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YERVOY 5 mg/ml concentrate for solution for infusion

Active Ingredient:
ipilimumab
Company:  
Bristol Myers Squibb Pharmaceuticals limited See contact details
ATC code: 
L01FX04
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About Medicine
{healthcare_pro_orange} This information is for use by healthcare professionals
Last updated on emc: 06 Feb 2024
1. Name of the medicinal product

YERVOY 5 mg/ml concentrate for solution for infusion

2. Qualitative and quantitative composition

Each ml of concentrate contains 5 mg ipilimumab.

One 10 ml vial contains 50 mg of ipilimumab.

One 40 ml vial contains 200 mg of ipilimumab.

Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1κ ) produced in Chinese hamster ovary cells by recombinant DNA technology.

Excipients with known effect:

Each ml of concentrate contains 0.1 mmol sodium, which is 2.30 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates and has a pH of 7.0 and an osmolarity of 260-300 mOsm/kg.

4. Clinical particulars
4.1 Therapeutic indications

Melanoma

YERVOY as monotherapy or combination with nivolumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults, and adolescents 12 years of age and older (see section 4.4).

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression (see sections 4.4 and 5.1).

Renal cell carcinoma (RCC)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (see section 5.1).

Non-small cell lung cancer (NSCLC)

YERVOY in combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation.

Malignant pleural mesothelioma (MPM)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC)

YERVOY in combination with nivolumab is indicated for the treatment of adult patients with mismatch repair deficient or microsatellite instability-high metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy (see section 5.1).

Oesophageal squamous cell carcinoma (OSCC)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%.

4.2 Posology and method of administration

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

PD-L1 testing

If specified in the indication, patient selection for treatment with YERVOY based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, and 5.1).

Posology

YERVOY as monotherapy

Melanoma

Adults and adolescents 12 years of age and older

The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously over a 30-minute period every 3 weeks for a total of 4 doses. Patients should receive the entire induction regimen (4 doses) as tolerated, regardless of the appearance of new lesions or growth of existing lesions. Assessments of tumour response should be conducted only after completion of induction therapy.

YERVOY in combination with nivolumab

Melanoma

In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks.

In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg every 4 weeks.

Table 1: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

Adults and adolescents 12 years of age and older:

1 mg/kg over 30 minutes

Adults and adolescents (12 years of age and older weighing at least 50 kg):

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 60 minutes

Adolescents (12 years of age and older and weighing less than 50 kg):

3 mg/kg every 2 weeks over 30 minutes or

6 mg/kg every 4 weeks over 60 minutes

Ipilimumab

Adults and adolescents 12 years of age and older:

3 mg/kg over 30 minutes

-

Renal cell carcinoma and dMMR or MSI-H colorectal cancer

The recommended dose is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (RCC only), as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should be administered;

▪ 3 weeks after the last dose of the combination of ipilimumab and nivolumab if using 240 mg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of ipilimumab and nivolumab if using 480 mg every 4 weeks (RCC only).

Table 2: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for RCC and dMMR or MSI-H CRC

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

3 mg/kg over 30 minutes

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 60 minutes (RCC only)

Ipilimumab

1 mg/kg over 30 minutes

-

Malignant pleural mesothelioma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks. Treatment is continued for up to 24 months in patients without disease progression.

Oesophageal squamous cell carcinoma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every 3 weeks administered intravenously over 30 minutes. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

YERVOY in combination with nivolumab and chemotherapy

Non-small cell lung cancer

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 1 mg/kg ipilimumab every 6 weeks in combination with 360 mg nivolumab administered intravenously every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Duration of treatment

Treatment with YERVOY in combination with nivolumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. (and up to maximum duration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with YERVOY in combination with nivolumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before each dose of YERVOY. In addition, any signs or symptoms of immune-related adverse reactions, including diarrhoea and colitis, must be assessed during treatment with YERVOY (see Tables 3A, 3B, and section 4.4).

Children younger than 12 years of age

The safety and efficacy of ipilimumab in children younger than 12 years of age has not been established.

Permanent discontinuation of treatment or withholding of doses

Management of immune-related adverse reactions may require withholding of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In some cases, addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability.

Guidelines for permanent discontinuation or withholding of doses are described in Tables 3A and 3B for YERVOY as monotherapy, and in Table 3C for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 3A When to permanently discontinue YERVOY as monotherapy

Permanently discontinue YERVOY in patients with the following adverse reactions. Management of these adverse reactions may also require systemic high-dose corticosteroid therapy if demonstrated or suspected to be immune-related (see section 4.4 for detailed management guidelines).

Adverse reactions

NCI-CTCAE v4 Gradea

Gastrointestinal:

Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation)

▪ Grade 3 or 4 diarrhoea or colitis

Hepatic:

Severe elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin or symptoms of hepatotoxicity

▪ Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Skin:

Life threatening skin rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) or severe widespread pruritus interfering with activities of daily living or requiring medical intervention

▪ Grade 4 rash or Grade 3 pruritus

Neurologic:

New onset or worsening severe motor or sensory neuropathy

▪ Grade 3 or 4 motor or sensory neuropathy

Other organ systemsb:

(e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis, diabetes)

▪ ≥ Grade 3 immune-related reactionsc

▪ ≥ Grade 2 for immune-related eye disorders NOT responding to topical immunosuppressive therapy

▪ Grade 4 diabetes

a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).

b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to CTCAE. Decision whether to discontinue YERVOY should be based on severity.

c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy.

Table 3B When to withhold dose of YERVOY as monotherapy

Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines.

Adverse reactions

Action

Gastrointestinal:

Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5-7 days) or recurs

1. Withhold dose until an adverse reaction resolves to Grade 1 or Grade 0 (or returns to baseline).

2. If resolution occurs, resume therapy.d

3. If resolution has not occurred, continue to withhold doses until resolution then resume treatment.d

4. Discontinue YERVOY if resolution to Grade 1 or Grade 0 or return to baseline does not occur.

Hepatic:

Grade 2 elevation in AST, ALT, or total bilirubin

Skin:

Moderate to severe (Grade 3)b skin rash or (Grade 2) widespread/intense pruritus regardless of etiology

Endocrine:

Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or high-dose immunosuppressive therapy

Grade 3 diabetes

Neurological:

Moderate (Grade 2)b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days)

Other moderate adverse reactionsc

a No dose reduction of YERVOY is recommended.

b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).

c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE. Decision whether to withhold a dose should be based on severity.

d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Table 3C: Recommended treatment modifications for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment

Immune-related adverse reaction

Severity

Treatment modification

Immune-related pneumonitis

Grade 2 pneumonitis

Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete

Grade 3 or 4 pneumonitis

Permanently discontinue treatment

Immune-related colitis

Grade 2 diarrhoea or colitis

Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete

Grade 3 or 4 diarrhoea or colitis

Permanently discontinue treatment

Immune-related hepatitis

Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Permanently discontinue treatment

Immune-related nephritis and renal dysfunction

Grade 2 or 3 creatinine elevation

Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation

Permanently discontinue treatment

Immune-related endocrinopathies

Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis,

Grade 2 adrenal insufficiency

Grade 3 diabetes

Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete. Treatment should be continued in the presence of hormone replacement therapya as long as no symptoms are present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis

Grade 3 or 4 adrenal insufficiency

Grade 4 diabetes

Permanently discontinue treatment

Immune-related skin adverse reactions

Grade 3 rash

Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

Grade 4 rash

Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)

Permanently discontinue treatment (see section 4.4)

Immune-related myocarditis

Grade 2 myocarditis

Withhold dose(s) until symptoms resolve and management with corticosteroids is completeb

Grade 3 or 4 myocarditis

Permanently discontinue treatment

Other immune-related adverse reactions

Grade 3 (first occurrence)

Withhold dose(s)

Grade 4 or recurrent Grade 3 ; persistent Grade 2 or 3 despite treatment modification ; inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day

Permanently discontinue treatment

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).

a Recommendation for the use of hormone replacement therapy is provided in section 4.4.

b The safety of re-initiating ipilimumab in combination with nivolumab therapy in patients previously experiencing immune-related myocarditis is not known.

YERVOY in combination with nivolumab should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;

• Persistent Grade 2 or 3 adverse reactions despite management.

When YERVOY is administered in combination with nivolumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or nivolumab monotherapy could be resumed based on the evaluation of the individual patient.

Special populations

Paediatric population

The safety and efficacy of YERVOY as monotherapy in children younger than 12 years of age have not been established. Very limited data are available. YERVOY should not be used in children younger than 12 years of age.

The safety and efficacy of YERVOY in combination with nivolumab in children younger than 18 years of age have not been established, except in adolescents 12 years of age and older with melanoma. Currently available data are described in sections 4.2, 4.8, 5.1 and 5.2.

Elderly

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from first-line RCC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). No specific dose adjustment is necessary in this population (see section 5.1).

Renal impairment

The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild to moderate renal dysfunction (see section 5.2).

Hepatic impairment

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Based on the population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patients with transaminase levels ≥ 5 x ULN or bilirubin levels > 3 x ULN at baseline (see section 5.1).

Method of administration

YERVOY is for intravenous use. The recommended infusion period is 30 minutes.

YERVOY can be used for intravenous administration without dilution or may be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection to concentrations between 1 and 4 mg/ml.

YERVOY must not be administered as an intravenous push or bolus injection.

When administered in combination with nivolumab or in combination with nivolumab and chemotherapy, nivolumab should be given first followed by YERVOY and then by chemotherapy (if applicable) on the same day. Use separate infusion bags and filters for each infusion.

For instructions on the preparation and handling of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Assessment of PD-L1 status

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is used.

Ipilimumab in combination with nivolumab

When ipilimumab is administered in combination, refer to the Summary of Product Characteristics of the other combination therapy components prior to initiation of treatment. For additional information on warnings and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2). Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

Cardiac and pulmonary adverse events including pulmonary embolism have also been reported with combination therapy. Patients should be monitored for cardiac and pulmonary adverse reactions continuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration prior to and periodically during treatment. Ipilimumab in combination with nivolumab should be discontinued for life-threatening or recurrent severe cardiac and pulmonary adverse reactions (see section 4.2).

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with ipilimumab in combination with nivolumab may occur at any time during or after discontinuation of therapy.

Immune-related reactions

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity (immune-related adverse reactions), likely to be related to its mechanism of action. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-related adverse reactions occurred during the induction period, onset months after the last dose of ipilimumab has also been reported. Unless an alternate etiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab-related. Early diagnosis and appropriate management are essential to minimise life-threatening complications.

Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for management of severe immune-related adverse reactions.

Ipilimumab specific management guidelines for immune-related adverse reactions are described below for use as monotherapy and in combination with nivolumab.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, ipilimumab, or ipilimumab in combination with nivolumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction that occurs as a consequence of combination therapy, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.

Ipilimumab in combination with nivolumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.

Ipilimumab in combination with nivolumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Immune-related gastrointestinal reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20, see section 5.1), the median time to onset of severe or fatal (Grade 3-5) immune-related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol-specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks).

Patients must be monitored for gastrointestinal signs and symptoms that may be indicative of immune-related colitis or gastrointestinal perforation. Clinical presentation may include diarrhoea, increased frequency of bowel movements, abdominal pain, or haematochezia, with or without fever. In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration. Post-marketing cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid-refractory immune-related colitis. Stool infections work-up should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate etiologies.

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI-CTCAE v4 severity grading classification). Patients with mild to moderate (Grade 1 or 2) diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominal pain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluid replacement) and close monitoring are advised. If mild to moderate symptoms recur or persist for 5-7 days, the scheduled dose of ipilimumab should be withheld and corticosteroid therapy (e.g. prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0-1 or return to baseline occurs, ipilimumab may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and systemic high-dose intravenous corticosteroid therapy should be initiated immediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation or peritonitis.

The experience from clinical trials on the management of corticosteroid-refractory diarrhoea or colitis is limited. Addition of an alternative immunosuppressive agent to the corticosteroid regimen should be considered in corticosteroid-refractory immune-related colitis if other causes are excluded (including Cytomegalovirus (CMV) infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial and parasitic etiology). In clinical trials, a single dose of infliximab 5 mg/kg was added unless contraindicated. Infliximab must not be used if gastrointestinal perforation or sepsis is suspected (see the Summary of Product Characteristics for infliximab).

Immune-related colitis

Ipilimumab in combination with nivolumab

Severe diarrhoea or colitis has been observed with ipilimumab in combination with nivolumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out.

For Grade 4 diarrhoea or colitis, ipilimumab in combination with nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Grade 3 diarrhoea or colitis observed with ipilimumab in combination with nivolumab requires permanent discontinuation of treatment and initiation of corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 diarrhoea or colitis, ipilimumab in combination with nivolumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related pneumonitis

Ipilimumab in combination with nivolumab

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with ipilimumab in combination with nivolumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, ipilimumab in combination with nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, ipilimumab in combination with nivolumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related hepatotoxicity

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to severe or fatal (Grade 2-5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol-specified management guidelines, time to resolution ranged from 0.7 to 2 weeks.

Hepatic transaminase and bilirubin must be evaluated before each dose of ipilimumab, as early laboratory changes may be indicative of emerging immune-related hepatitis (see section 4.2). Elevations in LFTs may develop in the absence of clinical symptoms. Increases in AST and ALT or total bilirubin should be evaluated to exclude other causes of hepatic injury, including infections, tumour progression, or concomitant medication and monitored until resolution. Liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

For patients with Grade 2 transaminase or total bilirubin elevation, the scheduled dose of ipilimumab should be withheld, and LFTs must be monitored until resolution. Upon improvement, ipilimumab may be resumed (see section 4.2).

For patients with Grade 3 or 4 transaminase or total bilirubin elevation, treatment must be permanently discontinued (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients, LFTs must be monitored until normalization. Once symptoms have resolved and LFTs show sustained improvement or return to baseline, the initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month. Elevations in LFTs during taper may be managed with an increase in the dose of corticosteroid and a slower taper.

For patients with significant LFT elevations that are refractory to corticosteroid therapy, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinical trials, mycophenolate mofetil was used in patients without response to corticosteroid therapy, or who had an LFT elevation during corticosteroid tapering that was not responsive to an increase in the dose of corticosteroids (see the Summary of Product Characteristics for mycophenolate mofetil).

Ipilimumab in combination with nivolumab

Severe hepatitis has been observed with ipilimumab in combination with nivolumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 transaminase or total bilirubin elevation, ipilimumab in combination with nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 transaminase or total bilirubin elevation, ipilimumab in combination with nivolumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related skin adverse reactions

Caution should be used when considering the use of ipilimumab or ipilimumab in combination with nivolumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune stimulatory therapy).

Ipilimumab as monotherapy

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Rare cases of toxic epidermal necrolysis (TEN) (including Steven Johnson Syndrome) have been observed, some with fatal outcome. Rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported in clinical trials and during post-marketing use (see section 4.8).

DRESS presents as a rash with eosinophilia associated with one or more of the following features: fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary). DRESS may be characterized by a long latency (two to eight weeks) between medicinal product exposure and disease onset.

Ipilimumab-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, the median time to onset of moderate to severe or fatal (Grade 2-5) skin adverse reactions was 3 weeks (range 0.9-16 weeks) from start of treatment. With protocol-specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

Ipilimumab-induced rash and pruritus should be managed based on severity. Patients with a mild to moderate (Grade 1 or 2) rash may remain on ipilimumab therapy with symptomatic treatment (e.g. antihistamines). For mild to moderate rash or mild pruritus that persists for 1 to 2 weeks and does not improve with topical corticosteroids, oral corticosteroid therapy should be initiated (e.g. prednisone 1 mg/kg once daily or equivalent).

For patients with a severe (Grade 3) rash, the scheduled dose of ipilimumab should be withheld. If initial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with a very severe (Grade 4) rash or severe (Grade 3) pruritus (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled, initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe rash has been observed with ipilimumab in combination with nivolumab (see section 4.8). Ipilimumab in combination with nivolumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed. If symptoms or signs of SJS or TEN appear, treatment with ipilimumab in combination with nivolumab should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of ipilimumab in combination with nivolumab, permanent discontinuation of treatment is recommended (see section 4.2).

Immune-related neurological reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related neurological adverse reactions. Fatal Guillain-Barré syndrome has been reported in clinical trials. Myasthenia gravis-like symptoms have also been reported (see section 4.8). Patients may present with muscle weakness. Sensory neuropathy may also occur.

Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting > 4 days must be evaluated, and non-inflammatory causes such as disease progression, infections, metabolic syndromes and concomitant medication should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheld. If neurologic symptoms resolve to baseline, the patient may resume ipilimumab (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to ipilimumab (see section 4.2). Patients must be treated according to institutional guidelines for management of sensory neuropathy, and intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately.

Progressive signs of motor neuropathy must be considered immune-related and managed accordingly. Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see section 4.2).

Immune-related nephritis and renal dysfunction

Ipilimumab in combination with nivolumab

Severe nephritis and renal dysfunction have been observed with ipilimumab in combination with nivolumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, ipilimumab in combination with nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, ipilimumab in combination with nivolumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related endocrinopathy

Ipilimumab as monotherapy

Ipilimumab can cause inflammation of the endocrine system organs, manifesting as hypophysitis, hypopituitarism, adrenal insufficiency, hypothyroidism, Type 1 diabetes mellitus and diabetic ketoacidosis (see sections 4.2 and 4.8), and patients may present with nonspecific symptoms, which may resemble other causes such as brain metastasis or underlying disease. The most common clinical presentation includes headache and fatigue. Symptoms may also include visual field defects, behavioural changes, electrolyte disturbances, and hypotension. Adrenal crisis as a cause of the patient's symptoms must be excluded. Clinical experience with ipilimumab associated endocrinopathy is limited.

For patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to very severe (Grade 2-4) immune-related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrinopathy observed in clinical trials was generally controlled with immunosuppressive therapy and hormone replacement therapy.

If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, and the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in adrenal crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy (e.g. dexamethasone 4 mg every 6 hrs or equivalent) is recommended to treat the inflammation of the affected gland, and the scheduled dose of ipilimumab should be withheld (see section 4.2). It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long-term hormone replacement therapy may be necessary.

For symptomatic diabetes, ipilimumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Ipilimumab must be permanently discontinued for life-threatening diabetes.

Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with ipilimumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with ipilimumab in combination with nivolumab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.

For symptomatic hypothyroidism, ipilimumab in combination with nivolumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, ipilimumab in combination with nivolumab should be withheld and antithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

For symptomatic Grade 2 adrenal insufficiency, ipilimumab in combination with nivolumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. ipilimumab in combination with nivolumab must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.

For symptomatic Grade 2 or 3 hypophysitis, ipilimumab in combination with nivolumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

For symptomatic diabetes, ipilimumab in combination with nivolumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening diabetes.

Infusion reaction

Ipilimumab as monotherapy or in combination with nivolumab

Severe infusion reactions have been reported in clinical trials of ipilimumab or ipilimumab in combination with nivolumab (see section 4.8). In case of a severe or life-threatening infusion reaction, the ipilimumab or ipilimumab in combination with nivolumab infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive ipilimumab or ipilimumab in combination with nivolumab with close monitoring and use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.

Other immune-related adverse reactions

Ipilimumab as monotherapy

The following adverse reactions suspected to be immune-related have been reported in patients treated with ipilimumab 3 mg/kg monotherapy in MDX010-20: uveitis, eosinophilia, lipase elevation, and glomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi-organ failure, and pneumonitis have been reported in patients treated with ipilimumab 3 mg/kg + gp100 peptide vaccine in MDX010-20. Cases of Vogt-Koyanagi-Harada syndrome, serous retinal detachment, and cystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8).

If severe (Grade 3 or 4), these reactions may require immediate systemic high-dose corticosteroid therapy and discontinuation of ipilimumab (see section 4.2). For ipilimumab-related uveitis, iritis, serous retinal detachment or episcleritis, topical corticosteroid eye drops should be considered as medically indicated. Transient vision loss has been reported in patients with ipilimumab-related ocular inflammations.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with ipilimumab. Treatment with ipilimumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with ipilimumab versus the risk of possible organ rejection should be considered in these patients.

Ipilimumab as monotherapy or in combination with a PD-1 or PD-L1 inhibitor

Haemophagocytic lymphohistiocytosis (HLH) has been observed with ipilimumab as monotherapy and ipilimumab in combination with a PD-1 or PD-L1 inhibitor (including with nivolumab). Caution should be taken when ipilimumab is administered as monotherapy or in combination with a PD-1 or PD-L1 inhibitor. If HLH is confirmed, administration of ipilimumab or ipilimumab in combination with a PD-1 or PD-L1 inhibitor should be discontinued and treatment for HLH initiated.

Ipilimumab in combination with nivolumab

The following immune-related adverse reactions were reported in less than 1% of patients treated with ipilimumab in combination with nivolumab in clinical trials across doses and tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, aseptic meningitis, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, and rhabdomyolysis. Cases of Vogt-Koyanagi-Harada syndrome, serous retinal detachment, and cystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8). Transient vision loss has been reported in patients with ipilimumab-related ocular inflammations.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, ipilimumab in combination with nivolumab should be withheld and corticosteroids administered. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. Ipilimumab in combination with nivolumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have been reported with ipilimumab in combination with nivolumab. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, ipilimumab in combination with nivolumab should be withheld or discontinued (see section 4.2), and appropriate treatment instituted.

The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, ipilimumab in combination with nivolumab should be withheld or permanently discontinued (see section 4.2).

Disease specific precautions

Melanoma

Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not included in the MDX010-20 trial (see section 5.1).

Patients with ocular melanoma were not included in the CA184-169 clinical trial. However, patients with brain metastases were included in this study, if they were free of neurologic symptoms related to metastatic brain lesions and if they did not require or receive systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with ipilimumab were not included in the paediatric trial CA184070 (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with CTLA-4, PD-1, PD-L1, or CD137 targeted agents were not included in the paediatric trial CA184178 (see section 5.1).

Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the clinical trials of ipilimumab in combination with nivolumab. Patients with ocular/uveal melanoma were excluded from clinical trials of melanoma. In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Relative to nivolumab monotherapy, an increase in PFS for the combination of ipilimumab with nivolumab is established only in patients with low tumour PD-L1 expression. The improvement in OS was similar between ipilimumab with nivolumab and nivolumab monotherapy in patients with high tumour PD-L1 expression (PD-L1 ≥ 1%). Before initiating treatment with the combination, physicians are advised to carefully evaluate the individual patient and tumour characteristics, taking into consideration the observed benefits and the toxicity of the combination relative to nivolumab monotherapy (see sections 4.8 and 5.1).

Use of ipilimumab in combination with nivolumab in melanoma patients with rapidly progressing disease.

Physicians should consider the delayed onset of ipilimumab in combination with nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1).

Renal cell carcinoma

Patients with any history of concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of ipilimumab in combination with nivolumab (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Non-small cell lung cancer

Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, active (untreated) brain metastasis, who received prior systemic treatment for advanced disease, or who had sensitising EGFR mutations or ALK translocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5 and 5.1). Limited data are available in elderly patients (≥ 75 years) (see section 5.1). In these patients, ipilimumab in combination with nivolumab and chemotherapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.

Malignant pleural mesothelioma

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, and brain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolution within 3 months prior to inclusion in the study) were excluded from the pivotal trial in first-line treatment of MPM (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

dMMR or MSI-H colorectal cancer

Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trial in dMMR or MSI-H metastatic CRC (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Oesophageal squamous cell carcinoma

Patients with a baseline performance score ≥ 2, any history of concurrent brain metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, or at high risk of bleeding or fistula due to apparent invasion of tumour to organs adjacent to the oesophageal tumour were excluded from the clinical trial in OSCC (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with ipilimumab in combination with nivolumab compared to chemotherapy. Physicians should consider the delayed onset of effect of ipilimumab in combination with nivolumab before initiating treatment in patients with poorer prognostic features and/or aggressive disease (see section 5.1).

Patients with autoimmune disease

Patients with a history of autoimmune disease (other than vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism), including those who require systemic immunosuppressive therapy for pre-existing active autoimmune disease or for organ transplantation graft maintenance, were not evaluated in clinical trials. Ipilimumab is a T-cell potentiator that enables the immune response (see section 5.1) and may interfere with immunosuppressive therapy, resulting in an exacerbation of the underlying disease or increased risk of graft rejection. Ipilimumab should be avoided in patients with severe active autoimmune disease where further immune activation is potentially imminently life threatening. In other patients with a history of autoimmune disease, ipilimumab should be used with caution after careful consideration of the potential risk-benefit on an individual basis.

Patients on controlled sodium diet

This medicinal product contains 23 mg sodium per 10 ml vial and 92 mg sodium per 40 ml vial, respectively equivalent to 1.15% and 4.60% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration when treating patients on a controlled sodium diet.

Concurrent administration with vemurafenib

In a Phase 1 trial, asymptomatic grade 3 increases in transaminases (ALT/AST > 5 × ULN) and bilirubin (total bilirubin > 3 × ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended.

Sequential administration with vemurafenib

In a Phase 2 trial, the sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab in patients with BRAF-mutated metastatic melanoma showed a higher incidence of Grade 3+ skin adverse reactions than with ipilimumab alone. Caution should be used when ipilimumab is administered following prior vemurafenib.

Paediatric population

Limited, but no long-term, safety data is available on the use of ipilimumab in adolescents 12 years of age and older.

Only very limited data are available in children younger than 12 years of age. Therefore, ipilimumab should not be used in children younger than 12 years of age.

Before initiating treatment with ipilimumab monotherapy in adolescents of 12 years and older, physicians are advised to carefully evaluate the individual patient, taking into consideration the limited available data, the observed benefits and the toxicity of ipilimumab monotherapy in the paediatric population (see sections 4.8 and 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

Ipilimumab is a human monoclonal antibody that is not metabolized by cytochrome P450 enzymes (CYPs) or other drug metabolizing enzymes.

A drug-interaction study in adults of ipilimumab administered alone and in combination with chemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with CYP isozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with treatment-naive advanced melanoma. No clinically relevant pharmacokinetic drug-drug interaction was observed between ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite, 5-aminoimidazole-4-carboxamide (AIC).

Other forms of interaction

Corticosteroids

The use of systemic corticosteroids at baseline, before starting ipilimumab, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of ipilimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting ipilimumab to treat immune-related adverse reactions. The use of systemic corticosteroids after starting ipilimumab treatment does not appear to impair the efficacy of ipilimumab.

Anticoagulants

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with ipilimumab (see section 4.8), patients who require concomitant anticoagulant therapy should be monitored closely.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity (see section 5.3). Human IgG1 crosses the placental barrier. The potential risk of treatment to the developing foetus is unknown. YERVOY is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.

Breast-feeding

Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. It is unknown whether ipilimumab is secreted in human milk. Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Significant systemic exposure of the infant is not expected and no effects on the breast-fed newborn/infant are anticipated. However, because of the potential for adverse reactions in nursing infants, a decision must be made whether to discontinue breast-feeding or to discontinue from YERVOY therapy taking into account the benefit of breast-feeding for the child and the benefit of YERVOY therapy for the woman.

Fertility

Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect of ipilimumab on male and female fertility is unknown.

4.7 Effects on ability to drive and use machines

YERVOY has minor influence on the ability to drive and use machines.

Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that ipilimumab does not adversely affect them.

4.8 Undesirable effects

Ipilimumab as monotherapy (see section 4.2)

a. Summary of safety profile

Ipilimumab has been administered to approximately 10,000 patients in a clinical program evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study MDX010-20, (see section 5.1), patients received a median of 4 doses (range 1-4).

Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab (see section 4.4 for management of immune-related adverse reactions).

In patients who received 3 mg/kg ipilimumab monotherapy in MDX010-20, the most frequently reported adverse reactions (≥ 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate (Grade 1 or 2). Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.

b. Tabulated list of adverse reactions

Adverse reactions reported in patients with advanced melanoma who were treated with ipilimumab 3 mg/kg in clinical trials (n= 767) and from post-marketing surveillance are presented in Table 4.

These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Rates of immune-related adverse reactions in HLA-A2*0201 positive patients who received ipilimumab in MDX010-20 were similar to those observed in the overall clinical program.

The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 75; treated), in treatment-naive patients in two retrospective observational studies (N= 273 and N= 157), and in CA184-169 (N= 362) was similar to that in previously-treated advanced melanoma.

The safety data for patients with unresectable or metastatic melanoma, treated with ipilimumab (3 mg/kg, with a minimum of 3 year follow-up) and enrolled in multi-national, prospective, observational study CA184143 (N= 1151) were similar to what has been reported in ipilimumab clinical trials for advanced melanoma.

Table 4: Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kga

Infections and infestations

Common

sepsisb, urinary tract infection, respiratory tract infection

Uncommon

septic shockb, pneumonia

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

tumour pain

Uncommon

paraneoplastic syndrome

Blood and lymphatic system disorders

Common

anaemia, lymphopenia, thrombocytopenia, neutropenia

Uncommon

haemolytic anaemiab, eosinophilia

Not known

haemophagocytic lymphohistiocytosise

Immune system disorders

Uncommon

hypersensitivity

Very rare

anaphylactic reaction

Not known

solid organ transplant rejectione

Endocrine disorders

Common

hypopituitarism (including hypophysitis)c, hypothyroidismc

Uncommon

adrenal insufficiencyc, secondary adrenocortical insufficiencyd, hyperthyroidismc, hypogonadism

Rare

autoimmune thyroiditisd, thyroiditisd

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration, hypokalemia, weight decreased, hyponatremia

Uncommon

alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad

Rare

type 1 diabetes mellitus (including diabetic ketoacidosis)h

Psychiatric disorders

Common

confusional state, depression

Uncommon

mental status changes, decreased libido

Nervous system disorders

Common

peripheral sensory neuropathy, dizziness, headache, lethargy, cranial neuropathy, brain oedema, peripheral neuropathy

Uncommon

Guillain-Barré syndromeb,c, meningitis (aseptic), autoimmune central neuropathy (encephalitis)d, syncope, ataxia, tremor, myoclonus, dysarthria

Rare

myasthenia gravisd

Not known

myelitis

Eye disorders

Common

blurred vision, eye pain

Uncommon

uveitisc, vitreous haemorrhage, iritisc, eye oedemad, blepharitisd, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Rare

Vogt-Koyanagi-Harada syndromee, serous retinal detachment

Cardiac disorders

Common

arrhythmia, atrial fibrillation

Vascular disorders

Common

hypotension, flushing, hot flush

Uncommon

vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Rare

temporal arteritisd

Respiratory, thoracic and mediastinal disorders

Common

dyspnea, cough, allergic rhinitis

Uncommon

respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis

Gastrointestinal disorders

Very common

diarrhoeac, vomiting, nausea, constipation, abdominal pain

Common

gastrointestinal haemorrhage, colitisb,c, gastroesophageal reflux disease, mucosal inflammationd, gastroenteritis, stomatitis

Uncommon

gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd, proctitisd

Hepatobiliary disorders

Common

abnormal hepatic function

Uncommon

hepatic failureb,c, hepatitis, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, eczemad, alopecia, night sweats, dry skin

Uncommon

toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation, hair colour changesd

Rare

erythema multiformed, psoriasisd, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)d

Not known

pemphigoid

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal painf

Common

arthralgia, myalgia, muscle spasms, arthritis

Uncommon

polymyalgia rheumatica, myositisd, muscular weaknessd

Rare

polymyositisd

Renal and urinary disorders

Common

renal failureb

Uncommon

glomerulonephritisc, autoimmune nephritisd, renal tubular acidosis, haematuriad, cystitis noninfectiveg, proteinuriad

Reproductive system and breast disorders

Uncommon

amenorrhea

General disorders and administration site conditions

Very common

fatigue, injection site reaction, pyrexia, oedema, pain

Common

chills, asthenia, influenza-like illnessd

Uncommon

multi-organ failureb,c, systemic inflammatory response syndromed, infusion related reaction

Investigations

Common

increased alanine aminotransferasec, increased aspartate aminotransferasec, increased blood alkaline phosphatased, increased blood bilirubin, increased lipasec

Uncommon

increased gamma-glutamyltransferased, increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased blood amylasec, positive antinuclear antibodyd, decreased blood testosterone

Rare

decreased blood thyroid stimulating hormoned, decreased thyroxined, abnormal blood prolactind

Adverse reaction frequencies presented in Table 4 may not be fully attributable to ipilimumab, but may contain contributions from the underlying disease.

a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.

b Including fatal outcome.

c Additional information about these potentially inflammatory adverse reactions is provided in “ Description of selected adverse reactions” and section 4.4. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010-20.

d Data outside the 9 completed clinical trials in melanoma were included in frequency determinations.

e Post-marketing event (also see section 4.4).

f Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.

g Reported in clinical studies and in the post-marketing setting.

h Type 1 diabetes mellitus that may be associated with diabetic ketoacidosis

Additional adverse reactions not listed in Table 4 have been reported in patients who received other doses (either < or > 3 mg/kg) of ipilimumab in clinical trials of melanoma. These additional reactions occurred at a frequency of < 1% unless otherwise noted: meningism, myocarditis, pericardial effusion, cardiomyopathy, autoimmune hepatitis, erythema nodosum, autoimmune pancreatitis, hyperpituitarism, hypoparathyroidism, infectious peritonitis, episcleritis, scleritis, Raynaud's phenomenon, palmar-plantar erythrodysaesthesia syndrome, cytokine release syndrome, sarcoidosis, decreased blood gonadotrophin, leukopenia, polycythaemia, lymphocytosis, ocular myositis, and neurosensory hypoacusis.

The overall safety profile of ipilimumab 3 mg/kg in clinical trial CA184-169 (N=362) was consistent with that established for ipilimumb in patients treated for advanced melanoma.

Ipilimumab in combination with nivolumab (with or without chemotherapy) (see section 4.2)

a. Summary of the safety profile

When ipilimumab is administered in combination, refer to the SmPC for the other therapeutic agent(s) prior to initiation of treatment. For additional information on the safety profile of the other therapeutic agets used in combination with ipilimumab, please refer to the respective SmPC.

In the pooled dataset of ipilimumab administered in combination with nivolumab (with or without chemotherapy) across tumour types (n = 2094) with minimum follow-up ranging from 6 to 47 months, the most frequent adverse reactions (≥ 10%) were fatigue (50%), rash (38%), diarrhoea (37%), nausea (31%), pruritus (29%), musculoskeletal pain (28%), pyrexia (25%), cough (24%), decreased appetite (23%), vomiting (20%), dyspnoea (19%), constipation (19%), arthralgia (19%), abdominal pain (18%), hypothyroidism (16%), headache (16%), upper respiratory tract infection (15%), oedema (13%) and dizziness (11%). The incidence of Grade 3-5 adverse reactions was 67% for nivolumab in combination with ipilimumab (with or without chemotherapy), with 0.7% fatal adverse reactions attributed to study drug. Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%), pruritus (40%), pyrexia (36%), and headache (26%) were reported at an incidence rate ≥ 10% higher than the rates reported in the pooled dataset of ipilimumab in combination with nivolumab (with or without chemotherapy) incidence rate. Among patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg and chemotherapy, anaemia (32%) and neutropenia (15%) were reported at an incidence rate ≥ 10% higher than the rates reported in the pooled dataset of ipilimumab in combination with nivolumab (with or without chemotherapy) incidence rate.

b. Tabulated summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy) (n=2094) and from post-marketing are presented in Table 5. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 5: Adverse reactions with ipilimumab in combination with other therapeutic agents

Combination with nivolumab (with or without chemotherapy)

Infections and infestations

Very common

upper respiratory tract infection

Common

pneumonia, bronchitis, conjunctivitis

Rare

aseptic meningitis

Blood and lymphatic system disorders

Very common

anaemiab,i, thrombocytopaeniab, leucopoeniab, lymphopaeniab, neutropaeniab

Common

eosinophilia

Uncommon

febrile neutropaenia

Not known

haemophagocytic lymphohistiocytosis

Immune system disorders

Common

infusion-related reaction (including cytokine release syndrome), hypersensitivity

Rare

sarcoidosis

Not known

solid organ transplant rejectionf

Endocrine disorders

Very common

hypothyroidism

Common

hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetes mellitus

Uncommon

diabetic ketoacidosis

Rare

hypoparathyroidism

Metabolism and nutrition disorders

Very common

decreased appetite, hyperglycaemiab, hypoglycaemiab

Common

dehydration, hypoalbuminaemia, hypophosphataemia, weight decreased

Uncommon

metabolic acidosis

Not known

tumour lysis syndromeg

Nervous system disorders

Very common

headache, dizziness

Common

peripheral neuropathy

Uncommon

polyneuropathy, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis, myasthenia gravis

Rare

Guillain-Barré syndrome, neuritis, myelitis

Eye disorders

Common

blurred vision, dry eye

Uncommon

uveitis, episcleritis

Rare

Vogt-Koyanagi-Harada syndrome, serous retinal detachment

Cardiac disorders

Common

tachycardia, atrial fibrillation

Uncommon

myocarditisa, arrhythmia (including ventricular arrhythmia)a, bradycardia

Not known

pericardial disordersh

Vascular disorders

Common

hypertension

Respiratory, thoracic and mediastinal disorders

Very common

cough, dyspnoea

Common

pneumonitisa, pulmonary embolisma, pleural effusion

Gastrointestinal disorders

Very common

diarrhoea, vomiting, nausea, abdominal pain, constipation

Common

colitisa, pancreatitis, stomatitis, gastritis, dry mouth

Uncommon

duodenitis

Rare

intestinal perforationa

Hepatobiliary disorders

Common

hepatitis

Skin and subcutaneous tissue disorders

Very common

rashc, pruritus

Common

alopecia, vitiligo, urticaria, dry skin, erythema

Uncommon

Stevens-Johnson syndrome, erythema multiforme, psoriasis

Rare

toxic epidermal necrolysisa,d, lichen sclerosus, other lichen disorders

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal paine, arthralgia

Common

muscle spasms, muscular weakness, arthritis

Uncommon

polymyalgia rheumatica, myopathy, myositis (including polymyositis)a

Rare

spondyloarthropathy, Sjogren's syndrome, rhabdomyolysisa

Renal and urinary disorders

Common

renal failure (including acute kidney injury)a

Uncommon

tubulointerstitial nephritis, nephritis

Rare

cystitis noninfective

General disorders and administration site conditions

Very common

fatigue, pyrexia, oedema (including peripheral oedema)

Common

chest pain, pain, chills

Investigations

Very common

increased alkaline phosphataseb, increased ASTb, increased ALTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hyponatraemiab, hyperkalaemiab, hypokalaemiab, hypercalcaemiab, hypocalcaemiab

Common

hypernatraemiab, hypermagnesaemiab, increased thyroid stimulating hormone, increased gamma-glutamyltransferase

Adverse reaction frequencies presented in Table 5 may not be fully attributable to ipilimumab alone or in combination with other therapeutic agents, but may contain contributions from the underlying disease or from medicinal product used in combination.

a Fatal cases have been reported in completed or ongoing clinical studies

b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “ Description of selected adverse reactions; laboratory abnormalities” below.

c Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, nodular rash, and pemphigoid.

d Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.

e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.

f Post-marketing event (also see section 4.4).

g Reported in clinical studies and in the post-marketing setting.

h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler's syndrome.

i Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia, and red blood cell count decreased.

Description of selected adverse reactions

Except where noted, data relating to ipilimumab monotherapy are based on patients who received either ipilimumab 3 mg/kg monotherapy (n= 131) or ipilimumab 3 mg/kg in combination with gp100 (n= 380) in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20, see section 5.1).

Ipilimumab in combination is associated with immune-related adverse reactions. With appropriate medical therapy, immune-related adverse reactions resolved in most cases. Permanent discontinuation of treatment generally was required in a greater proportion of patients receiving ipilimumab in combination with nivolumab than in those receiving nivolumab monotherapy. Table 6 presents the percentage of patients with immune-related adverse reactions who were permanently discontinued from treatment. Additionally, for patients who experienced an event, Table 6 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents). The management guidelines for these adverse reactions are described in section 4.4.

Table 6: Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids

Ipilimumab in combination with nivolumab (with or without chemotherapy) %

Immune-related adverse reaction leading to permanent discontinuation

Pneumonitis

2.5

Colitis

6

Hepatitis

5

Nephritis and renal dysfunction

1.2

Endocrinopathies

2.0

Skin

1.0

Hypersensitivity/Infusion reaction

0.3

Immune-related adverse reaction requiring high-dose corticosteroidsa,b

Pneumonitis

59

Colitis

32

Hepatitis

37

Nephritis and renal dysfunction

27

Endocrinopathies

20

Skin

8

Hypersensitivity/Infusion reaction

16

a at least 40 mg daily prednisone equivalents

b frequency is based on the number of patients who experienced the immune-related adverse reaction

Immune-related gastrointestinal reactions

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in < 1% of patients who received ipilimumab 3 mg/kg in combination with gp100.

In the ipilimumab 3 mg/kg monotherapy group, diarrhoea and colitis of any severity were reported in 27% and 8%, respectively. The frequency of severe (Grade 3 or 4) diarrhoea and severe (Grade 3 or 4) colitis was 5% each. The median time to onset of severe or fatal (Grade 3 to 5) immune-related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol-specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks). In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration.

Immune-related colitis

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of diarrhoea or colitis was 27.7% (580/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 8.8% (184/2094), 6.8% (142/2094), and 0.1% (3/2094), of patients, respectively. One patient (< 0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0-48.9). Resolution occurred in 577 patients (90.8%) with a median time to resolution of 2.7 weeks (range: 0.1-159.4+). Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, the incidence of diarrhoea or colitis was 46.7%, including Grade 2 (13.6%), Grade 3 (15.8%), and Grade 4 (0.4%).

Immune-related pneumonitis

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of pneumonitis including interstitial lung disease, was 6.9% (145/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 3.5% (73/2094), 1.1% (24/2094), and 0.4% (8/2094) of patients, respectively. Four patients (0.2%) had a fatal outcome. Median time to onset was 2.7 months (range: 0.1-56.8). Resolution occurred in 119 patients (82.1%) with a median time to resolution of 6.1 weeks (range: 0.3-149.3+).

Immune-related hepatotoxicity

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in < 1% of patients who received ipilimumab 3 mg/kg monotherapy.

Increases in AST and ALT of any severity were reported in 1% and 2% of patients, respectively. There were no reports of severe (Grade 3 or 4) AST or ALT elevation. Time to onset of moderate to severe or fatal (Grade 2 to 5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol-specified management guidelines, time to resolution ranged from 0.7 to 2 weeks. In clinical trials, liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

In patients receiving ipilimumab at a higher than recommended dose in combination with dacarbazine, immune-related hepatotoxicity occurred more frequently than in patients receiving ipilimumab 3 mg/kg monotherapy.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of liver function test abnormalities was 19.2% (402/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 4.2% (88/2094), 7.8% (163/2094), and 1.2% (25/2094) of patients, respectively. Median time to onset was 1.9 months (range: 0.0-36.6). Resolution occurred in 351 patients (87.8%) with a median time to resolution of 5.3 weeks (range: 0.1-175.9+). Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, the incidence of liver function test abnormalities was 30.1%, including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4 (1.8%).

Immune-related skin adverse reactions

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Fatal toxic epidermal necrolysis (including SJS) has been reported in < 1% of patients who received ipilimumab in combination with gp100 (see section 5.1). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been rarely reported with Ipilimumab in clinical studies and during post-marketing use. Incidental cases of pemphigoid have been reported during post-marketing use.

In the ipilimumab 3 mg/kg monotherapy group, rash and pruritus of any severity were each reported in 26% of patients. Ipilimumab-induced rash and pruritus were predominantly mild (Grade 1) or moderate (Grade 2) and responsive to symptomatic therapy. The median time to onset of moderate to severe or fatal (Grade 2 to 5) skin adverse reactions was 3 weeks from start of treatment (range 0.9 to 16 weeks). With protocol-specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of rash was 46.2% (968/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 14.1% (296/2094), 4.6% (97/2094), and < 0.1% (2/2094) of patients, respectively. Median time to onset was 0.7 months (range: 0.0-33.8). Resolution occurred in 671 patients (69.6%) with a median time to resolution of 11.1 weeks (range: 0.1-268.7+). Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, the incidence of rash was 65.2%, including Grade 2 (20.3%) and Grade 3 (7.8%).

Immune-related neurological reactions

Ipilimumab is associated with serious immune-related neurological reactions. Fatal Guillain-Barré syndrome has been reported in < 1% of patients who received ipilimumab 3 mg/kg in combination with gp100. Myasthenia gravis-like symptoms have also been reported in < 1% of patients who received higher doses of ipilimumab in clinical trials.

Immune-related nephritis and renal dysfunction

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of nephritis or renal dysfunction was 6.1% (128/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 2.3% (49/2094), 1.0% (20/2094), and 0.5% (10/2094) of patients, respectively. Two patients (< 0.1%) had a fatal outcome. Median time to onset was 2.5 months (range: 0.0-34.8). Resolution occurred in 97 patients (75.8%) with a median time to resolution of 6.3 weeks (range: 0.1-172.1+).

Immune-related endocrinopathy

In the ipilimumab 3 mg/kg monotherapy group, hypopituitarism of any severity was reported in 4% of patients. Adrenal insufficiency, hyperthyroidism, and hypothyroidism of any severity were each reported in 2% of patients. The frequency of severe (Grade 3 or 4) hypopituitarism was reported in 3% of patients. Time to onset of moderate to very severe (Grade 2 to 4) immune-related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrinopathy observed in clinical trials was generally controlled with hormone replacement therapy.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of thyroid disorders was 22.9% (479/2094). Grade 2 and Grade 3 thyroid disorders were reported in 12.5% (261/2094) and 1.0% (21/2094) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 2.0% (42/2094) and 1.6% (33/2094) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.8% (16/2094) and 0.5% (11/2094) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.3% (49/2094), 1.5% (32/2094) and 0.2% (4/2094) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes mellitus occurred in 0.1% (1/2094), 0.2% (4/2094), < 0.1% (1/2094), and 0.1 (3/2094) of patients, respectively and Grade 4 diabetic ketoacidosis was reported in < 0.1% (2/2094) of patients. Median time to onset of these endocrinopathies was 2.1 months (range: 0.0-28.1). Resolution occurred in 201 patients (40.7%). Time to resolution ranged from 0.3 to 257.1+ weeks.

Infusion reactions

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the incidence of hypersensitivity/infusion reactions was 4.9% (103/2094). Grade 1, Grade 2, Grade 3, and Grade 4 cases were reported in 2.1% (44/2094), 2.5% (53/2094), 0.2% (5/2094), and < 0.1% (1/2094) of patients, respectively. Among patients with MPM treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

Immunogenicity

Less than 2% of patients with advanced melanoma who received ipilimumab in Phase 2 and 3 clinical trials developed antibodies against ipilimumab. None had any infusion-related or peri-infusional hypersensitivity or anaphylactic reactions. Neutralising antibodies against ipilimumab were not detected. Overall, no apparent association was observed between antibody development and adverse reactions.

Of the patients who were treated with ipilimumab in combination with nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 13.7%. Neutralising antibodies against ipilimumab ranged from 0 to 0.4%. Of the patients who were treated with ipilimumab in combination with nivolumab and chemotherapy and evaluable for the presence of anti-ipilimumab antibodies or neutralising antibodies against ipilimumab, the incidence of anti-ipilimumab antibodies was 7.5% and neutralising antibodies against ipilimumab was 1.6%. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 24.9% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks, and 33.8% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy. The incidence of neutralising antibodies against nivolumab was 0.8% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 1.5% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy.

When administered in combination with nivolumab, the CL of ipilimumab was unchanged in the presence of anti-ipilimumab antibodies and there was no evidence of altered toxicity profile.

Laboratory abnormalities

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy), the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.9% for anaemia, 1.5% for thrombocytopaenia, 2.3% for leucopoenia, 7.3% for lymphopaenia, 3.4% for neutropaenia, 2.9% for increased alkaline phosphatase, 7.3% for increased AST, 8.4% for increased ALT, 1.2% for increased total bilirubin, 1.6% for increased creatinine, 5.8% for hyperglycaemia, 8.4% for increased amylase, 16.7% for increased lipase, 0.8% for hypocalcaemia, 0.2% for hypernatraemia, 1.0% for hypercalcaemia, 1.9% for hyperkalaemia, 0.5% for hypermagnesaemia, 3.4% for hypokalaemia, and 9.8% for hyponatraemia. Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, a higher proportion of patients experienced a worsening from baseline to a Grade 3 or 4 increased ALT (15.3%).

Paediatric population

Ipilimumab as monotherapy

No new adverse drug reactions were reported in adolescents 12 years of age and older.

In study CA184070, no immune-related adverse reactions (irAR) ≥ Grade 3 were reported for the single patient 12 years of age and older who was treated with ipilimumab 3 mg/kg. Two (25.0%) of 8 patients treated with 5 mg/kg and 1 (11.1%) of 9 patients treated with 10 mg/kg reported Grade 3– 4 events. None of the events were fatal. The types of irARs were consistent with the adult experience, with the most commonly reported irARs across all groups in the categories of gastrointestinal (0 [3 mg/kg], 62.5% [5 mg/kg], and 44.4% [10 mg/kg]), hepatic function (0 [3 mg/kg], 75.0% [5 mg/kg], 33.3% [10 mg/kg]), and skin (0 [3 mg/kg], 25.0% [5 mg/kg], 33.3% [10 mg/kg]) events. No new or unexpected irARs were observed in this study. No differences in the spectrum of irARs reported in adults and the paediatric population were evident.

In study CA184178, no new or unexpected irARs were observed, and the observed irARs were similar in frequency, intensity and organ site to what has been reported in adult studies. Two patients in the 10 mg/kg group experienced a Grade 1 and Grade 3 on-study endocrine irAR of hyperglycemia. No other endocrine abnormalities were reported.

A summary of adverse events in adolescents 12 years of age and older, as well as adults, is presented in Table 7.

Table 7: Summary of adverse events after up to four doses of 3, 5 and 10 mg/kg, all treated patients

Number of patients (%)

Age 12 to 21 years

Age 12 to < 18 years

Adults

Advanced melanoma and non-melanoma solid tumours

Advanced melanoma

Advanced melanoma

CA184070

CA184178

CA184004/022 pooled

CA184004/007 /008/022 pooled

3 mg/kg

n = 1

5 mg/kg

n = 8

10 mg/kg

n = 9

3 mg/kg

n = 4

10 mg/kg

n = 8

3 mg/kg

n = 111

10 mg/kg

n = 325

All deaths, n (%)

1 (100.0)

4 (50.0)

2 (22.2)

2 (50.0)

3 (37.5)

26 (23.4)

71 (21.8)

Treatment-related deaths, n (%)

0

0

0

0

0

2 (1.8)

6 (1.8)

SAEs, n (%)

1 (100.0)

7 ( 87.5)

4 ( 44.4)

1 (25.0)

6 (75.0)

50 (45.0)

168 (51.7)

SAEs, drug-related, n (%)

1 (100.0)

5 ( 62.5)

4 ( 44.4)

1 (25.0)

5 (62.5)

19 (17.1)

95 (29.2)

AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

12 (10.8)

88 (27.1)

Drug-related AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

9 (8.1)

61 (18.8)

irAEs, n (%)

1 (100.0)

7 ( 87.5)

7 ( 77.8)

2 (50.0)

4 (50.0)

68 (61.3)

234 (72.0)

AE, n (%)

1 (100.0)

8 (100.0)

9 (100.0)

4 (100.0)

8 (100.0)

108 (97.3)

315 (96.9)

Drug-related AEs, n (%)

1 (100.0)

7 ( 87.5)

9 (100.0)

2 (50.0)

7 (87.5)

88 (79.3)

274 (84.3)

MedDRA v.17.0 for CA184070, v.19.0 for CA184178, and V.12.1 for adult safety pool. NA = not assessed

For adults, deaths reported in this table are within 70 days of the last dose, regardless of relationship. Deaths for paediatric patients are those with on-study events within 30 days of the last dose, except for “ all deaths,” which were >30 days after the last dose. In CA184178, deaths were reported at least 90 days of the last dose.

Attribution to ipilimumab reported as possible, probable, definite, or missing for CA184178 and adult safety pool, and related or missing for CA184070.

Abbreviations: SAEs = serious adverse events; AEs = adverse events; irAEs = immune-related adverse events

Ipilimumab in combination with nivolumab

The safety of ipilimumab (1 mg/kg every 3 weeks) in combination with nivolumab (1 mg/kg or 3 mg/kg for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks) was evaluated in 33 paediatric patients aged ≥ 1 year to < 18 years (including 20 patients 12 to < 18 years) with recurrent or refractory solid or haematological tumours, including advanced melanoma, in clinical study CA209070. The safety profile in paediatric patients was generally similar to that seen in adults treated with ipilimumab in combination with nivolumab. No new safety signals were observed.

The most common adverse reactions (reported in at least 20% of paediatric patients) for ipilimumab in combination with nivolumab were fatigue (33.3%) and rash maculo-papular (21.2%). The majority of adverse reactions reported for ipilimumab in combination with nivolumab were of Grades 1 or 2 in severity. Ten patients (30%) had one or more Grades 3 to 4 adverse reactions.

No new safety signals were observed in clinical study CA209908 of 74 paediatric patients with high-grade primary central nervous system (CNS) malignancies (see section 5.1) relative to data available in adult studies across indications.

Elderly

In MPM patients, there was a higher rate of serious adverse reactions and discontinuation rate due to adverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to all patients who received ipilimumab in combination with nivolumab (54% and 28%, respectively). Data from dMMR or MSI-H CRC patients 75 years of age or older are limited (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

The maximum tolerated dose of ipilimumab has not been determined. In clinical trials, patients received up to 20 mg/kg without apparent toxic effects.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX04.

Mechanism of action

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function, which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete T-regulatory cells at the tumour site, leading to an increase in the intratumoural T-effector/ T-regulatory cell ratio which drives tumour cell death.

Pharmacodynamic effects

In patients with melanoma who received ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase was dose-dependent. In MDX010-20 (see section 5.1), ipilimumab at 3 mg/kg with or without gp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC was observed in the control group of patients who received an investigational gp100 peptide vaccine alone.

In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+ CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanism of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T cells and a smaller, but significant, mean increase in the percent of effector memory (CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab.

Clinical efficacy and safety

Ipilimumab in combination with nivolumab

For additional information on clinical efficacy and safety associated with the dosing recommendations of nivolumab when administered as monotherapy following combination therapy with ipilimumab, please refer to the nivolumab SmPC.

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in advanced melanoma and RCC.

Clinical trials with ipilimumab monotherapy

Melanoma

Overall survival (OS) advantage of ipilimumab at the recommended dose of 3 mg/kg in patients with previously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brain metastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included in the MDX010-20 clinical trial. Clinical trials excluded patients with ECOG performance status > 1 and mucosal melanoma. Patients without liver metastasis who had a baseline AST > 2.5 x ULN, patients with liver metastasis who had a baseline AST > 5 x ULN, and patients with a baseline total bilirubin ≥ 3 x ULN were also excluded.

For patients with a history of autoimmune disease, see also section 4.4.

MDX010-20

A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanoma who had previously been treated with regimens containing one or more of the following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kg monotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports the immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation status. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy). Patients with apparent tumour burden increase before completion of the induction period were continued on induction therapy as tolerated if they had adequate performance status. Assessment of tumour response to ipilimumab was conducted at approximately Week 12, after completion of induction therapy.

Additional treatment with ipilimumab (re-treatment) was offered to those who developed PD after initial clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from the first tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. the gp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the ipilimumab monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group.

A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 doses during induction. Thirty-two patients received re-treatment: 8 in the ipilimumab monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged up to 55 months. Baseline characteristics were well balanced across groups. The median age was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had an elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously treated brain metastases.

The ipilimumab-containing regimens demonstrated a statistically significant advantage over the gp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumab monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p = 0.0026).

By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and number of prior therapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumab treatment were limited. As the subgroups analysis includes only small numbers of patients, no definitive conclusions can be drawn from these data.

Median and estimated rates of OS at 1 year and 2 years are presented in Table 8.

Table 8: Overall survival in MDX010-20

Ipilimumab 3 mg/kg

n= 137

gp100 a

n= 136

Median Months (95% CI)

10 months

(8.0, 13.8)

6 months

(5.5, 8.7)

OS at 1 year % (95% CI)

46% (37.0, 54.1)

25% (18.1, 32.9)

OS at 2 years % (95% CI)

24% (16.0, 31.5)

14% (8.0, 20.0)

a gp100 peptide vaccine is an experimental control.

In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patients with SD and those with PD, respectively. At the time of this analysis, medians were not reached for patients with CR or PR.

For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumab monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patients in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-treatment can be drawn.

The development or maintenance of clinical activity following ipilimumab treatment was similar with or without the use of systemic corticosteroids.

CA184-169

A Phase 3, double-blind study enrolled patients with previously treated or untreated unresectable Stage III or Stage IV melanoma. A total of 727 patients were randomized, 362 to receive ipilimumab 3 mg/kg and 365 to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses. In the ipilimumab 10 mg/kg group, the median OS (95% CI) was 16 months (11.63, 17.84) and in the ipilimumab 3 mg/kg group the median OS (95% CI) was 12 months (9.86, 13.27). Overall survival compared between Ipilimumab 10 mg/kg and 3 mg/kg groups showed HR = 0.84 (95% CI: 0.70, 0.99; P-value = 0.04). No statistically significant difference in progression free survival (PFS) was observed between the 10 mg/kg and the 3 mg/kg groups. (HR 0.89 with a 95% CI of 0.76, 1.04 and log-rank test P-value = 0.1548). BORR was similar in the 10 mg/kg and 3 mg/kg groups. BORR in the 10 mg/kg group was 15.3% (95% CI: 11.8, 19.5) and in the 3 mg/kg group was 12.2% (95% CI: 9.0, 16.0). Ipilimumab 10 mg/kg was associated with higher rates of adverse events compared with the 3 mg/kg dose. The frequencies of serious adverse reactions in the 10 mg/kg and 3 mg/kg groups were 37% and 18%, with the 3 most common serious adverse reactions being diarrhea (10.7% vs 5.5%), colitis (8.0% vs 3.0%), and hypophysitis (4.4% vs 1.9%). Adverse events leading to discontinuation in the 10 mg/kg and 3 mg/kg groups occurred in 31% and 19% of patients, with AEs leading to death in 4 and 2 patients, respectively.

At the recommended dose of 3 mg/kg median OS was similar in the subgroup of females ≥ 50 years of age compared to the overall population (11.40 vs 11.53 months). Median OS in the subgroup with brain metastases at baseline was 5.67 months at the recommended dose of 3 mg/kg.

Other studies with ipilimumab monotherapy

Melanoma

CA184332 and CA184338

OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 78; randomised) and in treatment-naive patients in two retrospective observational studies (N= 273 and N= 157) were generally consistent. In the two observational studies, 12.1% and 33.1% of the patients had brain metastases at the time of advanced melanoma diagnosis. Median OS and estimated 1-year, 2-year, 3-year and 4-year survival rates are presented in Table 9. The estimated 1-year, 2-year and 3-year survival rates for chemotherapy-naive patients (N= 78) pooled across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6), 31.6% (95% CI: 20.7 - 42.9) and 23.7% (95% CI: 14.3 - 34.4) respectively.

Table 9: Overall survival in observational studies

CA184338

n= 273

CA184332

n= 157

Median OS (95% CI)

14 months

(12.8-18.7)

10 months

(7.0-12.8)

OS at 1 year % (95% CI)

59% (52.5-64.3)

44% (35.5, 51.4)

OS at 2 years % (95% CI)

39% (33.1-44.8)

26% (18.9-33.3)

OS at 3 years % (95% CI)

31% (25.5-36.7)

22% (15.5-29.2)

OS at 4 years % (95% CI)

26% (20.4-31.3)

22% (15.5-29.2)

Patients with brain metastases in study CA184332 had a median OS of 7 months (95% CI: 5.06 - 12.81) and patients without brain metastases had a median OS of 14.1 months (95% CI: 9.96-Not estimated).

Patients with brain metastases in study CA184338 had a median OS of 6.3 months (95% CI: 3.2 - 12.0) and patients without brain metastases had a median OS of 17.7 months (95% CI: 13.6 – 12.1).

Long term survival benefit of treatment with ipilimumab (at 3mg/kg) is demonstrated through a pooled analysis of OS data from clinical trials in patients with previously treated and treatment naive advanced melanoma (N = 965). The Kaplan-Meier OS curve revealed a plateau beginning around year 3 (OS rate = 21% [95% CI: 17-24]) that extended up to 10 years in some patients (see Figure 1).

Figure 1: Overall survival with ipilimumab 3 mg/kg in pooled analysis

SMPC_24779_215585a_42.png

Clinical trials with ipilimumab in combination with nivolumab

Melanoma

Randomised phase 3 study of ipilimumab in combination with nivolumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg nivolumab 3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The differences between the two nivolumab-containing groups were evaluated descriptively. The study included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.

A total of 945 patients were randomised to receive ipilimumab in combination with nivolumab (n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The primary outcome measures were progression-free survival and OS. ORR and the duration of response were also assessed.

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

At primary analysis (minimum follow-up 9 months) the median PFS was 6.9 months in the nivolumab group as compared with 2.9 months in the ipilimumab group (HR = 0.57, 99.5% CI: 0.43, 0.76; p < 0.0001). The median PFS was 11.5 months in the ipilimumab in combination with nivolumab group, as compared with 2.9 months in the ipilimumab group (HR = 0.42, 99.5% CI: 0.31, 0.57; p < 0.0001).

PFS results from descriptive analysis (with minimum follow up of 90 months) are shown in Figure 2 (all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour PD-L1 1% cut off).

Figure 2: Progression-free survival (CA209067)

SMPC_24779_215585b_42.png

Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067)

PD-L1 expression < 5%

SMPC_24779_215585c_42.png

PD-L1 expression ≥ 5%

SMPC_24779_215585d_42.png

Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)

PD-L1 expression < 1%

SMPC_24779_215585e_42.png

PD-L1 expression ≥ 1%

SMPC_24779_215585f_42.png

The final (primary) OS analysis occurred when all patients had a minimum follow-up of 28 months. At 28 months, median OS was not reached in the nivolumab group as compared with 19.98 months in the ipilimumab group (HR = 0.63, 98% CI: 0.48, 0.81; p-value: < 0.0001). Median OS was not reached in the ipilimumab in combination with nivolumab group as compared with the ipilimumab group (HR = 0.55, 98% CI: 0.42, 0.72; p-value: < 0.0001).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 90 months show outcomes consistent with the original primary analysis. OS results from this follow-up analysis are shown in Figure 5 (all randomised), Figure 6 and 7 (at the tumour PD-L1 5% and 1% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic therapy was received by 36.0%, 49.1%, and 66.3% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 19.1%, 34.2%, and 48.3% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Figure 5 Overall survival (CA209067) - Minimum follow-up of 90 months

SMPC_24779_215585g_42.png

Figure 6: Overall survival by PD-L1 expression: 5% cut off (CA209067) - Minimum follow-up of 90 months

PD-L1 expression < 5%

SMPC_24779_215585h_42.png

PD-L1 expression ≥ 5%

SMPC_24779_215585i_42.png

Figure 7: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum follow-up of 90 months

PD-L1 expression < 1%

SMPC_24779_215585j_42.png

PD-L1 expression ≥ 1%

SMPC_24779_215585k_42.png

Minimum follow-up for the analysis of ORR was 90 months. Responses are summarised in Table 10.

Table 10: Objective response (CA209067)

nivolumab + ipilimumab

(n = 314)

nivolumab

(n = 316)

ipilimumab

(n = 315)

Objective response

183 (58%)

142 (45%)

60 (19%)

(95% CI)

(52.6, 63.8)

(39.4, 50.6)

(14.9, 23.8)

Odds ratio (vs. ipilimumab)

6.35

3.5

(95% CI)

(4.38, 9.22)

(2.49, 5.16)

Complete response (CR)

71 (23%)

59 (19%)

19 (6%)

Partial response (PR)

112 (36%)

83 (26%)

41 (13%)

Stable disease (SD)

38 (12%)

29 (9%)

69 (22%)

Duration of response

Median (range), months

N.A.

(69.1-N.A.)

90.8

(45.7-N.A.)

19.3

(8.8-47.4)

Proportion ≥ 12 months in duration

68%

73%

44%

Proportion ≥ 24 months in duration

58%

63%

30%

ORR (95% CI) by tumour PD-L1 expression

<5%

56% (48.7, 62.5)

n = 210

43% (36, 49.8)

n = 208

18% (12.8, 23.8)

n = 202

≥ 5%

72% (59.9, 82.3)

n = 68

59% (47.2, 69.6)

n = 80

21% (12.7, 32.3)

n = 75

<1%

54% (44.4, 62.7)

n = 123

36% (27.2, 45.3)

n = 117

18% (11.2, 26.0)

n = 113

≥ 1%

65% (56.4, 72)

n = 155

55% (47.2, 62.6)

n = 171

20% (13.7, 26.4)

n = 164

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, and baseline LDH level. This observation was maintained with the OS results with a minimum follow-up of 90 months.

Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 10) after 90 months of follow-up, with a best overall response of complete response correlating to an improved survival rate.

After 90 months of follow-up, median durations of response for patients with tumour PD-L1 expression level ≥ 5% were 78.19 months (range: 18.07-N.A.) in the combination arm, 77.21 months (range: 26.25-N.A.) in the nivolumab monotherapy arm and 31.28 months (range: 6.08-N.A.) in the ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached (range: 61.93-N.A.) in the combination arm, were 90.84 months (range: 50.43-N.A.) in the nivolumab monotherapy arm and 19.25 months (range: 5.32-47.44) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status:

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had a median PFS of 16.76 months (95% CI: 8.28, 32.0) and 11.17 months (95% CI: 7.0, 19.32), while those in the nivolumab monotherapy arm had a median PFS of 5.62 months (95% CI: 2.79, 9.46) and 8.18 months (95% CI: 5.13, 19.55), respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab monotherapy had a median PFS of 3.09 months (95% CI: 2.79, 5.19) and 2.83 months (95% CI: 2.76, 3.06), respectively.

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had an ORR of 67.0% (95% CI: 57.0, 75.9; n = 103) and 54.0% (95% CI: 47.1, 60.9; n = 211), while those in the nivolumab monotherapy arm had an ORR of 37.87% (95% CI: 28.2, 48.1; n = 98) and 48.2% (95% CI: 41.4, 55.0; n = 218), respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab monotherapy had an ORR of 23.0% (95% CI: 15.2, 32.5; n = 100) and 17.2% (95% CI: 12.4, 22.9; n = 215),

After 90 months of follow-up, in BRAF [V600] mutation-positive patients median OS was not reached in the combination arm and 45.5 months in the nivolumab monotherapy arm. Median OS for BRAF [V600] mutation-positive patients in the ipilimumab monotherapy arm was 24.6 months. In BRAF wild-type patients median OS was 39.06 months in the combination arm, 34.37 months in the nivolumab monotherapy arm, and 18.5 months in the ipilimumab monotherapy arm. The OS HRs for ipilimumab in combination with nivolumab vs. nivolumab monotherapy were 0.66 (95% CI: 0.44, 0.98) for BRAF[V600] mutation-positive patients and 0.95 (95% CI: 0.74, 1.22) for BRAF wild-type patients.

Randomised phase 2 study of ipilimumab in combination with nivolumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% (95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44% (95% CI: 28, 60), respectively, for ipilimumab (n = 37).

Renal cell carcinoma

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. sunitinib (CA209214)

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for the treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study (CA209214). The study included patients (18 years or older) with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component. The primary efficacy population included those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). This study included patients regardless of their tumour PD-L1 status. Patients with Karnofsky performance status < 70% and patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were stratified by IMDC prognostic score and region.

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either ipilimumab 1 mg/kg (n = 425) administered intravenously over 30 minutes in combination with nivolumab administered intravenously over 60 minutes every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.

Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patients were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 0.4 years in both the ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg and sunitinib groups. The median duration of treatment was 7.9 months (range: 1 day- 21.4+ months) in ipilimumab with nivolumab- treated patients and was 7.8 months (range: 1 days- 20.2+ months) in sunitinib-treated patients. Ipilimumab with nivolumab was continued beyond progression in 29% of patients.

Efficacy results for the intermediate/poor risk patients are shown in Table 11 (primary analysis with a minimum follow-up of 17.5 months and with a minimum follow-up of 60 months) and in Figure 8 (minimum follow-up of 60 months).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 60 months show outcomes consistent with the original primary analysis.

Table 11: Efficacy results in intermediate/poor risk patients (CA209214)

nivolumab + ipilimumab

(n = 425)

sunitinib

(n = 422)

Primary analysis

minimum follow-up: 17.5 months

Overall survival

Events

140 (33%)

188 (45%)

Hazard ratioa

0.63

99.8% CI

(0.44, 0.89)

p-valueb, c

< 0.0001

Median (95% CI)

NE (28.2, NE)

25.9 (22.1, NE)

Rate (95% CI)

At 6 months

89.5 (86.1, 92.1)

86.2 (82.4, 89.1)

At 12 months

80.1 (75.9, 83.6)

72.1 (67.4, 76.2)

Progression-free survival

Events

228 (53.6%)

228 (54.0%)

Hazard ratioa

0.82

99.1% CI

(0.64, 1.05)

p-valueb,h

0.0331

Median (95% CI)

11.6 (8.71, 15.51)

8.4 (7.03, 10.81)

Confirmed objective response (BICR)

177 (41.6%)

112 (26.5%)

(95% CI)

(36.9, 46.5)

(22.4, 31.0)

Difference in ORR (95% CI)d

16.0 (9.8, 22.2)

p-valuee,f

< 0.0001

Complete response (CR)

40 (9.4%)

5 (1.2%)

Partial response (PR)

137 (32.2%)

107 (25.4%)

Stable disease (SD)

133 (31.3%)

188 (44.5%)

Median duration of responseg

Months (range)

NE (1.4+-25.5+)

18.17 (1.3+-23.6+)

Median time to response

Months (range)

2.8 (0.9-11.3)

3.0 (0.6-15.0)

Updated analysis*

minimum follow-up: 60 months

Overall survival

Events

242 (57%)

282 (67%)

Hazard ratioa

0.68

95% CI

(0.58, 0.81)

Median (95% CI)

46.95 (35.35, 57.43)

26.64 (22.08, 33.54)

Rate (95% CI)

At 24 months

66.3 (61.5, 70.6)

52.4 (47.4, 57.1)

At 36 months

54.6 (49.7, 59.3)

43.7 (38.7, 48.5)

At 48 months

49.9 (44.9, 54.6)

35.8 (31.1, 40.5)

At 60 months

43.0 (38.1, 47.7)

31.3 (26.8, 35.9)

Progression-free survival

Events

245 (57.6%)

253 (60.0%)

Hazard ratioa

0.73

95% CI

(0.61, 0.87)

Median (95% CI)

11.6 (8.44, 16.63)

8.3 (7.03, 10.41)

Confirmed objective response (BICR)

179 (42.1%)

113 (26.8%)

(95% CI)

(37.4, 47.0)

(22.6, 31.3)

Difference in ORR (95% CI)d,e

16.2 (10.0, 22.5)

Complete response (CR)

48 (11.3%)

9 (2.1%)

Partial response (PR)

131 (30.8%)

104 (24.6%)

Stable disease (SD)

131 (30.8%)

187 (44.3%)

Median duration of responseg

Months (range)

NE (50.89-NE)

19.38 (15.38-25.10)

Median time to response

Months (range)

2.8 (0.9-35.0)

3.1 (0.6-23.6)

a Based on a stratified proportional hazards model.

b Based on a stratified log-rank test.

c p-value is compared to alpha 0.002 in order to achieve statistical significance.

d Strata adjusted difference.

e Based on the stratified DerSimonian-Laird test.

f p-value is compared to alpha 0.001 in order to achieve statistical significance.

g Computed using Kaplan-Meier method.

h p-value is compared to alpha 0.009 in order to achieve statistical significance.

+” denotes a censored observation.

NE = non-estimable

* Descriptive analysis based on data cut-off: 26-Feb-2021.

Figure 8: Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214) Minimum follow-up of 60 months

SMPC_24779_215585l_42.png

An updated descriptive OS analysis was performed when all patients had a minimum follow-up of 24 months. At the time of this analysis, the hazard ratio was 0.66 (99.8% CI 0.48-0.91) with 166/425 events in the combination arm and 209/422 events in the sunitinib arm. In intermediate/poor-risk patients, OS benefit was observed in the ipilimumab in combination with nivolumab arm vs. sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 expression ≥ 1% was not reached for ipilimumab in combination with nivolumab, and was 19.61 months in the sunitinib arm (HR = 0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression < 1%, the median OS was 34.7 months for the ipilimumab in combination with nivolumab and was 32.2 months in the sunitinib arm (HR = 0.70; 95% CI: 0.54, 0.92).

CA209214 also randomised 249 favourable risk patients as per IMDC criteria to ipilimumab plus nivolumab (n = 125) or to sunitinib (n = 124). These patients were not evaluated as part of the primary efficacy population. At a minimum of 24 months follow-up, OS in favourable risk patients receiving ipilimumab plus nivolumab compared to sunitinib had a hazard ratio of 1.13 (95% CI: 0.64, 1.99; p = 0.6710). With 60 months minimum follow-up, the HR for OS was 0.94 (95% CI: 0.65, 1.37).

There are no data on the use of ipilimumab in combination with nivolumab in patients with only a non clear-cell histology in first-line RCC.

Patients ≥ 75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and the combination of ipilimumab and nivolumab showed numerically less effect on OS (HR 0.97, 95% CI: 0.48, 1.95) in this subgroup versus the overall population at a minimum follow-up of 17.5 months. Because of the small size of this subgroup, no definitive conclusions can be drawn from these data.

First-line treatment of non-small cell lung cancer

Randomised phase 3 study of ipilimumab in combination with nivolumab and 2 cycles of platinum-based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA)

The safety and efficacy of ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-based chemotherapy were evaluated in a phase 3, randomised, open-label study (CA2099LA). The study included patients (18 years or older) with histologically confirmed non-squamous or squamous Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors). Patients were enrolled regardless of their tumour PD-L1 status.

Patients with sensitising EGFR mutations or ALK translocations, active (untreated) brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of < 10 mg daily prednisone equivalents. Randomisation was stratified by histology (squamous vs non-squamous), tumour PD-L1 expression level (≥ 1% vs < 1%), and gender (male vs female).

A total of 719 patients were randomised to receive either ipilimumab in combination with nivolumab and platinum-based chemotherapy (n = 361) or platinum-based chemotherapy (n = 358). Patients in the ipilimumab in combination with nivolumab and platinum-based chemotherapy arm received ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks in combination with nivolumab 360 mg administered intravenously over 30 minutes every 3 weeks and platinum-based chemotherapy administered every 3 weeks for 2 cycles. Patients in the chemotherapy arm received platinum-based chemotherapy administered every 3 weeks for 4 cycles; non-squamous patients could receive optional pemetrexed maintenance therapy.

Platinum-based chemotherapy consisted of carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2; or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC.

Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue nivolumab monotherapy. Tumour assessments were performed every 6 weeks after first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued.

CA2099LA baseline characteristics were generally balanced across all treatment groups. The median age was 65 years (range: 26-86) with 51% ≥ 65 years of age and 10% ≥ 75 years of age. The majority of patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% of patients with PD-L1 ≥ 1% and 37% with PD-L1 < 1%, 31% had squamous and 69% had non-squamous histology, 17% had brain metastases, and 86% were former/current smokers. No patients received prior immunotherapy.

CA2099LA primary efficacy outcome measure was OS. Additional efficacy endpoints were PFS, ORR, and duration of response as assessed by BICR.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR for patients randomised to ipilimumab in combination with nivolumab and platinum-based chemotherapy as compared to platinum-based chemotherapy alone at the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis). Minimum follow-up for OS was 8.1 months.

Efficacy results are shown in Figure 9 (updated OS analysis with a minimum follow-up of 12.7 months) and Table 12 (primary analysis with a minimum follow-up of 8.1 months).

An updated efficacy analysis was performed when all patients had a minimum follow-up of 12.7 months (see Figure 9). At the time of this analysis, the hazard ratio for OS was 0.66 (95% CI: 0.55, 0.80) and the hazard ratio for PFS was 0.68 (95% CI: 0.57, 0.82).

Figure 9: Kaplan-Meier plot of OS (CA2099LA)