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Melanoma metastatic ipilimumab and nivolumab (induction)

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 to 4

Drug Dose Route Day
Nivolumab 1 mg/kg IV infusion 1
Ipilimumab 3 mg/kg 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​.
Frequency:
21 days 
Cycles:
4 
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:

Ipilimumab and nivolumab are PBS authority opens in a new tab or window

Cost:
~ $28,270 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 to 4

Day 1
Nivolumab 1 mg/kg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Ipilimumab 3 mg/kg (IV infusion) in 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​.

* Wait for 30 minutes after the completion of nivolumab before commencing ipilimumab1

# Ipilimumab infusion time is reflective of eviQ reference committee consensus, based on clinical practice and supportive evidence2

Frequency:
21 days 
Cycles:
4 

Cycle 1 to 4

Drug Dose Route Day
Nivolumab 1 mg/kg IV infusion 1
Ipilimumab 3 mg/kg 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​.
Frequency:
21 days 
Cycles:
4 
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:

Ipilimumab and nivolumab are PBS authority opens in a new tab or window

Cost:
~ $28,270 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 to 4

Day 1
Nivolumab 1 mg/kg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Ipilimumab 3 mg/kg (IV infusion) in 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​.

* Wait for 30 minutes after the completion of nivolumab before commencing ipilimumab1

# Ipilimumab infusion time is reflective of eviQ reference committee consensus, based on clinical practice and supportive evidence2

Frequency:
21 days 
Cycles:
4 
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 induction part of the ipilimumab and nivolumab followed by nivolumab regimen.  

After 4 cycles of combination therapy with ipilimumab and nivolumab, continue with single agent nivolumab maintenance (weight based or flat dosing).

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 
  • ECOG 0-1.

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
  • pre-existing deranged liver function tests (this is not predictive of ipilimumab toxicity but extra attention should be applied)
  • in patients with asymptomatic or treated brain metastases, clinical judgement should be used and individual cases discussed with an expert in the field
  • in patients who have received ipilimumab and stereotactic therapy, case series have reported the development of radiation necrosis at irradiated sites.
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. These events occur at higher frequencies and earlier when nivolumab is administered in combination with ipilimumab when compared to monotherapy. 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 serum cortisol and TFTs every 4-6 weeks during the course of treatment and every 12 weeks after finalising the 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.
  • 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.
  • When nivolumab is administered in combination with ipilimumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, clinical judgement and/or discussion with an expert in the field is advisable to decide whether the patient should be rechallenged with combination treatment or monotherapy with nivolumab.

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 Ipilimumab*
≥ 60

Full dose

No dose reduction required in mild or moderate kidney dysfunction.

This drug has not been studied in patients with severe kidney dysfunction.

 

 

 

 
45 - 59

Full dose
30 - 44

Full dose
15 - 29

Full dose
< 15
(without kidney replacement therapy)

Full dose

* This drug was not included in the ADDIKD guideline.

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.

Ipilimumab
  Interaction Clinical management
Immunosuppressants (inc. corticosteroids) Reduced efficacy of both immunosuppressants and ipilimumab 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 ipilimumab the use of corticosteroids to treat immune related adverse events (irAEs) does not appear to impact the clinical response to ipilimumab. 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.
Vemurafenib (for melanoma) Increased risk of hepatotoxicity Combination not recommended outside of a clinical trial
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
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: 2 hours

Pre treatment assessment

Check for adverse events during previous treatment.

Any toxicity may require 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%:

  • nivolumab and ipilimumab both require low protein-binding 0.2 to 1.2 micrometre inline filters
  • ensure a separate line and filter is used for each drug
  • attach a second IV line via a luer lock connector for both nivolumab and ipilimumab 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. 

Ipilimumab

Wait for 30 minutes after the completion of nivolumab before commencing ipilimumab.

Administer ipilimumab (3 mg/kg):
  • via IV infusion over 30 minutes
    • the product information recommends giving ipilimumab 3 mg/kg over 90 minutes, it is the consensus of the eviQ reference committee and based on clinical practice and supportive evidence that it is safe to give over 30 minutes2
  • 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 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.1

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).1 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.1

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).3

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.3

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 12.4

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 group5

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.6

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.7

The phase II CheckMate 069 study showed similar efficacy and toxicity for patients receiving combination ipilumumab/nivolumab and ipilimumab monotherapy respectively.3

Response to treatment7

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 survival7

 

© 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.4

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).5

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).5​

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.5

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.7

Adverse events5

© N Engl J Med 2017

1
Larkin, J., V. Chiarion-Sileni, R. Gonzalez, et al. 2015. "Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma." N Engl J Med 373(1):23-34.
2
Momtaz, P., V. Park, K. S. Panageas, et al. 2015. "Safety of Infusing Ipilimumab Over 30 Minutes." J Clin Oncol 33(30):3454-3458.
3
Postow, M. A., J. Chesney, A. C. Pavlick, et al. 2015. "Nivolumab and ipilimumab versus ipilimumab in untreated melanoma." N Engl J Med 372(21):2006-2017.
4
Long, G. V., V. Atkinson, S. Lo, et al. 2018. "Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study." Lancet Oncol 19(5):672-681.
5
Wolchok, J. D., V. Chiarion-Sileni, R. Gonzalez, et al. 2017. "Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma." N Engl J Med 377(14):1345-1356.
6
Larkin, J., V. Chiarion-Sileni, R. Gonzalez, et al. 2019. "Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma." N Engl J Med 381(16):1535-1546.
7
Wolchok, J. D., V. Chiarion-Sileni, R. Gonzalez, et al. 2022. "Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma." J Clin Oncol 40(2):127-137.

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Version 10

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.

  • Patient information side effects preamble updated to include examples of 'common, less common and rare' side effects following consensus at the immunotherapy and skin reference committee meeting held on 23rd of February 2024. 

Version number changed to V.10.

Version 9

Date Summary of changes
22/08/2022

Protocol reviewed electronically by Medical Oncology Reference Committee. Evidence updated with CheckMate 067 6.5 years data. Version number change to V.9. Next review in 4 years.

Version 8

Date Summary of changes
13/04/2022

Protocol updated based on the consensus gained 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.8. 

Version 7

Date Summary of changes
11/05/2021

 Protocol updated to align with other ipilimumab and nivolumab protocols:

  • Treatment time in administration section and patient information changed to 2 hours.
  • "Immunotherapy can potentially affect any organ of the body" added to your treatment section in patient information.

Version number increased to V.7. 

Version 6

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.
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Version number increased to V.6.

Version 5

Date Summary of changes
20/01/2020 Treatment schedule, treatment schema, patient information and related pages updated to include nivolumab maintenance weight based and flat dosing options (ID 3682 and ID 3677). Premedication block removed from clinical information. Indications and side effects updated. Evidence updated to include 5 year data. Version number changed to V.5. Next review in 1 year.
21/07/2020 Protocol reviewed electronically by Medical Oncology Reference Committee. M1c disease and elevated LDH removed from indications. Next review in 2 years.

Version 4

Date Summary of changes
06/02/2017 New protocol taken to Medical Oncology Reference Committee meeting on 8 April 2016. Further work continued via email. Protocol published on eviQ. Next review in 1 year. 
15/03/2017 Discussed with Medical Oncology Reference Committee via email and alert issued by MOGA in April 2016 added to vaccination information in protocol: in patients receiving combination ipilimumab and nivolumab there have been reported cases of fatal myocarditis, myositis and rhabdomyolysis shortly after administration of the influenza vaccine. Advice for patients regarding vaccinations in patient information sheet changed to: Do not have any vaccinations without talking to the doctor who is managing your cancer treatment (medical oncologist). People you live with should be fully vaccinated, according to the current vaccination schedule. Extra care needs to be taken with hand washing and careful disposal of soiled nappies for infants who have recently received the rotavirus vaccine.
31/05/2017 Transferred to new eviQ website.
11/08/2017 Vaccination wording changed as per reference committee.
15/06/2018 Protocol reviewed at Medical Oncology Reference Committee meeting on 15 June 2018. Evidence updated. Infusion duration for ipilimumab and nivolumab changed to 30 minutes. Version number changed to V.3. Next review in 2 years. 
11/10/2018 Clinical information made consistent across immune checkpoint inhibitor protocols. 
Dose modifications disclaimer made consistent across immune checkpoint inhibitor protocols. 
Side-effects grouped into immune and non-immune related side effects and content made consistent across protocols and patient information. 
Protocol version number increased to V.4.
03/12/2018 Indication and drug status updated as per PBS listing.
17/01/2019 General patient assessment tool removed and immunotherapy patient assessment tool added to administration section. 
22/01/2019 Nivolumab infusion time note removed from treatment schedule detail as now included in product information.

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25 May 2025