Nivolumab (Opdivo)

General information

Class/mechanism: PD-1 receptor antibody. Nivolumab is an IgG4 kappa human monoclonal antibody which binds to the PD-1 (programmed death receptor-1) receptor and blocks its interaction with the ligands PD-L1 and PD-L2. Normally, PD-L1 and PD-L2 binding to the PD-1 receptor on T cells inhibits T-cell proliferation and cytokine production, which can impede immune system surveillance of tumors. By interfering with the binding of PD-L1 and PD-L2 to the PD-1 receptor, nivolumab can cause upregulation of the anti-tumor immune response.
Route: IV
Extravasation: no information

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, UpToDate (courtesy of Lexicomp), or the prescribing information.

Toxicity management

• Immunotherapy toxicity management

Diseases for which it is established (work in progress)

• Carcinoma of unknown primary
• Esophageal cancer
  • Esophageal adenocarcinoma
  • Esophageal squamous cell carcinoma
• Gastric cancer
• Head and neck cancer
• Hepatocellular carcinoma
• Malignant pleural mesothelioma
• Melanoma
  • Uveal melanoma
• Non-small cell lung cancer
  • Non-small cell lung cancer, nonsquamous
  • Non-small cell lung cancer, squamous
• Renal cell carcinoma
  • Clear cell renal cell carcinoma
• Urothelial carcinoma

Diseases for which it is used

• Anal cancer
• Cholangiocarcinoma
• Colorectal cancer
• Classical Hodgkin lymphoma

Diseases for which it was used

• Small cell lung cancer

Patient drug information

• Nivolumab (Opdivo) package insert
• Nivolumab (Opdivo) patient drug information (Chemocare)
• Nivolumab (Opdivo) patient drug information (UpToDate)

History of changes in FDA dosing recommendations

• 2016-09-13: FDA dosing recommendation changed to 240 mg IV every two weeks until disease progression or intolerable toxicity for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer. When combined with ipilimumab for melanoma, after completion of ipilimumab, the recommended nivolumab dose will be 240 mg every two weeks until disease progression or intolerable toxicity.

History of changes in FDA indication

Classical Hodgkin lymphoma

• 2016-05-17: Accelerated approval for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin (Adcetris). (New disease entity; based on CheckMate 039 and CheckMate 205)

Colorectal cancer

• 2017-08-01: Granted FDA accelerated approval for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. (Based on CheckMate 142)
• 2018-07-10: Accelerated approval for treatment of adult and pediatric patients 12 years of age and older 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, in combination with ipilimumab. (Based on CheckMate 142)

Esophageal cancer

• 2021-05-20: Approved for patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy. (Based on CheckMate 577)

Esophageal adenocarcinoma

• 2021-04-16: Approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. (Based on CheckMate 649)

Esophageal squamous cell carcinoma

• 2020-06-10: for patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. (New disease entity; based on ATTRACTION-3)
• 2022-05-27: Approved for the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) in combination with fluoropyrimidine- and platinum-based chemotherapy. (Based on CheckMate 648)
• 2022-05-27: Approved for the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) in combination with ipilimumab. (Based on CheckMate 648)

Gastric cancer

• 2021-04-16: Approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. (Based on CheckMate 649)

Head and neck cancer

• 2016-11-10: FDA approved for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy. (New disease entity; based on CheckMate 141)

Hepatocellular carcinoma - PARTIALLY WITHDRAWN

• 2017-09-22: Granted FDA accelerated approval for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib. (New disease entity; based on CheckMate 040)
  • 2021-07-23: Accelerated approval withdrawn. (Based on CheckMate 459)
• 2020-03-10: Accelerated approval in combination with ipilimumab for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. (Approval extended to combination therapy; based on CheckMate 040_combo)

Malignant pleural mesothelioma

• 2020-10-02: Approved in combination with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma. (New disease entity; based on CheckMate 743)

Melanoma

• 2014-12-22: Accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor.(Based on CheckMate 037)
  • 2019-03-07: Converted to regular approval. (Based on CheckMate 037 & CheckMate 067)
• 2015-09-30: Granted accelerated approval in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. (Based on CheckMate 066 and CheckMate 067)
  • 2019-03-07: Converted to regular approval. (Based on CheckMate 037 & CheckMate 067)
• 2017-12-20: Granted regular approval for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. (Based on CheckMate 238)
• 2023-10-13: Approved for the adjuvant treatment of completely resected Stage IIB/C melanoma in patients 12 years and older. (Based on CheckMate 76K)

Non-small cell lung cancer

• 2015-10-09: Approval expanded for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. (Histology indication expanded to include nonsquamous; based on CheckMate 057)
  • Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Opdivo.
• 2020-05-15: Approved in combination with ipilimumab as first-line treatment for patients with metastatic non-small cell lung cancer whose tumors express PD-L1 (at least 1%), as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. (Expanded to first-line setting, with PD-L1 expression requirement; based on CheckMate 227)
• 2020-05-26: Approved in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. (PD-L1 expression requirement removed when given with chemotherapy; based on CheckMate 9LA)
• 2022-03-04: Approved with platinum-doublet chemotherapy for adult patients with resectable non-small cell lung cancer (NSCLC) in the neoadjuvant setting. (Based on CheckMate 816)

Non-small cell lung cancer, squamous

• 2015-03-04: Approved for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. (New disease entity; based on CheckMate 017)

Renal cell carcinoma

• 2015-11-23: FDA approval expanded for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy. (New disease entity; based on CheckMate 025)
• 2018-04-16: FDA approved to be used in combination with Ipilimumab (Yervoy) for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma. (Based on CheckMate 214)
• 2021-01-22: Approved to be used in combination with Cabozantinib (Cabometyx) as first-line treatment for patients with advanced renal cell carcinoma (RCC). (Based on CheckMate 9ER)

Small cell lung cancer - WITHDRAWN

• 2018-08-16: Granted FDA accelerated approval for patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. (Based on CheckMate 032_SCLC)
  • 2020-12-29: Accelerated approval withdrawn. (Based on CheckMate 331 & CheckMate 451)

Urothelial carcinoma

• 2017-02-02: Granted accelerated approval for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy. (New disease entity; based on CheckMate 275)
• 2017-02-02: Granted accelerated approval for treatment of patients with urothelial carcinoma who have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. (New disease entity; based on CheckMate 275)
• 2021-08-19: Full approval for the adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection. (Extended to adjuvant setting; converted to regular approval; based on CheckMate 274)
• 2024-03-06: Approved in combination with cisplatin and gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC). (Based on CheckMate 901 part 1)

History of changes in EMA indication

Colorectal cancer

• 2021-06-24: Extension of indication to include the combination of nivolumab with ipilimumab in the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) after prior fluoropyrimidine based combination chemotherapy.

Esophageal cancer

• 2021-07-28: Extension of indication to include adjuvant treatment of adult patients with oesophageal, or gastrooesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy for OPDIVO. (Based on CheckMate 577)

Esophageal squamous cell carcinoma

• 2020-11-20: Extension of indication to include treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (OSCC) after prior fluoropyrimidine- and platinumbased chemotherapy.
• 2022-04-01: Extension of indication to include treatment of firstline treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (OSCC) with tumour cell PD-L1 expression at least 1% for Opdivo in combination with Yervoy.
• 20220-04-01: Extension of indication to include in combination with fluoropyrimidine- and platinum-based combination chemotherapy the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (OSCC) with tumour cell PD-L1 expression at least 1% for OPDIVO. (Based on CheckMate 648)

Gastric cancer

• 2021-10-19: Extension of indication to use OPDIVO (nivolumab) in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in first-line treatment of adult patients with HER2-negative advanced or metastatic gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma whose tumours express PD-L1 with a combined positive score (CPS) at least 5. (Based on CheckMate 649)

Head and neck cancer

• 2017-04-28: Extension of Indication to include treatment of squamous cell cancer of the head and neck (SCCHN) in adults progressing on or after platinum-based therapy for OPDIVO as monotherapy.

Malignant pleural mesothelioma

• 2021-06-01: Extension of indication to include first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM) for combination treatment of Opdivo and Yervoy.

Melanoma

• 2015-06-19: Initial marketing authorization as Opdivo. Opdivo as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.
• 2016-05-11: Extension of Indication to include treatment in combination with ipilimumab of advanced (unresectable or metastatic) melanoma in adults. (Based on CheckMate 067 & CheckMate 069)
• 2018-07-30: Extension of Indication to include adjuvant treatment of adults with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. (Based on CheckMate 238)
• 2023-06-16: Opdivo as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older.
• 2023-06-16: Opdivo in combination with ipilimumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older.
• 2023-06-16: Opdivo as monotherapy is indicated for the adjuvant treatment of adults and adolescents 12 years of age and older with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
• 2023-08-21: Extension of indication to include OPDIVO for the adjuvant treatment of adults and adolescents 12 years of age and older with stage IIB or IIC melanoma who have undergone complete resection. (Based on CheckMate 76K)

Non-small cell lung cancer

• 2020-11-05: Extension of indication to include first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation for combination of OPDIVO/Yervoy and chemotherapy.
• 2023-06-26: Extension of indication to include OPDIVO in combination with platinum-based chemotherapy for neoadjuvant treatment of adult patients with resectable Stage IB-IIIA non-small cell lung cancer (NSCLC). (Based on CheckMate 816)

Non-small cell lung cancer, nonsquamous

• 2016-04-04: Extension of Indication to include treatment as monotherapy of locally advanced or metastatic nonsquamous NSCLC after prior chemotherapy in adults. (Based on CheckMate 057)

Non-small cell lung cancer, squamous

• 2015-10-28: Extension of indication to include treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) after prior chemotherapy in adults.

Renal cell carcinoma

• 2016-04-04: Extension of Indication to add treatment as monotherapy of patients with advanced renal cell carcinoma (RCC) after prior therapy in adults. (Based on CheckMate 025)
• 2019-01-11: Extension of indication to include the combination treatment with nivolumab and ipilimumab of adult patients with intermediate/poor-risk advanced renal cell carcinoma.
• 2021-04-13: Extension of indication to include in combination with cabozantinib for the first line treatment of advanced renal cell carcinoma for Opdivo.

Urothelial carcinoma

• 2017-06-02: Extension of Indication to include the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy for OPDIVO.
• 2022-04-01: Extension of indication for Opdivo to include as monotherapy for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression at least 1%, who are at high risk of recurrence after undergoing radical resection of MIUC.

History of changes in Health Canada indication

• 2016-10-26: Notice of compliance with conditions for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma in previously untreated adults.
• 2016-10-26: Notice of compliance with conditions for the treatment of patients with unresectable or metastatic melanoma in previously untreated adults when used in combination with ipilimumab.
• 2018-03-23: Notice of compliance with conditions as a monotherapy for the treatment of adult patients with advanced (not amenable to curative therapy or local therapeutic measures) or metastatic hepatocellular carcinoma (HCC) who are intolerant to or have progressed on sorafenib therapy.
• 2021-02-11: Notice of compliance with conditions in combination with ipilimumab. Indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer after prior fluoropyrimidine-based therapy in combination with oxaliplatin or irinotecan.
• 2022-06-27: Notice of compliance with conditions as a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

History of changes in PMDA indication

Carcinoma of unknown primary

• 2021-12-24: New indication and a new dosage for the treatment of carcinoma of unknown primary. (Based on Tanizaki et al. 2021)

Classical Hodgkin lymphoma

• 2016-12-02: New additional indication for the treatment of relapsed or refractory classical Hodgkin's lymphoma.

Colorectal cancer

• 2020-02-21: New indication for the treatment of unresectable advanced or recurrent microsatellite instability-high (MSI-High) colorectal cancer that has progressed after cancer chemotherapy.

Esophageal cancer

• 2020-02-21: New indication for the treatment of unresectable advanced or recurrent esophageal cancer that has progressed after cancer chemotherapy.
• 2021-11-25: New indication and a new dosage for postoperative adjuvant therapy for esophageal cancer.
• 2022-05-26: New indication and a new dosage for the treatment of unresectable advanced or recurrent esophageal cancer.

Gastric cancer

• 2017-09-22: New additional indication for the treatment of unresectable advanced or recurrent gastric cancer which has progressed after cancer chemotherapy.
• 2021-11-25: New indication and a new dosage for the treatment of unresectable advanced or recurrent gastric cancer.

Head and neck cancer

• 2017-03-24: New additional indication for the treatment of relapse or distant metastasis of head and neck cancer.

Malignant pleural mesothelioma

• 2018-08-21: New indication and a new dosage for the treatment of unresectable or recurrent malignant pleural mesothelioma and melanoma that has progressed after chemotherapy.
• 2021-05-27: New indication and a new dosage for the treatment of unresectable advanced or recurrent malignant pleural mesothelioma.

Melanoma

• 2014-07-04: Initial approval for the treatment of unresectable malignant melanoma.
• 2018-08-21: New indication and a new dosage for the treatment of unresectable or recurrent melanoma that has progressed after chemotherapy.

Non-small cell lung cancer

• 2015-12-17: New additional indication and a new dosage for the treatment of unresectable advanced/relapsed non-small cell lung cancer.

Renal cell carcinoma

• 2016-08-26: New additional indication for the treatment of unresectable or metastatic renal cell carcinoma.

Urothelial carcinoma

• 2022-03-28: New indication and a new dosage for the postoperative adjuvant therapy for urothelial carcinoma.

Also known as

• Code names: BMS-936558, MDX-1106, ONO-4538
• Brand name: Opdivo