze.
Administration
- •
- Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
- •
- Administer OPDIVO in combination with other therapeutic agents as follows:
- o
- With ipilimumab: administer OPDIVO first followed by ipilimumab on the same day.
- o
- With platinum-doublet chemotherapy: administer OPDIVO first followed by platinum-doublet chemotherapy on the same day
- o
- With ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.
- o
- With fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
- •
- Use separate infusion bags and filters for each infusion.
- •
- Flush the intravenous line at end of infusion.
- •
- Do not co-administer other drugs through the same intravenous line.
3. Dosage Forms and Strengths
Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale-yellow solution in a single-dose vial.
5. Warnings and Precautions
5.1 Severe and Fatal Immune-Mediated Adverse Reactions
OPDIVO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. 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 [see Dosage and Administration (2.3)]. In general, if OPDIVO requires interruption or discontinuation, 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, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
OPDIVO as a Single Agent
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients.
Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.
OPDIVO with Ipilimumab
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients.
Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab.
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. 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.
OPDIVO as a Single Agent
Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients.
Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients.
Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.
OPDIVO as a Single Agent
Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients.
Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients.
Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.
OPDIVO with Cabozantinib
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. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt OPDIVO and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].
With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either OPDIVO (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].
OPDIVO as a Single Agent
Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients.
Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2.0% of patients.
Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.
Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.
OPDIVO with Cabozantinib
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO and cabozantinib in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom OPDIVO with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Hypophysitis
OPDIVO can cause immune-mediated hypophysitis. 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. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].
OPDIVO as a Single Agent
Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO in 0.2% of patients.
Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients.
Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.
Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.
Thyroid Disorders
OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].
Thyroiditis
OPDIVO as a Single Agent
Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients.
Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis.
Hyperthyroidism
OPDIVO as a Single Agent
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients.
Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients.
Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC.
Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.
Hypothyroidism
OPDIVO as a Single Agent
Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients.
Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients.
Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC.
Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].
OPDIVO as a Single Agent
Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients.
No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes.
Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.
OPDIVO as a Single Agent
Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients.
Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. 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 depending on severity [see Dosage and Administration (2.3)].
OPDIVO as a Single Agent
Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients.
Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients.
Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.
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 or OPDIVO in combination with ipilimumab, 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-Barre syndrome, nerve paresis, autoimmune neuropathy
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some 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, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic
Endocrine: Hypoparathyroidism
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection
5.2 Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.3)].
OPDIVO as a Single Agent
In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of OPDIVO.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.
5.3 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 a PD-1 receptor blocking antibody. 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) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.
5.4 Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. 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 and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
5.5 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 a PD-1 blocking antibody, including OPDIVO, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, 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.
6. Adverse Reactions/Side Effects
The following clinically significant adverse reactions are described elsewhere in the labeling.
- •
- Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
- •
- Infusion-Related Reactions [see Warnings and Precautions (5.2)]
- •
- Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.
The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).
Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.
Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.
Toxicity was graded per NCI CTCAE v4. a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis. b Includes rhinitis, pharyngitis, and nasopharyngitis. |
||||
Adverse Reaction |
OPDIVO
|
Chemotherapy
|
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Skin and Subcutaneous Tissue |
||||
Rasha |
21 |
0.4 |
7 |
0 |
Pruritus |
19 |
0 |
3.9 |
0 |
Respiratory, Thoracic and Mediastinal |
||||
Cough |
17 |
0 |
6 |
0 |
Infections |
||||
Upper respiratory tract infectionb |
11 |
0 |
2.0 |
0 |
General |
||||
Peripheral edema |
10 |
0 |
5 |
0 |
Clinically important adverse reactions in <10% of patients who received OPDIVO were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
General Disorders and Administration Site Conditions: infusion-related reactions
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). | ||||
Laboratory Abnormality |
OPDIVO |
Chemotherapy |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Increased AST |
28 |
2.4 |
12 |
1.0 |
Hyponatremia |
25 |
5 |
18 |
1.1 |
Increased alkaline phosphatase |
22 |
2.4 |
13 |
1.1 |
Increased ALT |
16 |
1.6 |
5 |
0 |
Hyperkalemia |
15 |
2.0 |
6 |
0 |
Previously Untreated Metastatic Melanoma
CHECKMATE-066
The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year.
The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%).
Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. 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 increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.
Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.
Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction. d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis. |
||||
Adverse Reaction |
OPDIVO
|
Dacarbazine
|
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
General | ||||
Fatigue |
49 |
1.9 |
39 |
3.4 |
Edemaa |
12 |
1.5 |
4.9 |
0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal painb |
32 |
2.9 |
25 |
2.4 |
Skin and Subcutaneous Tissue | ||||
Rashc |
28 |
1.5 |
12 |
0 |
Pruritus |
23 |
0.5 |
12 |
0 |
Vitiligo |
11 |
0 |
0.5 |
0 |
Erythema |
10 |
0 |
2.9 |
0 |
Infections | ||||
Upper respiratory tract infectiond |
17 |
0 |
6 |
0 |
Clinically important adverse reactions in <10% of patients who received OPDIVO were:
Nervous System Disorders: peripheral neuropathy
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients). | ||||
Laboratory Abnormality |
OPDIVO |
Dacarbazine |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Increased ALT |
25 |
3.0 |
19 |
0.5 |
Increased AST |
24 |
3.6 |
19 |
0.5 |
Increased alkaline phosphatase |
21 |
2.6 |
14 |
1.6 |
Increased bilirubin |
13 |
3.1 |
6 |
0 |
CHECKMATE-067
The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.
Patients were randomized to receive:
- •
- OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or
- •
- OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or
- •
- Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).
The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 40% for >1 year.
The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.
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 and ipilimumab arm relative to the OPDIVO arm.
The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).
The most common (≥20%) adverse reactions in the OPDIVO and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.
Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.
Toxicity was graded per NCI CTCAE v4. a Includes asthenia and fatigue. b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash. c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. e Includes hypertension and blood pressure increased. |
||||||
Adverse Reaction |
OPDIVO and Ipilimumab
|
OPDIVO
|
Ipilimumab
|
|||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
General | ||||||
Fatiguea |
62 |
7 |
59 |
1.6 |
51 |
4.2 |
Pyrexia |
40 |
1.6 |
16 |
0 |
18 |
0.6 |
Gastrointestinal | ||||||
Diarrhea |
54 |
11 |
36 |
5 |
47 |
7 |
Nausea |
44 |
3.8 |
30 |
0.6 |
31 |
1.9 |
Vomiting |
31 |
3.8 |
20 |
1.0 |
17 |
1.6 |
Skin and Subcutaneous Tissue | ||||||
Rashb |
53 |
6 |
40 |
1.9 |
42 |
3.5 |
Vitiligo |
9 |
0 |
10 |
0.3 |
5 |
0 |
Musculoskeletal and Connective Tissue | ||||||
Musculoskeletal painc |
32 |
2.6 |
42 |
3.8 |
36 |
1.9 |
Arthralgia |
21 |
0.3 |
21 |
1.0 |
16 |
0.3 |
Metabolism and Nutrition | ||||||
Decreased appetite |
29 |
1.9 |
22 |
0 |
24 |
1.3 |
Respiratory, Thoracic and Mediastinal | ||||||
Cough/productive cough |
27 |
0.3 |
28 |
0.6 |
22 |
0 |
Dyspnea/exertional dyspnea |
24 |
2.9 |
18 |
1.3 |
17 |
0.6 |
Infections | ||||||
Upper respiratory tract infectiond |
23 |
0 |
22 |
0.3 |
17 |
0 |
Endocrine | ||||||
Hypothyroidism |
19 |
0.6 |
11 |
0 |
5 |
0 |
Hyperthyroidism |
11 |
1.3 |
6 |
0 |
1 |
0 |
Investigations | ||||||
Decreased weight |
12 |
0 |
7 |
0 |
7 |
0.3 |
Vascular | ||||||
Hypertensione |
7 |
2.2 |
11 |
5 |
9 |
2.3 |
Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO as a single agent were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
Laboratory Abnormality | OPDIVO and Ipilimumab | OPDIVO | Ipilimumab | |||
---|---|---|---|---|---|---|
All Grades (%) | Grade 3-4 (%) | All Grades (%) | Grade 3-4 (%) | All Grades (%) | Grade 3-4 (%) | |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab (range: 75 to 297); OPDIVO (range: 81 to 306); ipilimumab (range: 61 to 301). | ||||||
Chemistry | ||||||
Increased ALT |
55 |
16 |
25 |
3.0 |
29 |
2.7 |
Hyperglycemia |
53 |
5.3 |
46 |
7 |
26 |
0 |
Increased AST |
52 |
13 |
29 |
3.7 |
29 |
1.7 |
Hyponatremia |
45 |
10 |
22 |
3.3 |
26 |
7 |
Increased lipase |
43 |
22 |
32 |
12 |
24 |
7 |
Increased alkaline phosphatase |
41 |
6 |
27 |
2.0 |
23 |
2.0 |
Hypocalcemia |
31 |
1.1 |
15 |
0.7 |
20 |
0.7 |
Increased amylase |
27 |
10 |
19 |
2.7 |
15 |
1.6 |
Increased creatinine |
26 |
2.7 |
19 |
0.7 |
17 |
1.3 |
Hematology | ||||||
Anemia |
52 |
2.7 |
41 |
2.6 |
41 |
6 |
Lymphopenia |
39 |
5 |
41 |
4.9 |
29 |
4.0 |
Adjuvant Treatment of Melanoma
The safety of OPDIVO as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.2)]. The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received OPDIVO for >6 months.
Serious adverse reactions occurred in 18% of OPDIVO-treated patients. Study therapy was discontinued for adverse reactions in 9% of OPDIVO-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of OPDIVO-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.
Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness. c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity. e Includes postural dizziness and vertigo. f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis. g Includes secondary hypothyroidism and autoimmune hypothyroidism. |
||||
Adverse Reaction |
OPDIVO |
Ipilimumab 10 mg/kg |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
General | ||||
Fatiguea |
57 |
0.9 |
55 |
2.4 |
Gastrointestinal | ||||
Diarrhea |
37 |
2.4 |
55 |
11 |
Nausea |
23 |
0.2 |
28 |
0 |
Abdominal painb |
21 |
0.2 |
23 |
0.9 |
Constipation |
10 |
0 |
9 |
0 |
Skin and Subcutaneous Tissue | ||||
Rashc |
35 |
1.1 |
47 |
5.3 |
Pruritus |
28 |
0 |
37 |
1.1 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind |
32 |
0.4 |
27 |
0.4 |
Arthralgia |
19 |
0.4 |
13 |
0.4 |
Nervous System | ||||
Headache |
23 |
0.4 |
31 |
2.0 |
Dizzinesse |
11 |
0 |
8 |
0 |
Infections | ||||
Upper respiratory tract infectionf |
22 |
0 |
15 |
0.2 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough |
19 |
0 |
19 |
0 |
Dyspnea/exertional dyspnea |
10 |
0.4 |
10 |
0.2 |
Endocrine | ||||
Hypothyroidismg |
12 |
0.2 |
7.5 |
0.4 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients). | ||||
Laboratory Abnormality |
OPDIVO |
Ipilimumab 10 mg/kg |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Hematology | ||||
Lymphopenia |
27 |
0.4 |
12 |
0.9 |
Anemia |
26 |
0 |
34 |
0.5 |
Leukopenia |
14 |
0 |
2.7 |
0.2 |
Neutropenia |
13 |
0 |
6 |
0.5 |
Chemistry | ||||
Increased Lipase |
25 |
7 |
23 |
9 |
Increased ALT |
25 |
1.8 |
40 |
12 |
Increased AST |
24 |
1.3 |
33 |
9 |
Increased Amylase |
17 |
3.3 |
13 |
3.1 |
Hyponatremia |
16 |
1.1 |
22 |
3.2 |
Hyperkalemia |
12 |
0.2 |
9 |
0.5 |
Increased Creatinine |
12 |
0 |
13 |
0 |
Hypocalcemia |
10 |
0.7 |
16 |
0.5 |
Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer
The safety of OPDIVO in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.3)]. Patients received either OPDIVO 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.
The median age of patients who received OPDIVO in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African-American.
Serious adverse reactions occurred in 30% of patients 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.
Study therapy with OPDIVO in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of OPDIVO in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).
The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.
Tables 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.
Toxicity was graded per NCI CTCAE v4. a Includes fatigue and asthenia b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash. c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy. |
||||
Adverse Reaction |
OPDIVO and Platinum-Doublet Chemotherapy |
Platinum-Doublet Chemotherapy |
||
All Grades (%) |
Grades 3 or 4 (%) |
All Grades (%) |
Grades 3 or 4 (%) |
|
Gastrointestinal |
||||
Nausea |
38 |
0.6 |
45 |
1.1 |
Constipation |
34 |
0 |
32 |
1.1 |
Vomiting |
11 |
1.1 |
13 |
0.6 |
General |
||||
Fatiguea |
26 |
2.3 |
23 |
1.1 |
Malaise |
15 |
0.6 |
14 |
0.6 |
Metabolism and Nutrition |
||||
Decreased appetite |
20 |
1.1 |
23 |
2.3 |
Skin and Subcutaneous Tissue |
||||
Rashb |
20 |
2.3 |
7 |
0 |
Alopecia |
11 |
0 |
15 |
0 |
Nervous System |
||||
Peripheral neuropathyc |
13 |
0 |
6 |
0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and platinum-doublet chemotherapy group (range: 73 to 171 patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients). | ||||
Laboratory Abnormality |
OPDIVO and Platinum-Doublet Chemotherapya |
Platinum-Doublet Chemotherapya |
||
All Grades (%) |
Grades 3 or 4 (%) |
All Grades (%) |
Grades 3 or 4 (%) |
|
Hematology |
||||
Anemia |
63 |
3.5 |
70 |
6 |
Neutropenia |
58 |
22 |
58 |
27 |
Leukopenia |
53 |
5 |
51 |
11 |
Lymphopenia |
38 |
4.7 |
31 |
1.8 |
Thrombocytopenia |
24 |
2.9 |
22 |
3.0 |
Chemistry |
||||
Hyperglycemia |
37 |
6 |
35 |
2.9 |
Hypomagnesemia |
25 |
1.2 |
29 |
1.2 |
Hyponatremia |
25 |
2.4 |
28 |
1.8 |
Increased amylase |
23 |
3.6 |
13 |
1.8 |
Increased ALT |
23 |
0 |
20 |
1.2 |
Metastatic Non-Small Cell Lung Cancer
First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab
The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.4)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received OPDIVO 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received OPDIVO and ipilimumab for >6 months and 23% of patients received OPDIVO and ipilimumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.
Serious adverse reactions occurred in 58% of patients. OPDIVO and ipilimumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.
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. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.
Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.
a Includes fatigue and asthenia. b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema. c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption. d Includes pruritus and pruritus generalized. e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity. f Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral. g Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. h Includes dyspnea and dyspnea exertional. i Includes cough and productive cough. j Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased. k Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased. l Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased. m Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia. |
||||
Adverse Reaction |
OPDIVO and Ipilimumab |
Platinum-Doublet Chemotherapy |
||
All Grades |
Grades 3-4 |
All Grades |
Grades 3-4 |
|
General |
||||
Fatiguea |
44 |
6 |
42 |
4.4 |
Pyrexia |
18 |
0.5 |
11 |
0.4 |
Edemab |
14 |
0.2 |
12 |
0.5 |
Skin and Subcutaneous Tissue |
||||
Rashc |
34 |
4.7 |
10 |
0.4 |
Pruritusd |
21 |
0.5 |
3.3 |
0 |
Metabolism and Nutrition |
||||
Decreased appetite |
31 |
2.3 |
26 |
1.4 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal paine |
27 |
1.9 |
16 |
0.7 |
Arthralgia |
13 |
0.9 |
2.5 |
0.2 |
Gastrointestinal |
||||
Diarrhea/colitisf |
26 |
3.6 |
16 |
0.9 |
Nausea |
21 |
1.0 |
42 |
2.5 |
Constipation |
18 |
0.3 |
27 |
0.5 |
Vomiting |
13 |
1.0 |
18 |
2.3 |
Abdominal paing |
10 |
0.2 |
9 |
0.7 |
Respiratory, Thoracic, and Mediastinal |
||||
Dyspneah |
26 |
4.3 |
16 |
2.1 |
Coughi |
23 |
0.2 |
13 |
0 |
Hepatobiliary |
||||
Hepatitisj |
21 |
9 |
10 |
1.2 |
Endocrine |
||||
Hypothyroidismk |
16 |
0.5 |
1.2 |
0 |
Hyperthyroidisml |
10 |
0 |
0.5 |
0 |
Infections and Infestations |
||||
Pneumoniam |
13 |
7 |
8 |
4.0 |
Nervous System |
||||
Headache |
11 |
0.5 |
6 |
0 |
Other clinically important adverse reactions in CHECKMATE-227 were:
Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo
Gastrointestinal: stomatitis, pancreatitis, gastritis
Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis
Nervous System: peripheral neuropathy, autoimmune encephalitis
Blood and Lymphatic System: eosinophilia
Eye Disorders: blurred vision, uveitis
Cardiac: atrial fibrillation, myocarditis
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients). | ||||
Laboratory Abnormality |
OPDIVO and Ipilimumab |
Platinum-Doublet Chemotherapy |
||
Grades 1-4 |
Grades 3-4 |
Grades 1-4 |
Grades 3-4 |
|
Hematology | ||||
Anemia |
46 |
3.6 |
78 |
14 |
Lymphopenia |
46 |
5 |
60 |
15 |
Chemistry |
||||
Hyponatremia |
41 |
12 |
26 |
4.9 |
Increased AST |
39 |
5 |
26 |
0.4 |
Increased ALT |
36 |
7 |
27 |
0.7 |
Increased lipase |
35 |
14 |
14 |
3.4 |
Increased alkaline phosphatase |
34 |
3.8 |
20 |
0.2 |
Increased amylase |
28 |
9 |
18 |
1.9 |
Hypocalcemia |
28 |
1.7 |
17 |
1.3 |
Hyperkalemia |
27 |
3.4 |
22 |
0.4 |
Increased creatinine |
22 |
0.9 |
17 |
0.2 |
First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy
The safety of OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.4)]. Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year.
Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy. 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.
Study therapy with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.
Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.
Adverse Reaction | OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy (n=358) | Platinum-Doublet Chemotherapy (n=349) |
||
---|---|---|---|---|
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Toxicity was graded per NCI CTCAE v4. a Includes fatigue and asthenia b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blenorrhagica, palmar-plantar erythrodysaesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria f Includes pruritus and generalized pruritus g Includes cough, productive cough, and upper-airway cough syndrome h Includes dyspnea, dyspnea at rest, and exertional dyspnea i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine j Includes dizziness, vertigo and positional vertigo |
||||
General |
||||
Fatiguea |
49 |
5 |
40 |
4.9 |
Pyrexia |
14 |
0.6 |
10 |
0.6 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal painb |
39 |
4.5 |
27 |
2.0 |
Gastrointestinal |
||||
Nausea |
32 |
1.7 |
41 |
0.9 |
Diarrheac |
31 |
6 |
18 |
1.7 |
Constipation |
21 |
0.6 |
23 |
0.6 |
Vomiting |
18 |
2.0 |
17 |
1.4 |
Abdominal paind |
12 |
0.6 |
11 |
0.9 |
Skin and Subcutaneous Tissue |
||||
Rashe |
30 |
4.7 |
10 |
0.3 |
Pruritusf |
21 |
0.8 |
2.9 |
0 |
Alopecia |
11 |
0.8 |
10 |
0.6 |
Metabolism and Nutrition |
||||
Decreased appetite |
28 |
2.0 |
22 |
1.7 |
Respiratory, Thoracic and Mediastinal |
||||
Coughg |
19 |
0.6 |
15 |
0.9 |
Dyspneah |
18 |
4.7 |
14 |
3.2 |
Endocrine |
||||
Hypothyroidismi |
19 |
0.3 |
3.4 |
0 |
Nervous System |
||||
Headache |
11 |
0.6 |
7 |
0 |
Dizzinessj |
11 |
0.6 |
6 |
0 |
Laboratory Abnormality | OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy | Platinum-Doublet Chemotherapy | ||
---|---|---|---|---|
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients). | ||||
Hematology |
||||
Anemia |
70 |
9 |
74 |
16 |
Lymphopenia |
41 |
6 |
40 |
11 |
Neutropenia |
40 |
15 |
42 |
15 |
Leukopenia |
36 |
10 |
40 |
9 |
Thrombocytopenia |
23 |
4.3 |
24 |
5 |
Chemistry |
||||
Hyperglycemia |
45 |
7 |
42 |
2.6 |
Hyponatremia |
37 |
10 |
27 |
7 |
Increased ALT |
34 |
4.3 |
24 |
1.2 |
Increased lipase |
31 |
12 |
10 |
2.2 |
Increased alkaline phosphatase |
31 |
1.2 |
26 |
0.3 |
Increased amylase |
30 |
7 |
19 |
1.3 |
Increased AST |
30 |
3.5 |
22 |
0.3 |
Hypomagnesemia |
29 |
1.2 |
33 |
0.6 |
Hypocalcemia |
26 |
1.4 |
22 |
1.8 |
Increased creatinine |
26 |
1.2 |
23 |
0.6 |
Hyperkalemia |
22 |
1.7 |
21 |
2.1 |
Second-line Treatment of Metastatic NSCLC
The safety of OPDIVO was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.4)]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in OPDIVO-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for >6 months and 20% of patients received OPDIVO for >1 year.
Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).
In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.
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. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Tables 19 and 20 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.
Adverse Reaction | OPDIVO
(n=418) | Docetaxel
(n=397) |
||
---|---|---|---|---|
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Toxicity was graded per NCI CTCAE v4. | ||||
Respiratory, Thoracic and Mediastinal | ||||
Cough |
31 |
0.7 |
24 |
0 |
Metabolism and Nutrition | ||||
Decreased appetite |
28 |
1.4 |
23 |
1.5 |
Skin and Subcutaneous Tissue | ||||
Pruritus |
10 |
0.2 |
2.0 |
0 |
Other clinically important adverse reactions observed in OPDIVO-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: OPDIVO group n=314 and docetaxel group n=297. b Not graded per NCI CTCAE v4. |
||||
Laboratory Abnormality |
OPDIVO |
Docetaxel |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Chemistry | ||||
Hyponatremia |
35 |
7 |
34 |
4.9 |
Increased AST |
27 |
1.9 |
13 |
0.8 |
Increased alkaline phosphatase |
26 |
0.7 |
18 |
0.8 |
Increased ALT |
22 |
1.7 |
17 |
0.5 |
Increased creatinine |
18 |
0 |
12 |
0.5 |
Increased TSHb |
14 |
N/A |
6 |
N/A |
Malignant Pleural Mesothelioma
The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.5)]. Patients received either OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received OPDIVO and ipilimumab for >6 months and 24% of patients received OPDIVO and ipilimumab for >1 year.
Serious adverse reactions occurred in 54% of patients who were treated with OPDIVO in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions 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.
Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.
The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.
Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.
a Includes fatigue and asthenia. b Includes pyrexia and tumor-associated fever. c Includes edema, generalized edema, peripheral edema, and peripheral swelling. d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain. e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blenorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria. f Includes pruritus, allergic pruritus, and generalized pruritus. g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis. h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. i Includes dyspnea, dyspnea at rest, and exertional dyspnea. j Includes cough, productive cough, and upper-airway cough syndrome. k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism. l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia. |
||||
Adverse Reaction |
OPDIVO and Ipilimumab |
Chemotherapy |
||
All Grades |
Grades 3-4 |
All Grades |
Grades 3-4 |
|
General |
||||
Fatiguea |
43 |
4.3 |
45 |
6 |
Pyrexiab |
18 |
1.3 |
4.6 |
0.7 |
Edemac |
17 |
0 |
8 |
0 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal paind |
38 |
3.3 |
17 |
1.1 |
Arthralgia |
13 |
1.0 |
1.1 |
0 |
Skin and Subcutaneous Tissue |
||||
Rashe |
34 |
2.7 |
11 |
0.4 |
Pruritusf |
21 |
1.0 |
1.4 |
0 |
Gastrointestinal |
||||
Diarrheag |
32 |
6 |
12 |
1.1 |
Nausea |
24 |
0.7 |
43 |
2.5 |
Constipation |
19 |
0.3 |
30 |
0.7 |
Abdominal painh |
15 |
1 |
10 |
0.7 |
Vomiting |
14 |
0 |
18 |
2.1 |
Respiratory, Thoracic, and Mediastinal |
||||
Dyspneai |
27 |
2.3 |
16 |
3.2 |
Coughj |
23 |
0.7 |
9 |
0 |
Metabolism and Nutrition |
||||
Decreased appetite |
24 |
1.0 |
25 |
1.4 |
Endocrine |
||||
Hypothyroidismk |
15 |
0 |
1.4 |
0 |
Infections and Infestations |
||||
Upper respiratory tract infectionl |
12 |
0.3 |
7 |
0 |
Pneumoniam |
10 |
4.0 |
4.2 |
2.1 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients). | ||||
Laboratory Abnormality |
OPDIVO and Ipilimumab |
Chemotherapy |
||
Grades 1-4 |
Grades 3-4 |
Grades 1-4 |
Grades 3-4 |
|
Chemistry |
||||
Hyperglycemia |
53 |
3.7 |
34 |
1.1 |
Increased AST |
38 |
7 |
17 |
0 |
Increased ALT |
37 |
7 |
15 |
0.4 |
Increased lipase |
34 |
13 |
9 |
0.8 |
Hyponatremia |
32 |
8 |
21 |
2.9 |
Increased alkaline phosphatase |
31 |
3.1 |
12 |
0 |
Hyperkalemia |
30 |
4.1 |
16 |
0.7 |
Hypocalcemia |
28 |
0 |
16 |
0 |
Increased amylase |
26 |
5 |
13 |
0.9 |
Increased creatinine |
20 |
0.3 |
20 |
0.4 |
Hematology |
||||
Lymphopenia |
43 |
8 |
57 |
14 |
Anemia |
43 |
2.4 |
75 |
15 |
Advanced Renal Cell Carcinoma
First-line Renal Cell Carcinoma
CHECKMATE-214
The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.6)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the OPDIVO and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 59% of patients receiving OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.
Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab-treated patients in CHECKMATE-214.
Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema, peripheral swelling. c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. |
||||
Adverse Reaction |
OPDIVO and Ipilimumab |
Sunitinib |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Adverse Reaction |
99 |
65 |
99 |
76 |
General | ||||
Fatiguea |
58 |
8 |
69 |
13 |
Pyrexia |
25 |
0.7 |
17 |
0.6 |
Edemab |
16 |
0.5 |
17 |
0.6 |
Skin and Subcutaneous Tissue | ||||
Rashc |
39 |
3.7 |
25 |
1.1 |
Pruritus/generalized pruritus |
33 |
0.5 |
11 |
0 |
Gastrointestinal | ||||
Diarrhea |
38 |
4.6 |
58 |
6 |
Nausea |
30 |
2.0 |
43 |
1.5 |
Vomiting |
20 |
0.9 |
28 |
2.1 |
Abdominal pain |
19 |
1.6 |
24 |
1.9 |
Constipation |
17 |
0.4 |
18 |
0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind |
37 |
4.0 |
40 |
2.6 |
Arthralgia |
23 |
1.3 |
16 |
0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough |
28 |
0.2 |
25 |
0.4 |
Dyspnea/exertional dyspnea |
20 |
2.4 |
21 |
2.1 |
Metabolism and Nutrition | ||||
Decreased appetite |
21 |
1.8 |
29 |
0.9 |
Nervous System | ||||
Headache |
19 |
0.9 |
23 |
0.9 |
Endocrine | ||||
Hypothyroidism |
18 |
0.4 |
27 |
0.2 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). | ||||
Laboratory Abnormality |
OPDIVO and Ipilimumab |
Sunitinib |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Chemistry | ||||
Increased lipase |
48 |
20 |
51 |
20 |
Increased creatinine |
42 |
2.1 |
46 |
1.7 |
Increased ALT |
41 |
7 |
44 |
2.7 |
Increased AST |
40 |
4.8 |
60 |
2.1 |
Increased amylase |
39 |
12 |
33 |
7 |
Hyponatremia |
39 |
10 |
36 |
7 |
Increased alkaline phosphatase |
29 |
2.0 |
32 |
1.0 |
Hyperkalemia |
29 |
2.4 |
28 |
2.9 |
Hypocalcemia |
21 |
0.4 |
35 |
0.6 |
Hypomagnesemia |
16 |
0.4 |
26 |
1.6 |
Hematology | ||||
Anemia |
43 |
3.0 |
64 |
9 |
Lymphopenia |
36 |
5 |
63 |
14 |
In addition, among patients with TSH ≤ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).
CHECKMATE-9ER
The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.6)]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ≥20% of patients treated with OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.
Toxicity was graded per NCI CTCAE v4. a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b Includes gastroesophageal reflux disease. c Includes asthenia. d 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. e Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes blood pressure increased, blood pressure systolic increased. h Includes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, rhinitis. |
||||
Adverse Reaction |
OPDIVO and Cabozantinib |
Sunitinib |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Gastrointestinal |
||||
Diarrhea |
64 |
7 |
47 |
4.4 |
Nausea |
27 |
0.6 |
31 |
0.3 |
Abdominal paina |
22 |
1.9 |
15 |
0.3 |
Vomiting |
17 |
1.9 |
21 |
0.3 |
Dyspepsiab |
15 |
0 |
22 |
0.3 |
General |
||||
Fatiguec |
51 |
8 |
50 |
8 |
Hepatobiliary |
||||
Hepatotoxicityd |
44 |
11 |
26 |
5 |
Skin and Subcutaneous Tissue |
||||
Palmar-plantar erythrodysaesthesia syndrome |
40 |
8 |
41 |
8 |
Stomatitise |
37 |
3.4 |
46 |
4.4 |
Rashf |
36 |
3.1 |
14 |
0 |
Pruritus |
19 |
0.3 |
4.4 |
0 |
Vascular |
||||
Hypertensiong |
36 |
13 |
39 |
14 |
Endocrine |
||||
Hypothyroidismh |
34 |
0.3 |
30 |
0.3 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal paini |
33 |
3.8 |
29 |
3.1 |
Arthralgia |
18 |
0.3 |
9 |
0.3 |
Metabolism and Nutrition |
||||
Decreased appetite |
28 |
1.9 |
20 |
1.3 |
Nervous System |
||||
Dysgeusia |
24 |
0 |
22 |
0 |
Headache |
16 |
0 |
12 |
0.6 |
Respiratory, Thoracic and Mediastinal |
||||
Coughj |
20 |
0.3 |
17 |
0 |
Dysphonia |
17 |
0.3 |
3.4 |
0 |
Infections and Infestations |
||||
Upper respiratory tract infectionk |
20 |
0.3 |
8 |
0.3 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). | ||||
Laboratory Abnormality |
OPDIVO and Cabozantinib |
Sunitinib |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Chemistry |
||||
Increased ALT |
79 |
9.8 |
39 |
3.5 |
Increased AST |
77 |
7.9 |
57 |
2.6 |
Hypophosphatemia |
69 |
28 |
48 |
10 |
Hypocalcemia |
54 |
1.9 |
24 |
0.6 |
Hypomagnesemia |
47 |
1.3 |
25 |
0.3 |
Hyperglycemia |
44 |
3.5 |
44 |
1.7 |
Hyponatremia |
43 |
11 |
36 |
12 |
Increased lipase |
41 |
14 |
38 |
13 |
Increased amylase |
41 |
10 |
28 |
6 |
Increased alkaline phosphatase |
41 |
2.8 |
37 |
1.6 |
Increased creatinine |
39 |
1.3 |
42 |
0.6 |
Hyperkalemia |
35 |
4.7 |
27 |
1 |
Hypoglycemia |
26 |
0.8 |
14 |
0.4 |
Hematology |
||||
Lymphopenia |
42 |
6.6 |
45 |
10 |
Thrombocytopenia |
41 |
0.3 |
70 |
9.7 |
Anemia |
37 |
2.5 |
61 |
4.8 |
Leukopenia |
37 |
0.3 |
66 |
5.1 |
Neutropenia |
35 |
3.2 |
67 |
12 |
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.6)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.
Rate of death on treatment or within 30 days of the last dose was 4.7% on the OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.
Toxicity was graded per NCI CTCAE v4. a Includes asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI). c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema. |
||||
Adverse Reaction |
OPDIVO |
Everolimus |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Adverse Reaction |
98 |
56 |
96 |
62 |
General | ||||
Fatiguea |
56 |
6 |
57 |
7 |
Pyrexia |
17 |
0.7 |
20 |
0.8 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough |
34 |
0 |
38 |
0.5 |
Dyspnea/exertional dyspnea |
27 |
3.0 |
31 |
2.0 |
Upper respiratory infectionb |
18 |
0 |
11 |
0 |
Gastrointestinal | ||||
Nausea |
28 |
0.5 |
29 |
1 |
Diarrheac |
25 |
2.2 |
32 |
1.8 |
Constipation |
23 |
0.5 |
18 |
0.5 |
Vomiting |
16 |
0.5 |
16 |
0.5 |
Skin and Subcutaneous Tissue | ||||
Rashd |
28 |
1.5 |
36 |
1.0 |
Pruritus/generalized pruritus |
19 |
0 |
14 |
0 |
Metabolism and Nutrition | ||||
Decreased appetite |
23 |
1.2 |
30 |
1.5 |
Musculoskeletal and Connective Tissue | ||||
Arthralgia |
20 |
1.0 |
14 |
0.5 |
Back pain |
21 |
3.4 |
16 |
2.8 |
Other clinically important adverse reactions in CHECKMATE-025 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: palmar-plantar erythrodysesthesia
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients). | ||||
Laboratory Abnormality |
OPDIVO |
Everolimus |
||
Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
Hematology | ||||
Lymphopenia |
42 |
6 |
53 |
11 |
Anemia |
39 |
8 |
69 |
16 |
Chemistry | ||||
Increased creatinine |
42 |
2.0 |
45 |
1.6 |
Increased AST |
33 |
2.8 |
39 |
1.6 |
Increased alkaline phosphatase |
32 |
2.3 |
32 |
0.8 |
Hyponatremia |
32 |
7 |
26 |
6 |
Hyperkalemia |
30 |
4.0 |
20 |
2.1 |
Hypocalcemia |
23 |
0.9 |
26 |
1.3 |
Increased ALT |
22 |
3.2 |
31 |
0.8 |
Hypercalcemia |
19 |
3.2 |
6 |
0.3 |
Lipids | ||||
Increased triglycerides |
32 |
1.5 |
67 |
11 |
Increased cholesterol |
21 |
0.3 |
55 |
1.4 |
Classical Hodgkin Lymphoma
The safety of OPDIVO was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies (14.7)]. Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.
The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months).
Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients.
The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.
Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.
Adverse Reactiona |
OPDIVO (n=266) |
|
All Grades (%) |
Grades 3-4 (%) |
|
Infections |
||
Upper respiratory tract infectionb |
44 |
0.8 |
Pneumonia/bronchopneumoniac |
13 |
3.8 |
Nasal congestion |
11 |
0 |
General |
||
Fatigued |
39 |
1.9 |
Pyrexia |
29 |
<1 |
Respiratory, Thoracic and Mediastinal |
||
Cough/productive cough |
36 |
0 |
Dyspnea/exertional dyspnea |
15 |
1.5 |
Gastrointestinal |
||
Diarrheae |
33 |
1.5 |
Nausea |
20 |
0 |
Vomiting |
19 |
<1 |
Abdominal painf |
16 |
<1 |
Constipation |
14 |
0.4 |
Musculoskeletal and Connective Tissue |
||
Musculoskeletal paing |
26 |
1.1 |
Arthralgia |
16 |
<1 |
Skin and Subcutaneous Tissue |
||
Rashh |
24 |
1.5 |
Pruritus |
20 |
0 |
Nervous System | ||
Headache |
17 |
<1 |
Neuropathy peripherali |
12 |
<1 |
Injury, Poisoning and Procedural Complications |
||
Infusion-related reaction |
14 |
<1 |
Endocrine | ||
Hypothyroidism/thyroiditis |
12 |
0 |
- Toxicity was graded per NCI CTCAE v4.
a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course.
b Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
d Includes asthenia.
e Includes colitis.
f Includes abdominal discomfort and upper abdominal pain.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.
Additional information regarding clinically important adverse reactions:
Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis.
Peripheral neuropathy: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.
Complications of allogeneic HSCT after OPDIVO: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.
Table 30 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase.
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: range: 203 to 266 patients. b Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course. c In addition, in the safety population, fasting hyperglycemia (all grade 1-2) was reported in 27 of 69 (39%) evaluable patients and fasting hypoglycemia (all grade 1-2) in 11 of 69 (16%). |
||
Laboratory Abnormality |
OPDIVOa
|
|
All Grades (%)b |
Grades 3-4 (%)b |
|
Hematology |
||
Leukopenia |
38 |
4.5 |
Neutropenia |
37 |
5 |
Thrombocytopenia |
37 |
3.0 |
Lymphopenia |
32 |
11 |
Anemia |
26 |
2.6 |
Chemistryc |
||
Increased AST |
33 |
2.6 |
Increased ALT |
31 |
3.4 |
Increased lipase |
22 |
9 |
Increased alkaline phosphatase |
20 |
1.5 |
Hyponatremia |
20 |
1.1 |
Hypokalemia |
16 |
1.9 |
Increased creatinine |
16 |
<1 |
Hypocalcemia |
15 |
<1 |
Hyperkalemia |
15 |
1.5 |
Hypomagnesemia |
14 |
<1 |
Increased amylase |
13 |
1.5 |
Increased bilirubin |
11 |
1.5 |
Squamous Cell Carcinoma of the Head and Neck
The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.8)]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year.
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.
Serious adverse reactions occurred in 49% of patients receiving OPDIVO. OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.
The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.
Adjuvant Treatment of Urothelial Carcinoma
The safety of OPDIVO was evaluated in CHECKMATE-274, a randomized, double-blind, multicenter trial of adjuvant OPDIVO versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.9)]. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of OPDIVO treatment was 8.8 months (range: 0 to 12.5).
Serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). OPDIVO was discontinued for adverse reactions in 18% of patients. OPDIVO was delayed for adverse reaction in 33% of patients.
The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.
Table 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274
Toxicity was graded per NCI CTCAE v4. a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria. b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain. d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis. f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis. g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment. h Includes cough, productive cough, and upper-airway cough syndrome. i Includes dyspnea and exertional dyspnea. j Includes dizziness, postural dizziness and vertigo. k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased. |
||||
Adverse Reaction |
OPDIVO (n=351) |
Placebo (n=348) |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Skin and Subcutaneous Tissue |
||||
Rasha |
36 |
1.7 |
19 |
0.3 |
Pruritus |
30 |
0 |
16 |
0 |
General |
||||
Fatigue/Asthenia |
36 |
1.1 |
32 |
0.3 |
Pyrexia |
10 |
0.3 |
10 |
0.3 |
Gastrointestinal |
||||
Diarrheab |
30 |
2.8 |
27 |
1.7 |
Nausea |
16 |
0.6 |
13 |
0 |
Abdominal painc |
15 |
0.9 |
15 |
0.6 |
Constipation |
13 |
0.3 |
15 |
0.3 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal paind |
28 |
0.6 |
24 |
0.9 |
Arthralgia |
11 |
0.3 |
13 |
0 |
Infections |
||||
Urinary tract infectione |
22 |
6 |
23 |
9 |
Upper respiratory tract infectionf |
16 |
0.3 |
16 |
0.6 |
Endocrine |
||||
Hyperthyroidism |
11 |
0 |
1.1 |
0 |
Hypothyroidism |
11 |
0 |
2.3 |
0 |
Renal and Urinary Disorders |
||||
Renal dysfunctiong |
17 |
1.7 |
16 |
0.9 |
Respiratory, Thoracic and Mediastinal |
||||
Coughh |
14 |
0 |
11 |
0 |
Dyspneai |
11 |
0.3 |
6 |
0.3 |
Metabolism and Nutrition |
||||
Decreased appetite |
13 |
0.9 |
7 |
0.3 |
Nervous System Disorders |
||||
Dizzinessj |
11 |
0.3 |
9 |
0 |
Hepatobiliary |
||||
Hepatitisk |
11 |
4 |
8 |
0.6 |
Table 32: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-274
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients). | ||||
Laboratory Abnormality |
OPDIVO (n=351) |
Placebo (n=348) |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Chemistry |
||||
Increased creatinine |
36 |
1.7 |
36 |
2.6 |
Increased amylase |
34 |
8 |
23 |
3.2 |
Increased lipase |
33 |
12 |
31 |
10 |
Hyperkalemia |
32 |
5 |
30 |
6 |
Increased alkaline phosphatase |
24 |
2.3 |
15 |
0.6 |
Increased AST |
24 |
3.5 |
16 |
0.9 |
Increased ALT |
23 |
2.9 |
15 |
0.6 |
Hyponatremia |
22 |
4.1 |
17 |
1.8 |
Hypocalcemia |
17 |
1.2 |
11 |
0.9 |
Hypomagnesemia |
16 |
0 |
9 |
0 |
Hypercalcemia |
12 |
0.3 |
8 |
0.3 |
Hematology |
||||
Lymphopenia |
33 |
2.9 |
27 |
1.5 |
Anemia |
30 |
1.4 |
28 |
0.9 |
Neutropenia |
11 |
0.6 |
10 |
0.3 |
Advanced or Metastatic Urothelial Carcinoma
The safety of OPDIVO was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic urothelial carcinoma had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.9)]. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.
Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO was discontinued for adverse reactions in 17% of patients.
The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.
Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.
Toxicity was graded per NCI CTCAE v4. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. b Includes abdominal discomfort, lower and upper abdominal pain. c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic. d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased. |
||
Adverse Reaction |
OPDIVO |
|
All Grades (%) |
Grades 3-4 (%) |
|
Adverse Reaction |
99 |
51 |
General | ||
Asthenia/fatigue/malaise |
46 |
7 |
Pyrexia/tumor associated fever |
17 |
0.4 |
Edema/peripheral edema/peripheral swelling |
13 |
0.4 |
Musculoskeletal and Connective Tissue | ||
Musculoskeletal paina |
30 |
2.6 |
Arthralgia |
10 |
0.7 |
Metabolism and Nutrition | ||
Decreased appetite |
22 |
2.2 |
Gastrointestinal | ||
Nausea |
22 |
0.7 |
Diarrhea |
17 |
2.6 |
Constipation |
16 |
0.4 |
Abdominal painb |
13 |
1.5 |
Vomiting |
12 |
1.9 |
Respiratory, Thoracic and Mediastinal | ||
Cough/productive cough |
18 |
0 |
Dyspnea/exertional dyspnea |
14 |
3.3 |
Infections | ||
Urinary tract infection/escherichia/fungal urinary tract infection |
17 |
7 |
Skin and Subcutaneous Tissue | ||
Rashc |
16 |
1.5 |
Pruritus |
12 |
0 |
Endocrine | ||
Thyroid disordersd |
15 |
0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients. | ||
Laboratory Abnormality |
OPDIVOa |
|
All Grades (%) |
Grades 3-4 (%) |
|
Chemistry | ||
Hyperglycemia |
42 |
2.4 |
Hyponatremia |
41 |
11 |
Increased creatinine |
39 |
2.0 |
Increased alkaline phosphatase |
33 |
5.5 |
Hypocalcemia |
26 |
0.8 |
Increased AST |
24 |
3.5 |
Increased lipase |
20 |
7 |
Hyperkalemia |
19 |
1.2 |
Increased ALT |
18 |
1.2 |
Increased amylase |
18 |
4.4 |
Hypomagnesemia |
16 |
0 |
Hematology | ||
Lymphopenia |
42 |
9 |
Anemia |
40 |
7 |
Thrombocytopenia |
15 |
2.4 |
Leukopenia |
11 |
0 |
MSI-H or dMMR Metastatic Colorectal Cancer
The safety of OPDIVO administered as a single agent or in combination with ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies (14.10)]. In CHECKMATE-142, 74 patients with mCRC received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.
In the OPDIVO with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.
Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction.
Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema and peripheral swelling. c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain. e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized. f Includes nasopharyngitis and rhinitis. |
||||
Adverse Reaction |
OPDIVO |
OPDIVO and Ipilimumab |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
General | ||||
Fatiguea |
54 |
5 |
49 |
6 |
Pyrexia |
24 |
0 |
36 |
0 |
Edemab |
12 |
0 |
7 |
0 |
Gastrointestinal | ||||
Diarrhea |
43 |
2.7 |
45 |
3.4 |
Abdominal painc |
34 |
2.7 |
30 |
5 |
Nausea |
34 |
1.4 |
26 |
0.8 |
Vomiting |
28 |
4.1 |
20 |
1.7 |
Constipation |
20 |
0 |
15 |
0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind |
28 |
1.4 |
36 |
3.4 |
Arthralgia |
19 |
0 |
14 |
0.8 |
Respiratory, Thoracic and Mediastinal | ||||
Cough |
26 |
0 |
19 |
0.8 |
Dyspnea |
8 |
1 |
13 |
1.7 |
Skin and Subcutaneous Tissue | ||||
Rashe |
23 |
1.4 |
25 |
4.2 |
Pruritus |
19 |
0 |
28 |
1.7 |
Dry Skin |
7 |
0 |
11 |
0 |
Infections | ||||
Upper respiratory tract infectionf |
20 |
0 |
9 |
0 |
Endocrine | ||||
Hyperglycemia |
19 |
2.7 |
6 |
1 |
Hypothyroidism |
5 |
0 |
14 |
0.8 |
Hyperthyroidism |
4 |
0 |
12 |
0 |
Nervous System | ||||
Headache |
16 |
0 |
17 |
1.7 |
Dizziness |
14 |
0 |
11 |
0 |
Metabolism and Nutrition | ||||
Decreased appetite |
14 |
1.4 |
20 |
1.7 |
Psychiatric | ||||
Insomnia |
9 |
0 |
13 |
0.8 |
Investigations | ||||
Weight decreased |
8 |
0 |
10 |
0 |
Clinically important adverse reactions reported in <10% of patients receiving OPDIVO with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the OPDIVO cohort and from 87 to 114 for the OPDIVO and ipilimumab cohort. | ||||
Laboratory Abnormality |
OPDIVO |
OPDIVO and Ipilimumab |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Hematology | ||||
Anemia |
50 |
7 |
42 |
9 |
Lymphopenia |
36 |
7 |
25 |
6 |
Neutropenia |
20 |
4.3 |
18 |
0 |
Thrombocytopenia |
16 |
1.4 |
26 |
0.9 |
Chemistry | ||||
Increased alkaline phosphatase |
37 |
2.8 |
28 |
5 |
Increased lipase |
33 |
19 |
39 |
12 |
Increased ALT |
32 |
2.8 |
33 |
12 |
Increased AST |
31 |
1.4 |
40 |
12 |
Hyponatremia |
27 |
4.3 |
26 |
5 |
Hypocalcemia |
19 |
0 |
16 |
0 |
Hypomagnesemia |
17 |
0 |
18 |
0 |
Increased amylase |
16 |
4.8 |
36 |
3.4 |
Increased bilirubin |
14 |
4.2 |
21 |
5 |
Hypokalemia |
14 |
0 |
15 |
1.8 |
Increased creatinine |
12 |
0 |
25 |
3.6 |
Hyperkalemia |
11 |
0 |
23 |
0.9 |
Hepatocellular Carcinoma
The safety of OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.11)] who progressed on or were intolerant to sorafenib. OPDIVO and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent OPDIVO 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the OPDIVO and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of OPDIVO and ipilimumab. During the entire treatment period, the median duration of exposure to OPDIVO was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.
The most frequent 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.
Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040.
Adverse Reaction |
OPDIVO and Ipilimumab (n=49) |
|
All Grades (%) |
Grades 3-4 (%) |
|
Skin and Subcutaneous Tissue |
||
Rash |
53 |
8 |
Pruritus |
53 |
4 |
Musculoskeletal and Connective Tissue |
||
Musculoskeletal pain |
41 |
2 |
Arthralgia |
10 |
0 |
Gastrointestinal |
||
Diarrhea |
39 |
4 |
Abdominal pain |
22 |
6 |
Nausea |
20 |
0 |
Ascites |
14 |
6 |
Constipation |
14 |
0 |
Dry mouth |
12 |
0 |
Dyspepsia |
12 |
2 |
Vomiting |
12 |
2 |
Stomatitis |
10 |
0 |
Respiratory, Thoracic and Mediastinal |
||
Cough |
37 |
0 |
Dyspnea |
14 |
0 |
Pneumonitis |
10 |
2 |
Metabolism and Nutrition |
||
Decreased appetite |
35 |
2 |
General |
||
Fatigue |
27 |
2 |
Pyrexia |
27 |
0 |
Malaise |
18 |
2 |
Edema |
16 |
2 |
Influenza-like illness |
14 |
0 |
Chills |
10 |
0 |
Nervous System |
||
Headache |
22 |
0 |
Dizziness |
20 |
0 |
Endocrine |
||
Hypothyroidism |
20 |
0 |
Adrenal insufficiency |
18 |
4 |
Investigations |
||
Weight decreased |
20 |
0 |
Psychiatric |
||
Insomnia |
18 |
0 |
Blood and Lymphatic System |
||
Anemia |
10 |
4 |
Infections |
||
Influenza |
10 |
2 |
Vascular |
||
Hypotension |
10 |
0 |
Clinically important adverse reactions reported in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).
Laboratory Abnormality |
OPDIVO and Ipilimumab (n=47) |
|
All Grades (%) |
Grades 3-4 (%) |
|
Hematology | ||
Lymphopenia |
53 |
13 |
Anemia |
43 |
4.3 |
Neutropenia |
43 |
9 |
Leukopenia |
40 |
2.1 |
Thrombocytopenia |
34 |
4.3 |
Chemistry | ||
Increased AST |
66 |
40 |
Increased ALT |
66 |
21 |
Increased bilirubin |
55 |
11 |
Increased lipase |
51 |
26 |
Hyponatremia |
49 |
32 |
Hypocalcemia |
47 |
0 |
Increased alkaline phosphatase |
40 |
4.3 |
Increased amylase |
38 |
15 |
Hypokalemia |
26 |
2.1 |
Hyperkalemia |
23 |
4.3 |
Increased creatinine |
21 |
0 |
Hypomagnesemia |
11 |
0 |
In patients who received OPDIVO with ipilimumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
The safety of OPDIVO was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.12)]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in OPDIVO-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received OPDIVO, 61% were exposed for >6 months and 54% were exposed for >9 months.
Serious adverse reactions occurred in 33% of patients receiving OPDIVO. A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received OPDIVO.
OPDIVO was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.
Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.
Table 39: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO - CHECKMATE-577
a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. b Includes gastroesophageal reflux. c Includes asthenia. d Includes productive cough. e Includes dyspnea exertional. f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain. |
||||
Adverse Reaction |
OPDIVO (n=532) |
Placebo (n=260) |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Adverse Reaction |
96 |
34 |
93 |
32 |
Gastrointestinal |
||||
Diarrhea |
29 |
0.9 |
29 |
0.8 |
Nausea |
23 |
0.8 |
21 |
0 |
Abdominal Paina |
17 |
0.8 |
20 |
1.5 |
Vomiting |
15 |
0.6 |
16 |
1.2 |
Dysphagia |
13 |
0.8 |
17 |
3.5 |
Dyspepsiab |
12 |
0.2 |
16 |
0.4 |
Constipation |
11 |
0 |
12 |
0 |
General |
||||
Fatiguec |
34 |
1.3 |
29 |
1.5 |
Respiratory, Thoracic and Mediastinal |
||||
Coughd |
20 |
0.2 |
21 |
0.4 |
Dyspneae |
12 |
0.8 |
12 |
0.4 |
Skin and Subcutaneous Tissue |
||||
Rashf |
21 |
0.9 |
10 |
0.4 |
Pruritus |
13 |
0.4 |
6 |
0 |
Investigations |
||||
Weight decreased |
13 |
0.4 |
9 |
0 |
Musculoskeletal and Connective Tissue |
||||
Musculoskeletal paing |
21 |
0.6 |
20 |
0.8 |
Arthralgia |
10 |
0.2 |
8 |
0 |
Metabolism and Nutrition |
||||
Decreased appetite |
15 |
0.9 |
10 |
0.8 |
Endocrine |
||||
Hypothyroidism |
11 |
0 |
1.5 |
0 |
Table 40: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-577
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients). b Includes alanine aminotransferase increased, aspartate aminotransferase increased. |
||||
Laboratory Abnormality |
OPDIVO (n=532) |
Placebo (n=260) |
||
All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
Chemistry |
||||
Increased AST |
27 |
2.1 |
22 |
0.8 |
Increased alkaline phosphatase |
25 |
0.8 |
18 |
0.8 |
Increased albumin |
21 |
0.2 |
18 |
0 |
Increased ALT |
20 |
1.9 |
16 |
1.2 |
Increased amylase |
20 |
3.9 |
13 |