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Metastatic nivolumab maintenance (flat dosing) following ipilimumab and nivolumab

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer using immunological agents. Before commencing immunotherapy treatment in any patient, clinicians should have an understanding of the immune-related adverse events (irAEs) associated with immunotherapy treatment and their management.

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

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Cycle 1 and further cycles

Drug Dose Route Day
Nivolumab 480 mg * # IV infusion 1
  • If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction.
  • If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

* Alternative dosing schedule 240 mg every 14 daysr,r 

# For patients with body weight less than 40 kg, the nivolumab recommended dose regimens are based on pharmacokinetic modelling.r It’s the consensus of the reference committee that the weight-based dosing of 3 mg/kg every 2 weeks be considered for this patient population.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity. Treatment cessation after 2 years of therapy may be considered.
Notes:
  • In clinical trials patients could be treated after progression, provided that they had a clinical benefit and did not have substantial adverse effects, as assessed by the investigator.
  • Patients should be assessed for tumour response after 12 weeks i.e. after induction treatment with combination of ipilimumab and nivolumab.
  • In the first few months after the start of immunotherapy, some patients can experience transient tumour flare (termed "pseudo progression" or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient remains well.
  • Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.
Drug status:

Nivolumab is PBS authority opens in a new tab or window

Cost:
~ $9,560 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Nivolumab 480 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes * #

  • If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction.
  • If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

* Alternative dosing schedule 240 mg every 14 daysr,r 

# For patients with body weight less than 40 kg, the nivolumab recommended dose regimens are based on pharmacokinetic modelling.r It’s the consensus of the reference committee that the weight-based dosing of 3 mg/kg every 2 weeks be considered for this patient population.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity. Treatment cessation after 2 years of therapy may be considered.

Cycle 1 and further cycles

Drug Dose Route Day
Nivolumab 480 mg * # IV infusion 1
  • If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction.
  • If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

* Alternative dosing schedule 240 mg every 14 daysr,r 

# For patients with body weight less than 40 kg, the nivolumab recommended dose regimens are based on pharmacokinetic modelling.r It’s the consensus of the reference committee that the weight-based dosing of 3 mg/kg every 2 weeks be considered for this patient population.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity. Treatment cessation after 2 years of therapy may be considered.
Notes:
  • In clinical trials patients could be treated after progression, provided that they had a clinical benefit and did not have substantial adverse effects, as assessed by the investigator.
  • Patients should be assessed for tumour response after 12 weeks i.e. after induction treatment with combination of ipilimumab and nivolumab.
  • In the first few months after the start of immunotherapy, some patients can experience transient tumour flare (termed "pseudo progression" or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient remains well.
  • Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.
Drug status:

Nivolumab is PBS authority opens in a new tab or window

Cost:
~ $9,560 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Nivolumab 480 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes * #

  • If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction.
  • If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

* Alternative dosing schedule 240 mg every 14 daysr,r 

# For patients with body weight less than 40 kg, the nivolumab recommended dose regimens are based on pharmacokinetic modelling.r It’s the consensus of the reference committee that the weight-based dosing of 3 mg/kg every 2 weeks be considered for this patient population.

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity. Treatment cessation after 2 years of therapy may be considered.
Induction (part 1) Ipilimumab and nivolumab every 3 weeks (for 4 doses only).
Maintenance (part 2) - weight based dosing (SUPERSEDED) Nivolumab every 2 weeks (weight based dosing). Continuous until disease progression or unacceptable toxicity. 
OR
Maintenance (part 2) - flat dosing Nivolumab every 2 or 4 weeks (flat dosing). Continuous until disease progression or unacceptable toxicity. 

This protocol is the maintenance (flat dosing) part of the ipilimumab and nivolumab followed by nivolumab regimen.

If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction. 

If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

Induction (part 1) Ipilimumab and nivolumab every 3 weeks (for 4 doses only).
Maintenance (part 2) - weight based dosing (SUPERSEDED) Nivolumab every 2 weeks (weight based dosing). Continuous until disease progression or unacceptable toxicity. 
OR
Maintenance (part 2) - flat dosing Nivolumab every 2 or 4 weeks (flat dosing). Continuous until disease progression or unacceptable toxicity. 

This protocol is the maintenance (flat dosing) part of the ipilimumab and nivolumab followed by nivolumab regimen.  

If using 4 weekly maintenance dosing, commence maintenance treatment 6 weeks after the last dose of ipilimumab/nivolumab induction. 

If using 2 weekly maintenance dosing, commence maintenance treatment 3 weeks after the last dose of ipilimumab/nivolumab induction​.

Indications:

  • Unresectable stage III or stage IV metastatic malignant melanoma following ipilimumab/nivolumab induction. 

Precautions:

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

  • significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
  • organ transplantation
  • previous history of viral hepatitis
  • HIV/acquired immune deficiency syndrome (AIDS)
  • previous radiation to the lungs.

Indications:

  • First line treatment of advanced unresectable or metastatic intermediate to poor risk clear cell renal cell carcinoma, following ipilimumab/nivolumab induction. 

Precautions:

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

  • significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
  • organ transplantation
  • previous history of viral hepatitis
  • HIV/acquired immune deficiency syndrome (AIDS)
  • previous radiation to the lungs.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Emetogenicity MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Immune-related adverse events (irAEs)

Immune-related adverse events (irAEs) can occur early and escalate quickly in patients receiving immune checkpoint inhibitors. irAEs can also occur after discontinuation of treatment. Fatalities have been reported. Management of irAEs is largely based on expert opinion and consensus guidelines.

Examples of irAEs with high risk of mortality include:

  • cardiac toxicity: myocarditis
  • musculoskeletal toxicity: myositis
  • neurological toxicity: encephalitis, Guillain-Barré syndrome, myelitis, myasthenia gravis
  • pulmonary toxicity: pneumonitis
  • skin toxicity: Stevens-Johnson syndrome, toxic epidermal necrolysis.

Examples of irAEs in order of frequency include:

  • Common
    • endocrinopathies: thyroid dysfunction
    • gastrointestinal toxicity: diarrhoea
    • musculoskeletal toxicity: arthralgia, myalgia
    • skin toxicity: rash, erythema, pruritus
  • Less common
    • endocrinopathies: hypophysitis, type I diabetes mellitus
    • gastrointestinal toxicity: colitis
    • musculoskeletal toxicity: inflammatory arthritis
    • ocular toxicity: dry eye
    • renal toxicity
    • skin toxicity: vitiligo
  • Rare
    • endocrinopathies: primary adrenal insufficiency
    • gastrointestinal toxicity: pancreatitis
    • haematological toxicity
    • musculoskeletal toxicity: vasculitis
    • ocular toxicity: uveitis, iritis.

Proactive monitoring, patient self-monitoring and early reporting of adverse events is critical. Treatment interruptions/discontinuation, consultation with specialist and administration of corticosteroids and/or supportive care is required to minimise the risk of death.

Read more about the management of immune-related adverse events (irAEs)
Baseline investigations

Consider ECG and troponin at baseline. There is no clear evidence regarding the efficacy/value of baseline ECG or troponin in patients receiving immune checkpoint inhibitor therapy. Some cancer specialists obtain baseline testing, and others continue this through the initial period of therapy. Consider urinalysis at baseline, particularly in patients with additional risk factors for developing immune-related acute kidney injury.
Blood tests

FBC, EUC, eGFR, LFTs, serum cortisol, TFTs and BSL at baseline.

Repeat FBC, EUC, eGFR, LFTs and BSL prior to each cycle. Check TFTs every 4-6 weeks during treatment and every 12 weeks as indicated after finalising treatment. Consider checking serum cortisol every 4-6 weeks during treatment and every 12 weeks as indicated after finalising treatment. Check lipase and amylase if symptomatic of pancreatitis.

In the absence of suspicion of immune-related adverse events less frequent monitoring may be applicable, according to institutional guidelines. Evidence for the frequency of routine blood testing with immunotherapies varies within published studies and guidelines.

Read more about immunotherapy blood test monitoring recommendations.
Hepatitis and HIV

Hepatitis screening is recommended in all patients who are to receive immune checkpoint inhibitors.

Immunotherapy is associated with inflammatory adverse reactions resulting from increased or excessive immune activity and patients are at risk of developing autoimmune hepatitis. It should be used with caution in patients who have a history of chronic hepatic infections (hepatitis B and C), detectable human immunodeficiency virus (HIV) viral load or acquired immune deficiency syndrome (AIDS).
Vaccinations

Live vaccines are not recommended for patients receiving this treatment. Caution is advised with inactivated vaccines, particularly the influenza vaccine.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Effects of cancer treatment on fertility

Studies to evaluate the effects of immune checkpoint inhibitor therapy on fertility have not been performed. Therefore, the effect on male and female fertility is unknown. Limited evidence supports that immune checkpoint inhibitor-related hypogonadism due to orchitis and hypophysitis can impact fertility. Immune checkpoint inhibitors can cause fetal harm when given to pregnant women. A pregnancy test should be considered in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. There is very limited evidence to provide guidance regarding contraception timelines. Some studies have demonstrated PD-1 receptor occupancy for greater than 9 months after anti-PD-1 therapy (Brahmer et al., 2010). As a result, some cancer specialists advise using contraception for at least six months or even as long as two years after treatment finishes.

Read more about the impact of cancer treatment on fertility opens in a new tab or window

Link to Brahmer et al., 2010 opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Immune checkpoint inhibitor dose modifications 

  • Dose reduction is not recommended
  • No dose adjustment is required in the elderly or mild hepatic impairment. Immune checkpoint inhibitors have not been studied in patients with moderate to severe hepatic impairment.

Management of immune-related adverse events (irAEs)

Link to Management of immune-related adverse events (irAEs)

Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Nivolumab
≥ 60

Full dose
45 - 59

Full dose
30 - 44

Full dose
15 - 29

Full dose 
< 15
(without kidney replacement therapy)

Full dose
Consider if immune-related adverse event. See Management of immune-related adverse events (irAEs)

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

Nivolumab
No formal pharmacokinetic drug interaction studies have been conducted with nivolumab.
  Interaction Clinical management
Immunosuppressants (inc. corticosteroids) Reduced efficacy of both immunosuppressants and nivolumab possible due to pharmacodynamic interaction

It is recommended that patients requiring corticosteroids prior to treatment receive the lowest possible dose (preferably no greater than 10 mg prednisolone or equivalent steroid per day). Once started on nivolumab the use of corticosteroids to treat immune related adverse events (irAEs) does not appear to impact the clinical response to nivolumab. In patients requiring ongoing corticosteroids post management of an irAE, the dose should be as low as possible.

Monitor for signs of organ rejection in transplant recipients.
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 60 minutes

Pre treatment assessment

Check for adverse events during previous treatment.

Any toxicity may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Immunotherapy patient assessment tool prior to each treatment.

Prior to administration

Prime required IV lines with sodium chloride 0.9%:

  • a low protein-binding 0.2 to 1.2 micrometre inline filter must be used
  • attach a second IV line via a luer lock connector as close as possible to the site of injection, this may be required in case of a hypersensitivity reaction or an infusion-related reaction (IRR). 

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify premedication and antiemetics taken or administer as prescribed, if required.

Nivolumab

Administer nivolumab:
  • via IV infusion over 30 minutes 
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR)

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency.

Grade 1 or 2:
  • consider holding or decreasing the rate of infusion, alert medical officer and monitor closely 
  • administer symptomatic medications as prescribed
  • further doses require close monitoring, premedications should be considered and prescribed by the medical officer as per local policy.
Grade 3 or 4: 
  • stop infusion immediately 
  • medical officer review. 

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

The most common side effects with this treatment are immune-related adverse events (irAEs). irAEs can escalate quickly and close monitoring of the patient is required. Symptoms should improve promptly after the introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice. Refer to the Management of immune related adverse events document for further information.

Immune related adverse events
Cardiotoxicity

Cardiotoxicity is a rare but serious side effect, which may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, myocarditis, pericarditis, cardiac fibrosis, hypertension, cardiac ischaemia, congestive heart failure (CHF) and cardiac arrest.

Read more about Management of immune related adverse events.
Gastrointestinal toxicity

Colitis, diarrhoea or more bowel movements than usual; blood or mucous in stools; dark, tarry, sticky stools; abdominal pain or tenderness.

Upper gastrointestinal tract inflammation including gastritis, duodenitis and oesophagitis can occur less commonly. Symptoms include nausea, vomiting, dysphagia, odynophagia, haematemesis and abdominal pain.

Read more about Management of immune related adverse events
Haematological toxicity

Autoimmune haemolytic anaemia (AIHA), acquired thrombotic thrombocytopenic purpura (TTP), aplastic anaemia (AA), immune thrombocytopenia (ITP), acquired haemophilia (AH), haemolytic uremic syndrome (HUS) and lymphopenia are rare but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Hepatotoxicity

Transaminase and total bilirubin elevation, jaundice, severe nausea or vomiting, pain on the right side of the abdomen, drowsiness, dark urine, bleeding or bruising more easily than normal, anorexia.

Read more about Management of immune related adverse events.
Musculoskeletal toxicity

Inflammatory arthritis, temporal arteritis, arthralgia, myalgia, synovitis, vasculitis, polymyalgia-like syndrome and myositis.

Read more about Management of immune related adverse events.
Neurological toxicity

Aseptic meningitis, myasthenia gravis, Guillain-Barre syndrome, encephalitis, meningeal symptoms, optic neuritis, neuropathy and acute inflammatory demyelinating polyneuropathy are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Ocular toxicity

Eye pain, blurred vision, Uveitis/iritis, episcleritis, blepharitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia. 

Read more about Management of immune related adverse events.
Other endocrinopathies

Type 1 diabetes mellitus, hypophysitis, hypopituitarism and adrenal insufficiency are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events
Pulmonary toxicity

Radiographic changes, dyspnoea, new or worsening cough, hypoxia, tachycardia, chest pain or fever.

Read more about Management of immune related adverse events.
Renal toxicity

Increase in serum creatinine, oliguria, haematuria, peripheral oedema and anorexia.

Read more about Management of immune related adverse events.
Skin toxicity

Rash including full thickness, pruritus, skin blisters, ulceration and necrosis. Radiation recall can occur at site of previous radiation therapy. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about Management of immune related adverse events
Thyroid toxicity

Thyroid toxicity is common with immune checkpoint inhibitors. Hypothyroidism is most frequent however hyperthyroidism can also occur.

Read more about Management of immune related adverse events

Non-immune related adverse events
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
Headache
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

The evidence for flat as opposed to weight based dosing for nivolumab comes from pharmacokinetic modelling papers by Long et alr and Zhao et al.r 

The Long study compared pharmacokinetic (PK) data for flat dose 480 mg every 4 weeks to 3 mg/kg every 2 weeks and 240 mg 2 every weeks.r Zhou et al studied flat dose 240 mg every 2 weeks compared with the standard 3 mg/kg every 2 weeks.r  Both studies used population PK modelling and simulation to compare nivolumab PK exposure and also evaluated the clinical safety of the various regimens.

In the Long paper data from clinical trials including 3817 patients across multiple tumour streams (including renal cell cancer, non small cell lung cancer, squamous cell cancer of head and neck, urothelial cancer, small cell lung cancer, hepatocellular cancer, colorectal cancer and gastric cancer) were pooled into a PK dataset. The results of the predicted steady state PK exposures in the flat dosing (480 mg every 4 weeks and 240 mg every 2 weeks) were compared with those already approved for the 3 mg/kg every 2 weeks regimen. Safety analysis was also performed in the following patient populations- advanced melanoma, renal cell cancer, non-squamous and squamous non small cell lung cancer who transitioned to 4 weekly dosing from 2 weekly or from the comparator arm in four phase III trials, CheckMate 066, 025, 057 and 017.r

Nivolumab PK exposure values were found to be comparable. Serum concentrations in the 480 mg every 4 weeks regimen rapidly approached steady state after the first month and remained at this level for the duration of the treatment. Similar time-averaged concentration, approximately 16% lower trough concentration and 45% higher peak concentration at steady state was produced with 480mg flat dose.

Clinical safety data was available for 61 patients from the phase III trials who transitioned from nivolumab dosing of 3 mg/kg to 480 mg every 4 weeks, which showed a comparable incidence of treatment related adverse events to those within the weight based dosing regimen and was consistent with other studies.r

The incidence of serious adverse events was comparable between body weight groups with no increase in the low body weight group. There were no reported infusion related reactions or adverse events resulting in treatment discontinuation or death.r

Similar conclusions for safety and efficacy were made in the Zhou study which compared flat dose 240 mg every 2 weeks with 3mg/kg every 2 weeks regimen.r

Summary of treatment related adverse eventsr

© Ann Oncol 2018

The evidence supporting this protocol is provided by three trials, CheckMate 067, CheckMate 069 and ABC. In the phase 3 double-blinded, multicentre, international, randomised trial CheckMate 067. In this trial, 945 eligible patients with previously untreated unresectable stage III or IV melanoma were randomised in a 1:1:1 ratio to receive either nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone.r

From July 2013 through to March 2014, a total of 1296 patients were enrolled at 137 centres worldwide. A total of 945 eligible patients underwent randomisation: 316 patients were assigned to the nivolumab group and received 3 mg/kg of nivolumab every 2 weeks (plus ipilimumab-matched placebo), 314 patients in the nivolumab plus ipilimumab group received 1 mg/kg of nivolumab every 3 weeks plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab every 2 weeks as maintenance treatment, and 315 patients in the ipilimumab group received 3 mg/kg of ipilimumab every 3 weeks for 4 doses (plus nivolumab-matched placebo).r Baseline characteristics were balanced across the three groups. Treatment was continued until disease progression or unacceptable toxicity.

The co-primary end points were progression-free survival (PFS) and overall survival (OS). Secondary end points were objective response rate (ORR), tumour PD-L1 expression as a predictive biomarker for efficacy outcomes, and safety. This study was not powered to compare nivolumab monotherapy with nivolumab plus ipilimumab.r

CheckMate 069 is a double-blind phase 2 study involving 142 patients with previously untreated stage III or IV melanoma. In this study patients were randomly assigned in a 2:1 ratio to receive ipilimumab (3 mg/kg) combined with either nivolumab (1 mg/kg) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg/kg ) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. Randomisation was stratified according to BRAF mutation status (V600 wild type vs mutation-positive).r

The primary end point was the rate of investigator-assessed, confirmed ORR among patients with BRAF V600 wild-type tumours. Secondary end points included investigator-assessed PFS in patients with BRAF wild-type tumours, the ORR and PFS among patients with BRAF V600 mutation–positive tumours, and safety.r

Patients with active brain metastases or leptomeningeal disease were previously excluded from clinical trials. The ABC (Anti-PD1 Brain Collaboration) trial provides data on activity of immunotherapy in brain metastasis. Immunotherapy-naïve patients with at least one brain metastasis between 5 and 40 mm with no prior local brain therapy were randomized to nivolumab or combination nivolumab-ipilimumab. Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in a third non-randomised cohort receiving nivolumab alone. The primary endpoint was  intracranial response from week 12.r

Efficacy

CheckMate 067

After a median follow-up ranging from 18.6 to 38.0 months across the three groups, the median PFS was 11.5 months (95% CI 8.7-19.3) in the nivolumab+ipilimumab group and 6.9 months (95% CI 5.1-9.7) in the nivolumab group, as compared with 2.9 months (95% CI 2.8-3.2) in the ipilimumab group. The hazard ratio for progression or death was 0.43 (95% CI 0.35-0.52) with nivolumab+ipilimumab vs ipilimumab (p<0.001) and was 0.55 (95% CI 0.45-0.66) with nivolumab vs ipilimumab (p<0.001). The rate of PFS at 3 years was 39% in the nivolumab+ipilimumab group and 32% in the nivolumab group as compared with 10% in the ipilimumab groupr

At a minimum follow-up of 60 months, the median OS had not been reached (NR) in the nivolumab+ipilimumab group and was 36.9 months in the nivolumab group, compared with 19.9 months in the ipilimumab group (HR=0.52; 95% CI 0.42-0.64; p<0.001 with nivolumab+ipilimumab vs ipilimumab; HR=0.63, 95% CI 0.52-0.76; p<0.001 with nivolumab vs ipilimumab). The OS rate at 5 years was 52% in the nivolumab+ipilimumab group and 44% in the nivolumab group, compared with 26% in the ipilimumab group.r

At a minimum follow-up of 77 months, the median OS was 72.1 months (95% CI 38.2-NR) in the combination therapy arm as compared with 36.9 months (95% CI 28.2-58.7) and 19.9 months (95% CI 16.8-24.6) in the nivolumab and ipilimumab arms, respectively (HR=0.52; 95% CI 0.43-0.64; p<0.0001 for combination therapy vs ipilimumab alone, HR=0.84; 95% CI 0.67-1.04 for combination therapy vs nivolumab alone and HR=0.63; 95% CI 0.52-0.76; p<0.0001 for nivolumab vs ipilimumab). 6.5-year OS rates were 49%, 42% and 23% in the nivolumab+ipilimumab, nivolumab and ipilimumab groups, respectively. PFS was 11.5 months (95% CI 8.7-19.3), 6.9 months (95% CI 5.1-10.2) and 2.9 months (95% CI 2.8-3.2) in the three groups, respectively.r

The phase II CheckMate 069 study showed similar efficacy and toxicity for patients receiving combination ipilumumab/nivolumab and ipilimumab monotherapy respectively.r

Response to treatmentr

Nivolumab 

(n=316)

Nivolumab
+
ipilimumab 

(n=314)

Ipilimumab 

(n=315)
Complete response (%) 19 23 6
Partial response (%) 26 36 13
Stable disease (%) 9    12 22 
Progressive disease (%) 38 24 50
Unknown (%) 8 6 9
ORR (%, 95% CI) 45 (39−51) 58 (53−64) 19 (15−24)
Median duration of response (months, 95% CI) NR (45.7-NR) NR (61.9-NR) 19.2 (8.8-47.4)

NR= Not reached

Kaplan Meier curves for (A) overall survival and (B) progression-free survivalr

 

© J Clin Oncol 2022

ABC study 

With a median follow up of 17 months, intracranial responses were achieved by 16 (46%) of 35 patients treated with combined nivolumab + ipilimumab, five (20%) of 25 patients treated with nivolumab monotherapy and one (6%) of 16 patients with poor prognostic features (neurological symptoms, progression after previous local brain treatment or leptomeningeal disease) treated with nivolumab monotherapy.r

Toxicity

CheckMate 067

Treatment-related adverse events were reported in 96% of the patients treated with combination therapy, 86% of those treated with nivolumab, and 86% of those treated with ipilimumab. Grade 3 or 4 adverse events occurred in 59%, 21%, and 28%, respectively. Treatment-related adverse events of any grade that led to the discontinuation of therapy occurred more frequently with combination therapy (39%) than with either monotherapy (12% nivolumab, 16% ipilimumab).r

The most common select adverse events of grade 3 or 4 were gastrointestinal events, which occurred in 15% of the patients who received combination therapy, in 4% of those who received nivolumab monotherapy, and in 12% of those who received ipilimumab monotherapy (specifically, diarrhoea in 9%, 3%, and 6% of patients respectively).r​

There were two deaths related to a study drug within 100 days of the last dose: one death due to neutropenia (nivolumab group) and one due to colon perforation (ipilimumab group). There were two deaths considered to be related to a study drug (>100 days after the last dose) in the combination therapy group: one due to autoimmune myocarditis (approximately 2 months after receiving a single dose of anti-PD1 outside the context of the trial) and one due to liver necrosis.r

At the time of 6.5-year analysis, grade 3/4 treatment-related adverse events were reported in 59% of patients treated with combination therapy as compared with 24%, and 28% in the nivolumab and ipilimumab groups, respectively. No new safety signals were detected.r

Adverse eventsr

© N Engl J Med 2017

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (CheckMate 214) involving 1096 patients comparing nivolumab plus ipilimumab with sunitinib alone in patients with previously untreated advanced renal cell carcinoma with a clear-cell component.r

Between October 2014 and February 2016, 550 patients were assigned to the nivolumab plus ipilimumab group, 3 mg/kg and 1 mg/kg respectively given every 3 weeks for 4 doses (induction phase), followed by nivolumab monotherapy 3 mg/kg given every 2 weeks (maintenance phase) until progression or discontinuation due to unacceptable toxicity. 535 patients were assigned to the sunitinib group and received 50 mg orally once daily for 4 weeks of a 6-week cycle.

The co-primary endpoints were overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) among patients with intermediate or poor (I/P)-risk by IMDC prognostic score criteria. Exploratory endpoints included the OS, ORR and PFS among favourable (FAV)-risk patients.

Efficacy

The efficacy outcomes of CheckMate 214 have previously been reported in primary, second and third interim analyses.rrr

The results of the interim and subsequent analyses amongst I/P- risk patients are summarised in the table below.The combination of ipilimumab and nivolumab was shown to be superior to sunitinib for all three co-primary endpoints.rrr

After a minimum of 5 years follow up (median follow up 67.7 months), OS superiority was maintained with nivolumab plus ipilimumab compared to sunitinib in the intention to treat (ITT) population (HR, 0.72; 95% CI, 0.62-0.85, P<0.0001) and in the intermediate-risk/poor-risk population (HR 0.68, 95% CI, 0.58-0.81, P<0.0001). OS benefits were observed with nivolumab plus ipilimumab compared to sunitinib in ITT patients regardless of PD-L1 expression status. PFS and ORR benefits were also maintained in the ITT and intermediate-risk/poor risk patient group.r The results are summarised in the table below.

Importantly, more responses to nivolumab plus ipilimumab were complete (11.6%) and durable (63% ongoing response) compared to sunitinib (3.1% complete response, 50.3% ongoing response) in the ITT population.r

Exploratory analysis in patients with favourable-risk disease showed improved outcomes in the sunitinib group compared to the nivolumab plus ipilimumab group, with prolonged median PFS (28.9 months vs 12.4 months, HR=1.6; 95% CI 1.13 to 2.26; p=0.0073) and higher ORR (51.6% vs 29.6%, p=0.0002). However, more responses in the nivolumab plus ipilimumab group were complete (12.8% vs 6.5%) and durable (59.5% vs 51.6%) compared to sunitinib.r Ongoing follow-up and data maturation for this patient subgroup is required before definitive conclusions can be made regarding optimal therapy.

Summary of co-primary endpoint analysis at each interim analysis for I/P-risk patients

Primary endpoint First interim analysis (median 25.2 months follow-up)r Second interim analysis (median 32.4 months follow-up)r Extended follow-up analysis (median 55 months follow-up)r Extended follow-up analysis (median 67.7 months follow-up)r

Ipilimumab/

nivolumab

 Sunitinib

Ipilimumab/

nivolumab

 Sunitinib

Ipilimumab/

nivolumab

 Sunitinib

Ipilimumab/

nivolumab

 Sunitinib 
Median OS (months) NR 26.0 NR 26.6 48.1 26.6 47 26.6
HR=0.63
99.8% CI 0.44-0.89; p<0.001		 HR=0.66
95% CI 0.54-0.80, p<0.0001		 HR=0.65
95% CI 0.54-0.78		 HR 0.68;(95% CI, 0.38-0.81); P<0.0001
ORR (%, 95% CI) 42 (37-47) 27 (22-31) 42 (37-47) 29 (25-34) 41.9 (37-47) 26.8 (23-31) 41.9 (37-47) 26.8 (23-31)
Median PFS (months) 11.6 8.4 8.2 8.3 11.2 8.3 11.6 8.3
HR=0.85
99.1% CI 0.64-1.05, p=0.03		 HR=0.77
95% CI 0.65-0.90, p=0.0014		 HR=0.74
95% CI 0.62-0.88		 HR 0.73;
(95% CI, 0.61-0.87); P=0.0004

NR = not reported

Kaplan-Meier curves for OS in (A) ITT, (B) I/P-risk and (C) FAV-risk patientsr

© ESMO Open 2020

Kaplan-Meier curves for PFS per investigator assessment in (A) ITT, (B) I/P-risk and (C) FAV-risk patientsr

© ESMO Open 2020

Toxicity

Treatment-related adverse events were reported in 94% of those who received nivolumab plus ipilimumab and 98% in those who received sunitinib. Fewer grade 3 and 4 treatment-related adverse events were reported in those who received nivolumab plus ipilimumab (48%) compared to those who received sunitinib (64%).r The most common severe toxicities (grade 3 or 4) experienced in both regimens are summarised below. Severe toxicity for nivolumab plus ipilimumab tended to occur within or soon after the initial four cycle induction phase, with far fewer events during the maintenance nivolumab phase. In comparison, patients who received sunitinib experience chronic toxicity in a cumulative fashion, especially vascular-related adverse events.r

Treatment discontinuation due to adverse events occurred in 23% of patients in the nivolumab plus ipilimumab group vs 13% in the sunitinib group. The use of corticosteroids (> 40 mg prednisolone daily or equivalent) to manage treatment-related select adverse events occurring within 30 days of last dose in the nivolumab plus ipilimumab group was 30% (162/547).r There were eight (1%) treatment-related deaths reported in the nivolumab plus ipilimumab group and five (<1%) treatment-related deaths reported in the sunitinib group.r

Adverse events

Grade 3-4 treatment-related adverse eventsr NIVO-IPI
(N = 547)		 SUN
(N = 535)
Fatigue 4% 10%
Pruritis <1% 0
Diarrhoea 4% 6%
Rash 2% 0
Nausea 1% 1%
Lipase increased 12% 7%
Hypothyroidism <1% <1%
Arthralgia 1% <1%
Pyrexia <1% <1%
Decreased appetite 1% 1%
Asthenia 2% 2%
Vomiting <1% 2%
Anaemia <1% 4%
Stomatitis 0 3%
Mucosal inflammation <1% 3%
Hypertension <1% 17%
Palmar-plantar erythrodysesthesia syndrome <1% 9%
Thrombocytopenia 0 4%

* Reported between first dose and 30 days after last dose of study therapy

Grade 3-4 treatment-related select^ adverse eventsr NIVO-IPI
(N = 547)		 SUN
(N = 535)
Skin 4% 10%
Endocrine 7% <1%
Gastrointestinal 5% 6%
Hepatic 9% 4%
Renal 1% 1%
Pulmonary 1% 0

^ Defined as events that might be immune-mediated

[%id%]
[%title%]

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Version 8

Date Summary of changes
16/09/2024 Protocol reviewed by urogenital reference committee on 24/05/2024. Evidence section updated to include 4 year follow up data. Version number increased to V.8. 

Version 7

Date Summary of changes
04/04/2024
  • Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section. PDF of previous protocol.
  • Protocol reviewed at Immunotherapy and Skin Medical Oncology Reference Committee meeting on 23/02/2024. Treatment schedule note added regarding nivolumab dosing in patients with very low body weight (< 40 kg). Patient information side effects preamble updated to include examples of 'common, less common and rare' side effects. Protocol to be reviewed in 4 years.

Version number changed to V.7.

Version 6

Date Summary of changes
04/09/2023

Protocol reviewed at the urogenital reference committee meeting on 18th August 2023. Evidence section for renal cell carcinoma updated to include long term efficacy data from CheckMate 214. Version increased to V.6. Review urogenital indication in 2 years.

Version 5

Date Summary of changes
22/08/2022

Evidence for melanoma indication reviewed by Medical Oncology Reference Committee. Efficacy and toxicity updated with CheckMate 067 6.5 years data. Version number change to V.5. No change to next review date.
20/09/2022 Blood tests in clinical information section updated to remove information about CTLA-4 containing regimens.

Version 4

Date Summary of changes
13/04/2022

Protocol reviewed at the immunotherapy reference committee meeting held on 4th of March 2022. The following changes have been made across all immune checkpoint inhibitor protocols:

  • Indications and patient populations- previous radiation to the lungs added to precautions.
  • Clinical information- general irAEs, hepatitis and HIV, and fertility blocks updated. Individual irAE-related blocks removed. New block (baseline investigations) added.
  • Patient information- pregnancy and breastfeeding block in general advice section updated.

Version number increased to V.4. Next review in 2 years.

Version 3

Date Summary of changes
12/11/2020

Protocol updated to align with ID 1993 Management of immune-related adverse events (irAEs) clinical resource which has been electronically reviewed and approved by the eviQ immunotherapy reference committee. The following changes have been made across all immune checkpoint inhibitor protocols:

  • Treatment schedule - additional note added: radiation recall.
  • Clinical information- cardiotoxicity, haematological toxicity, musculoskeletal toxicity and ocular toxicity added; rheumatological toxicity removed; immunotherapy clinical information changed to alphabetical order.
  • Side effects- haematological added; rheumatological replaced with musculoskeletal; immunotherapy side effects changed to alphabetical order.

Arthralgia and myalgia non-irAE side effect removed to align with other immune checkpoint inhibitor protocols.

Version number increased to V.3.

Version 2

Date Summary of changes
14/09/2020 Protocol reviewed electronically by urogenital reference committee. Renal cell efficacy and toxicity data updated. Version number changed to V.2. 

Version 1

Date Summary of changes
14/01/2020 New flat dosing multi-indication protocol reviewed and approved electronically by Medical Oncology Reference Committee (melanoma, urogenital)
20/01/2020 Protocol published on eviQ. Next review in 1 year.
21/07/2020 Protocol reviewed electronically by melanoma reference committee. M1c disease and elevated LDH removed from melanoma indication. Next review in 2 years.

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11 May 2025