Nivolumab

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, produced in Chinese hamster ovary cells, that binds the programmed death-1 (PD-1) receptor. PD-1 is a negative regulator of T-cell activity, and tumours use its ligands to switch off the T cells that would attack them. By blocking the receptor, nivolumab restores tumour-specific T-cell responses. Opdualag combines nivolumab with relatlimab, an antibody directed against the immune checkpoint LAG-3.

Mechanism of Action

• PD-1 pathway: PD-1 on T cells is engaged by PD-L1 and PD-L2, which are found on antigen-presenting cells and may also be produced by tumours or other cells in the tumour environment. This engagement inhibits T-cell proliferation and cytokine secretion.
• Blockade: nivolumab blocks the binding of PD-1 to PD-L1 and PD-L2 and so potentiates T-cell responses, including anti-tumour responses. In mouse models, blocking PD-1 reduced tumour growth.
• With ipilimumab: combined blockade of PD-1 (nivolumab) and CTLA-4 (ipilimumab) improved anti-tumour responses in metastatic melanoma, and dual blockade was synergistic in mouse tumour models.
• Dose schedules: modelling of dose, exposure, efficacy and safety showed no clinically significant difference between 240 mg every 2 weeks and 3 mg/kg every 2 weeks, nor between 480 mg every 4 weeks and 3 mg/kg every 2 weeks in adjuvant melanoma, advanced melanoma and advanced renal cell carcinoma.

Pharmacokinetics

• Exposure: given intravenously. Pharmacokinetics are linear between 0.1 and 10 mg/kg. At 3 mg/kg every 2 weeks, population analysis gave a clearance of 7.9 mL/h, a terminal half-life of 25.0 days and an average steady-state exposure of 86.6 µg/mL.
• Metabolism: the pathway has not been characterised; nivolumab is expected to be broken down into small peptides and amino acids by catabolic pathways, as endogenous IgG is.
• Combinations: with ipilimumab, with or without chemotherapy, changes in the clearance of both antibodies were not clinically relevant.
• Different diseases: clearance was about 32% lower in classical Hodgkin lymphoma than in lung cancer, and about 40% lower at baseline in adjuvant than in advanced melanoma; these differences were not clinically meaningful.
• Special populations: age, sex, race, tumour type, tumour size and hepatic impairment made no difference to clearance. ECOG status, baseline glomerular filtration rate, albumin, body weight and mild hepatic impairment had an effect that was not clinically meaningful. Mild and moderate renal or hepatic impairment did not change clearance; data in severe renal impairment are too limited and severe hepatic impairment (bilirubin above 3 times the upper limit of normal) has not been studied. In adolescents 12 years and older weighing at least 50 kg, exposure at the adult dose is expected to be comparable to that in adults.

Opdivo (nivolumab)

• Melanoma: as monotherapy for the adjuvant treatment of adults and adolescents 12 years and older with stage IIB or IIC melanoma, or melanoma with lymph node involvement or metastatic disease, after complete resection. As monotherapy or in combination with ipilimumab for advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years and older; compared with nivolumab alone, the combination is shown to improve progression-free and overall survival only in patients with low tumour PD-L1 expression.
• Non-small cell lung cancer (NSCLC):
  • in combination with platinum-based chemotherapy as neoadjuvant treatment of resectable NSCLC at high risk of recurrence in adults whose tumours have PD-L1 expression of 1% or more;
  • in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by nivolumab alone as adjuvant treatment, for the same population;
  • in combination with ipilimumab and 2 cycles of platinum-based chemotherapy as first-line treatment of metastatic NSCLC in adults with no sensitising EGFR mutation or ALK translocation;
  • as monotherapy for locally advanced or metastatic NSCLC after prior chemotherapy in adults.
• Malignant pleural mesothelioma (MPM): in combination with ipilimumab, first-line treatment of adults with unresectable disease.
• Renal cell carcinoma (RCC): in combination with ipilimumab, first-line treatment of adults with intermediate/poor-risk advanced RCC; in combination with cabozantinib, first-line treatment of adults with advanced RCC; as monotherapy for advanced RCC after prior therapy in adults.
• Classical Hodgkin lymphoma (cHL): in combination with doxorubicin, vinblastine and dacarbazine (AVD) for adults and adolescents 12 years and older with previously untreated stage III or IV disease; in combination with brentuximab vedotin for children 5 years and older, adolescents and adults up to 30 years with relapsed or refractory disease after one prior line of therapy; as monotherapy for adults with relapsed or refractory disease after autologous stem cell transplant and brentuximab vedotin.
• Squamous cell cancer of the head and neck (SCCHN): as monotherapy for recurrent or metastatic disease in adults progressing on or after platinum-based therapy.
• Urothelial carcinoma (UC): as monotherapy for the adjuvant treatment of adults with muscle invasive disease and tumour cell PD-L1 expression of 1% or more, at high risk of recurrence after radical resection; in combination with cisplatin and gemcitabine as first-line treatment of unresectable or metastatic UC; as monotherapy for locally advanced unresectable or metastatic UC in adults after failure of prior platinum-containing therapy.
• Colorectal cancer (CRC): in combination with ipilimumab, for adults with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) disease, as first-line treatment of unresectable or metastatic CRC or for metastatic CRC after prior fluoropyrimidine-based combination chemotherapy.
• Oesophageal squamous cell carcinoma (OSCC): in combination with ipilimumab, or in combination with fluoropyrimidine- and platinum-based combination chemotherapy, as first-line treatment of adults with unresectable advanced, recurrent or metastatic disease with tumour cell PD-L1 expression of 1% or more; as monotherapy after prior fluoropyrimidine- and platinum-based combination chemotherapy.
• Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer (OC or GEJC): as monotherapy in adults with residual pathologic disease after prior neoadjuvant chemoradiotherapy.
• Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma: in combination with fluoropyrimidine- and platinum-based combination chemotherapy as first-line treatment of adults with HER2-negative advanced or metastatic disease whose tumours express PD-L1 with a combined positive score of 5 or more.
• Hepatocellular carcinoma (HCC): in combination with ipilimumab, first-line treatment of adults with unresectable or advanced HCC.

Opdivo solution for injection (subcutaneous)

Opdivo solution for injection (nivolumab 120 mg/mL) is a separate product given under the skin. Its indications below are for adults; for melanoma, the intravenous concentrate also covers adolescents 12 years and older.

• Melanoma: as monotherapy for the adjuvant treatment of stage IIB or IIC melanoma, or melanoma with lymph node involvement or metastatic disease, after complete resection; as monotherapy or in combination with ipilimumab for advanced (unresectable or metastatic) melanoma. As for the intravenous product, the benefit of the combination over nivolumab alone is established only in patients with low tumour PD-L1 expression.
• Non-small cell lung cancer: in combination with platinum-based chemotherapy as neoadjuvant treatment of resectable disease at high risk of recurrence with tumour PD-L1 expression of 1% or more, or the same neoadjuvant treatment followed by nivolumab alone as adjuvant treatment; as monotherapy for locally advanced or metastatic disease after prior chemotherapy. The first-line combination with ipilimumab and chemotherapy is not listed for the subcutaneous product.
• Renal cell carcinoma: in combination with ipilimumab for first-line treatment of intermediate/poor-risk advanced disease; in combination with cabozantinib for first-line treatment of advanced disease; as monotherapy for advanced disease after prior therapy.
• Squamous cell cancer of the head and neck: as monotherapy for recurrent or metastatic disease progressing on or after platinum-based therapy.
• Urothelial carcinoma: as monotherapy for the adjuvant treatment of muscle invasive disease with tumour cell PD-L1 expression of 1% or more at high risk of recurrence after radical resection; in combination with cisplatin and gemcitabine for first-line treatment of unresectable or metastatic disease; as monotherapy for locally advanced unresectable or metastatic disease after failure of platinum-containing therapy.
• dMMR or MSI-H colorectal cancer: in combination with ipilimumab for first-line treatment of unresectable or metastatic disease, and for metastatic disease after prior fluoropyrimidine-based combination chemotherapy.
• Oesophageal squamous cell carcinoma: in combination with fluoropyrimidine- and platinum-based chemotherapy for first-line treatment of unresectable advanced, recurrent or metastatic disease with tumour cell PD-L1 expression of 1% or more; as monotherapy after prior fluoropyrimidine- and platinum-based chemotherapy.
• Oesophageal or gastro-oesophageal junction cancer: as monotherapy for adjuvant treatment of residual pathologic disease after neoadjuvant chemoradiotherapy.
• Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma: in combination with fluoropyrimidine- and platinum-based chemotherapy for first-line treatment of HER2-negative advanced or metastatic disease with a PD-L1 combined positive score of 5 or more.
• Hepatocellular carcinoma: in combination with ipilimumab for first-line treatment of unresectable or advanced disease.

Opdualag (nivolumab with relatlimab)

• Melanoma: first-line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years and older with tumour cell PD-L1 expression below 1%.

• Hypersensitivity to nivolumab or to any of the excipients.

With nivolumab alone (4,646 patients across tumour types), the most frequent reactions (10% or more) were fatigue (44%), musculoskeletal pain (28%), diarrhoea (26%), rash (24%), cough (22%), nausea (22%), pruritus (19%), decreased appetite (17%), arthralgia (17%), constipation (16%), dyspnoea (16%), abdominal pain (15%), upper respiratory tract infection (15%), pyrexia (13%), headache (13%), anaemia (13%) and vomiting (12%). Most were mild or moderate (grade 1 or 2). Grade 3 to 5 reactions occurred in 44% and fatal reactions attributed to the medicine in 0.3%. No new safety signals appeared after at least 63 months of follow-up in lung cancer.

The frequencies below are for monotherapy and may partly reflect the underlying disease. Combinations usually add the reactions of the partner medicine and, with ipilimumab, make immune-related reactions more frequent:

• With ipilimumab, with or without chemotherapy (2,626 patients): fatigue (47%), rash (37%), diarrhoea (35%), pruritus (29%), nausea (27%) and musculoskeletal pain (26%) were the most frequent. Grade 3 to 5 reactions occurred in 66% and fatal reactions in 1.0%.
• With chemotherapy (1,800 patients): nausea (48%), fatigue (40%), peripheral neuropathy (33%), decreased appetite (31%) and constipation (31%); grade 3 to 5 in 69% and fatal in 1.2%.
• With AVD in Hodgkin lymphoma (490 patients): nausea (70.4%), neutropenia (61%), fatigue (59.0%), anaemia (52%) and constipation (49.2%); grade 3 to 5 in 71.2% and fatal in 0.6%.
• With cabozantinib in RCC (320 patients): diarrhoea (64.7%), fatigue (51.3%), palmar-plantar erythrodysaesthesia syndrome (40.0%), stomatitis (38.8%), musculoskeletal pain (37.5%) and hypertension (37.2%); grade 3 to 5 in 78% and fatal in 0.3%.
• With brentuximab vedotin in relapsed or refractory Hodgkin lymphoma (72 patients): nausea (50.0%), rash (29.2%), pyrexia (26.4%), headache (25.0%) and diarrhoea (25.0%); grade 3 to 5 in 36.1% and none fatal.
• Opdualag: see its own SmPC for its safety profile.

Very common (≥1/10): upper respiratory tract infection, lymphopenia, anaemia, leucopenia, neutropenia, thrombocytopenia, decreased appetite, hyperglycaemia, headache, dyspnoea, cough, diarrhoea, vomiting, nausea, abdominal pain, constipation, rash, pruritus, musculoskeletal pain, arthralgia, fatigue, pyrexia, and laboratory changes (raised AST, ALT, alkaline phosphatase, creatinine, lipase and amylase; low sodium, albumin, calcium, magnesium and potassium; raised potassium and calcium).

Common (≥1/100 to <1/10): pneumonia, bronchitis, infusion-related reaction (including cytokine release syndrome), hypersensitivity (including anaphylactic reaction), hypothyroidism, hyperthyroidism, thyroiditis, dehydration, weight decrease, hypoglycaemia, peripheral neuropathy, dizziness, blurred vision, dry eye, tachycardia, atrial fibrillation, hypertension, pneumonitis, pleural effusion, colitis, stomatitis, dry mouth, vitiligo, dry skin, erythema, alopecia, arthritis, renal failure (including acute kidney injury), pain, chest pain, oedema, raised total bilirubin, raised sodium and magnesium.

Uncommon (≥1/1,000 to <1/100): eosinophilia, sarcoidosis, adrenal insufficiency, hypopituitarism, hypophysitis, diabetes mellitus, metabolic acidosis, polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), uveitis, myocarditis, pericardial disorders, arrhythmia (including ventricular arrhythmia), pulmonary infiltration, pancreatitis, gastritis, hepatitis, cholestasis, psoriasis, rosacea, erythema multiforme, urticaria, polymyalgia rheumatica.

Rare (≥1/10,000 to <1/1,000): aseptic meningitis, histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis), diabetic ketoacidosis, hypoparathyroidism, Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitis, optic neuritis, vasculitis, duodenal ulcer, exocrine pancreatic insufficiency, coeliac disease, toxic epidermal necrolysis, Stevens-Johnson syndrome, Sjögren’s syndrome, myopathy, myositis (including polymyositis), rhabdomyolysis, tubulointerstitial nephritis, non-infective cystitis.

Not known: haemophagocytic lymphohistiocytosis, solid organ transplant rejection, Vogt-Koyanagi-Harada syndrome, myelitis (including transverse myelitis), tumour lysis syndrome, lichen sclerosus and other lichen disorders.

Important serious reactions are the immune-related ones: pneumonitis, colitis, hepatitis, nephritis, endocrine disorders (thyroid, pituitary, adrenal, diabetes), skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, and myocarditis. Most improved or resolved with corticosteroids and treatment modification.

• Metabolism: nivolumab is a monoclonal antibody, so no pharmacokinetic interaction studies were done. Antibodies are not metabolised by cytochrome P450 or other drug-metabolising enzymes, so inhibition or induction of these enzymes by other medicines is not expected to change nivolumab levels.
• Systemic corticosteroids and other immunosuppressants: should be avoided before starting nivolumab, because they may interfere with its pharmacodynamic activity. They can be used after starting to treat immune-related reactions, and early results suggest this does not rule out a response to nivolumab.
• Combination partners: see the SmPC of ipilimumab, cabozantinib, chemotherapy, brentuximab vedotin or relatlimab for interactions relating to those medicines.

Treatment must be started and supervised by physicians experienced in cancer treatment. Where the indication requires it, PD-L1 expression must be assessed with a CE-marked test (or a validated test if none is available), and MSI-H/dMMR status with a CE-marked test. Patients receive the patient card and are told about the risks of treatment. Opdivo concentrate for solution for infusion is given only as an intravenous infusion over 30 or 60 minutes, through a sterile, non-pyrogenic, low protein binding in-line filter (pore size 0.2–1.2 µm), undiluted (10 mg/mL) or diluted with sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%). It is never given as a push or bolus injection. Opdivo solution for injection is a separate subcutaneous product with its own doses, described below. In combinations, nivolumab is given first, then ipilimumab, then chemotherapy on the same day (with AVD, the chemotherapy comes first; with brentuximab vedotin, nivolumab is given at least 30 minutes after it), using separate bags and filters.

Recommended Dose: Monotherapy

• Melanoma (advanced or adjuvant): adults and adolescents 12 years and older weighing at least 50 kg, 240 mg every 2 weeks (30 minutes) or 480 mg every 4 weeks (60 minutes, or 30 minutes for adjuvant melanoma). Adolescents under 50 kg, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
• Renal cell carcinoma and adjuvant muscle invasive urothelial carcinoma: 240 mg every 2 weeks or 480 mg every 4 weeks over 60 minutes.
• Adjuvant oesophageal or gastro-oesophageal junction cancer: 240 mg every 2 weeks, or 480 mg every 4 weeks over 30 minutes for the first 16 weeks and then 480 mg every 4 weeks.
• NSCLC, relapsed or refractory Hodgkin lymphoma, head and neck cancer, urothelial carcinoma and oesophageal squamous cell carcinoma: 240 mg every 2 weeks over 30 minutes.
• Adjuvant therapy lasts up to 12 months. When changing from the 2-weekly to the 4-weekly schedule, the first 480 mg dose is given 2 weeks after the last 240 mg dose; from 4-weekly to 2-weekly, the first 240 mg dose is given 4 weeks after the last 480 mg dose.

Recommended Dose: Combinations

• Melanoma with ipilimumab: nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses, then nivolumab alone at the monotherapy dose (first dose 3 weeks later for the 2-weekly schedule, 6 weeks later for the 4-weekly schedule).
• Mesothelioma with ipilimumab: nivolumab 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks, for up to 24 months in patients without progression.
• RCC with ipilimumab: nivolumab 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.
• RCC with cabozantinib: nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks with cabozantinib 40 mg orally once daily. Nivolumab continues until progression, unacceptable toxicity or up to 24 months without progression; cabozantinib until progression or unacceptable toxicity.
• dMMR or MSI-H colorectal cancer: first line, nivolumab 240 mg with ipilimumab 1 mg/kg every 3 weeks for up to 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. After prior fluoropyrimidine-based chemotherapy, nivolumab 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks. Treatment lasts up to 24 months without progression.
• Oesophageal squamous cell carcinoma with ipilimumab: nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks, until progression, unacceptable toxicity or up to 24 months without progression.
• Hepatocellular carcinoma with ipilimumab: nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for up to 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks, up to 24 months.
• NSCLC with ipilimumab and chemotherapy: nivolumab 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and platinum-based chemotherapy every 3 weeks for 2 cycles, then nivolumab 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks, up to 24 months without progression.
• Neoadjuvant NSCLC: nivolumab 360 mg every 3 weeks with platinum-based chemotherapy every 3 weeks for 3 cycles. Neoadjuvant and adjuvant NSCLC: the same combination for 4 cycles, then nivolumab 480 mg every 4 weeks alone until progression or recurrence, unacceptable toxicity, or up to 13 cycles.
• Oesophageal squamous cell carcinoma with chemotherapy: nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks with fluoropyrimidine- and platinum-based chemotherapy every 4 weeks, up to 24 months without progression.
• Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma: nivolumab 360 mg every 3 weeks or 240 mg every 2 weeks with fluoropyrimidine- and platinum-based chemotherapy every 3 weeks or every 2 weeks depending on the regimen, up to 24 months without progression.
• Urothelial carcinoma with cisplatin and gemcitabine: nivolumab 360 mg every 3 weeks with chemotherapy every 3 weeks for up to 6 cycles, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks, until progression, unacceptable toxicity or up to 24 months from the first dose.
• Previously untreated stage III or IV Hodgkin lymphoma with AVD: nivolumab 240 mg every 2 weeks (3 mg/kg for adolescents under 80 kg) with AVD every 2 weeks, for 6 cycles of 28 days.
• Relapsed or refractory Hodgkin lymphoma with brentuximab vedotin: nivolumab 3 mg/kg every 3 weeks with brentuximab vedotin 1.8 mg/kg (maximum 180 mg) every 3 weeks; in cycle 1 brentuximab vedotin is given on day 1 and nivolumab on day 8. Treatment is risk-based and response-adapted, up to 6 cycles for low risk of relapse and up to 4 cycles for standard risk, with tumour assessment after every 2 cycles.
• Opdualag: 480 mg nivolumab and 160 mg relatlimab every 4 weeks as an intravenous infusion over 30 minutes, for adults and adolescents 12 years and older (the dose is established for adolescents weighing at least 30 kg). PD-L1 expression must be confirmed by a validated test, and patients get the patient card. Opdualag may be given undiluted or diluted with sodium chloride 0.9% or glucose 5%, never as a push or bolus injection.
• Duration: for as long as clinical benefit is observed or until intolerable, within any maximum above. Clinically stable patients with early signs of progression (atypical responses occur) can continue until progression is confirmed. Dose escalation or reduction is not recommended, for Opdivo or for Opdualag.

Subcutaneous Solution for Injection

Opdivo solution for injection (120 mg/mL; 300 mg in a 2.5 mL vial or 600 mg in a 5 mL vial) is a separate, ready-to-use product that is injected under the skin. It is not diluted or mixed with other medicines. Patients receiving intravenous nivolumab alone, or with chemotherapy or cabozantinib, may switch to it. Treatment is started and supervised by physicians experienced in cancer treatment, and the PD-L1 and MSI-H/dMMR testing requirements are the same as for the infusion.

• Monotherapy: 600 mg every 2 weeks or 1,200 mg every 4 weeks. When changing from 600 mg every 2 weeks to 1,200 mg every 4 weeks, the first 1,200 mg dose is given 2 weeks after the last 600 mg dose; when changing from 1,200 mg every 4 weeks to 600 mg every 2 weeks, the first 600 mg dose is given 4 weeks after the last 1,200 mg dose.
• After nivolumab with ipilimumab (melanoma, renal cell carcinoma, dMMR or MSI-H colorectal cancer, hepatocellular carcinoma): up to 4 cycles of nivolumab with ipilimumab are given intravenously at the doses above, then nivolumab continues as the subcutaneous injection, 600 mg every 2 weeks or 1,200 mg every 4 weeks. In melanoma and renal cell carcinoma, the first subcutaneous dose is given 3 weeks after the last combination dose for the 2-weekly schedule and 6 weeks after it for the 4-weekly schedule; in colorectal cancer and hepatocellular carcinoma, it is given 3 weeks after the last combination dose. In colorectal cancer and hepatocellular carcinoma, treatment is recommended until disease progression, unacceptable toxicity or up to 24 months.
• With cabozantinib (renal cell carcinoma): nivolumab 600 mg every 2 weeks or 1,200 mg every 4 weeks with cabozantinib 40 mg orally every day. Nivolumab continues until disease progression, unacceptable toxicity or up to 24 months in patients without progression; cabozantinib continues until progression or unacceptable toxicity.
• With chemotherapy: for oesophageal squamous cell carcinoma, nivolumab 600 mg every 2 weeks or 1,200 mg every 4 weeks with fluoropyrimidine- and platinum-based chemotherapy every 4 weeks; for gastric, gastro-oesophageal junction or oesophageal adenocarcinoma, nivolumab 600 mg every 2 weeks or 900 mg every 3 weeks with such chemotherapy every 2 or 3 weeks, depending on the nivolumab regimen; in both, until progression, unacceptable toxicity or up to 24 months without progression. For urothelial carcinoma, nivolumab 900 mg every 3 weeks with cisplatin and gemcitabine every 3 weeks for up to 6 cycles, then 600 mg every 2 weeks or 1,200 mg every 4 weeks, until progression, unacceptable toxicity or up to 24 months from the first dose.
• Non-small cell lung cancer with platinum-based chemotherapy: neoadjuvant treatment, nivolumab 900 mg every 3 weeks with chemotherapy every 3 weeks for 3 cycles; neoadjuvant followed by adjuvant treatment, the same combination for 4 cycles, then nivolumab 1,200 mg every 4 weeks alone until progression or recurrence, unacceptable toxicity or up to 13 cycles.
• Duration: as long as clinical benefit is observed or until the patient no longer tolerates treatment, within any maximum above. Adjuvant therapy lasts up to 12 months.
• Giving the injection: the vial is not shaken and is allowed to reach room temperature. The dose is drawn up with a syringe and transfer needle (5 mL for 600 mg, 7.5 mL for 900 mg, 10 mL for 1,200 mg) and injected subcutaneously with a 23G–25G hypodermic needle or a subcutaneous administration set (for example winged or butterfly). The needle is attached to the syringe just before the injection, to avoid clogging, and the prepared dose is used immediately; see Shelf Life for storage in the syringe.

Withholding and Stopping Treatment

• Pneumonitis: grade 2, withhold until symptoms resolve, imaging improves and corticosteroid treatment is complete; grade 3 or 4, discontinue permanently.
• Colitis: grade 2 diarrhoea or colitis, withhold; grade 3, withhold on nivolumab alone but discontinue permanently with ipilimumab (and during the nivolumab phase that follows the combination); grade 4, discontinue.
• Hepatitis: grade 2 rise in AST, ALT or bilirubin, withhold; grade 3 or 4, discontinue. In hepatocellular carcinoma thresholds depend on baseline values (see the SmPC). With cabozantinib, if ALT or AST is above 3 and up to 10 times the upper limit without bilirubin of 2 times or more, both medicines are withheld; above 10 times, or above 3 times with bilirubin of 2 times or more, both are stopped.
• Nephritis and renal dysfunction: grade 2 or 3 creatinine rise, withhold; grade 4, discontinue.
• Endocrine disorders: symptomatic grade 2 or 3 thyroid disorders or hypophysitis, grade 2 adrenal insufficiency or grade 3 diabetes, withhold until symptoms resolve (treatment can continue on hormone replacement without symptoms); grade 4 thyroid disorders, hypophysitis or diabetes, and grade 3 or 4 adrenal insufficiency, discontinue.
• Skin: grade 3 rash, withhold; grade 4 rash, Stevens-Johnson syndrome or toxic epidermal necrolysis, discontinue.
• Myocarditis: grade 2, withhold; grade 3 or 4, discontinue. Myocarditis-myositis-myasthenia gravis overlap syndrome: grade 2, withhold; grade 3 or 4, discontinue.
• Other immune-related reactions: first grade 3 episode, withhold. Discontinue for any grade 4 or recurrent grade 3 reaction, grade 2 or 3 reactions that persist despite treatment modification, or if the corticosteroid dose cannot be reduced to 10 mg prednisone or equivalent per day.
• With ipilimumab: if either antibody is withheld, the other is withheld too; after a delay, either the combination or nivolumab alone can be resumed. With chemotherapy, other agents may continue if one is withheld.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment for mild or moderate impairment; data in severe impairment are too limited to draw conclusions.
• Hepatic impairment: no adjustment for mild or moderate impairment; data in severe impairment are too limited. Use with caution in severe impairment (bilirubin above 3 times the upper limit of normal with any AST).
• Children and adolescents: not established below 18 years, except adolescents 12 years and older with melanoma or previously untreated Hodgkin lymphoma, and patients 5 years and older with relapsed or refractory Hodgkin lymphoma. Opdualag is not established below 12 years.

Immune-Related Reactions

Immune-related reactions are more frequent when nivolumab is given with ipilimumab than alone, and occur at similar frequencies with cabozantinib, brentuximab vedotin or AVD as with nivolumab alone. They can affect several organs at once and can start at any time, during treatment or after it, so patients should be monitored for at least 5 months after the last dose. For suspected reactions the cause is confirmed or other causes excluded; depending on severity, treatment is withheld and corticosteroids given, tapered over at least 1 month after improvement because rapid tapering can bring the reaction back. A non-corticosteroid immunosuppressant is added if there is worsening or no improvement. Nivolumab is not resumed while the patient needs immunosuppressive doses. Observational data suggest the risk of immune-related reactions may be higher in patients with existing autoimmune disease, whose underlying disease often flared (mostly mildly).

Cardiac and Pulmonary Reactions with Combinations

Cardiac and pulmonary events, including pulmonary embolism, have been reported with combination therapy. Patients are monitored for these and for signs of electrolyte disturbance and dehydration, and nivolumab with ipilimumab is discontinued for life-threatening or recurrent severe cardiac or pulmonary reactions.

Other Immune-Related Problems

Solid organ transplant rejection has been reported after marketing with PD-1 inhibitors, and treatment may raise the risk in transplant recipients. Haemophagocytic lymphohistiocytosis has been observed; if confirmed, nivolumab is stopped and the condition treated. Severe infusion reactions are possible.

Hodgkin Lymphoma and Stem Cell Transplant

Acute graft-versus-host disease and transplant-related mortality have occurred in patients with Hodgkin lymphoma who had an allogeneic stem cell transplant after nivolumab. After allogeneic transplant, rapid-onset severe graft-versus-host disease, some fatal, has been reported with nivolumab, mainly with a prior history of it. Benefit and risk should be weighed case by case. With AVD, grade 3 and 4 neutropenia was more frequent, so blood counts are checked before each cycle and prophylaxis with granulocyte colony-stimulating factor considered in patients at increased risk of febrile neutropenia, including older adults.

Selecting Patients

PD-L1 and MSI/MMR status must be assessed with a well-validated, robust method. In melanoma, the combination with ipilimumab improves progression-free survival over nivolumab alone only in patients with low tumour PD-L1 expression, and patients with rapidly progressing disease should be assessed with the delayed onset of effect in mind.

Disease-Specific Precautions

• Early deaths: more deaths within 3 months occurred with nivolumab than with docetaxel in head and neck cancer; more within 4 months with nivolumab plus ipilimumab than with chemotherapy in first-line oesophageal squamous cell carcinoma; more within 2.5 months with nivolumab than with chemotherapy in previously treated oesophageal squamous cell carcinoma; and more within 6 months with nivolumab plus ipilimumab than with lenvatinib or sorafenib in hepatocellular carcinoma. The delayed onset of effect and poor prognostic features should be weighed before starting.
• Patients excluded from studies: baseline ECOG performance score of 2 or more, active autoimmune disease, need for systemic immunosuppression, untreated or active brain metastases and, depending on the indication, other conditions such as symptomatic interstitial lung disease. Use with caution in these groups after weighing benefit and risk.
• Oesophageal squamous cell carcinoma after chemotherapy: most clinical data are from patients of Asian origin.
• Gastric adenocarcinoma: patients with known HER2-positive disease were excluded; in the main study, HER2 status was undetermined in 40.3% of patients.

Sodium and Polysorbate 80

Each mL contains 2.5 mg of sodium, giving 10 mg per 4 mL vial, 25 mg per 10 mL, 30 mg per 12 mL and 60 mg per 24 mL, which should be considered in patients on a controlled sodium diet; dilution with sodium chloride adds to this. The medicine contains 0.94, 2.14, 2.6 or 5.0 mg of polysorbate 80 per 4, 10, 12 or 24 mL vial, which may cause allergic reactions. The solution for injection contains 1.25 mg of polysorbate 80 per 2.5 mL vial and 2.5 mg per 5 mL vial.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: no human data. Animal studies showed embryo-foetal toxicity, and nivolumab, an IgG4, can cross the placenta. It is not recommended in pregnancy or in women of childbearing potential not using effective contraception, unless the benefit outweighs the risk. Effective contraception should be used for at least 5 months after the last dose.
• Breastfeeding: it is not known whether nivolumab passes into human milk, and a risk to the infant cannot be excluded. A decision must be made between stopping breastfeeding and stopping treatment.
• Fertility: not studied.

Patient Card and Traceability

The prescriber must discuss the risks of treatment with the patient and give the patient card with each prescription. The name and batch number of the administered product should be clearly recorded.

Effect on Driving

Nivolumab, alone or with ipilimumab or other agents, may have a minor influence on the ability to drive and use machines. Because of reactions such as fatigue, patients should take care until they are sure it does not affect them.

Store vials in a refrigerator at 2–8 °C. Do not freeze. Keep in the original package to protect from light. The unopened vial of the concentrate for infusion can be kept at controlled room temperature up to 25 °C in room light for up to 48 hours. Keep the cold chain unbroken during transport and handling. For storage after preparation, see Shelf Life. For Opdualag, follow the storage instructions in its own SmPC.

• Unopened vial (Opdivo concentrate for infusion and solution for injection): 3 years.
• Solution for injection transferred to a syringe: use immediately, because it contains no antimicrobial preservative or bacteriostatic agent. If it is not used immediately, it can be stored in a refrigerator at 2–8 °C protected from light for up to 7 days and/or at room temperature (20–25 °C) in room light for up to 8 hours; it is discarded if these limits are exceeded. Aseptic handling must be ensured when the syringe is prepared.
• Prepared infusion (undiluted or diluted): chemical and physical in-use stability, including the infusion time, has been shown for 30 days at 2–8 °C protected from light and, within that period, 24 hours at up to 25 °C in room light, when undiluted or diluted with sodium chloride 0.9%. With glucose 5% it is 7 days at 2–8 °C and, within that period, 8 hours at up to 25 °C. From a microbiological point of view the prepared solution should be used immediately; if not, the user is responsible for storage, which would normally not exceed 7 days at 2–8 °C or 8 hours (of the total 7 days) at room temperature (up to 25 °C).

Prescription only (Rx); treatment is started and supervised by physicians experienced in cancer treatment. Opdivo and Opdualag are given as intravenous infusions in hospital or clinic, and Opdivo solution for injection is prepared by trained personnel and injected subcutaneously, so they are supplied to the hospital or clinic that administers them, under cold-chain conditions at 2–8 °C.