Tremelimumab

Tremelimumab is a fully human IgG2 monoclonal antibody, produced in murine myeloma cells by recombinant DNA technology, that blocks the immune checkpoint receptor CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4). CTLA-4 is found mainly on T lymphocytes, where it limits their activation. Blocking it enhances T-cell activation and strengthens the anti-tumour response. Tremelimumab is always given together with durvalumab, a PD-L1 inhibitor.

Mechanism of Action

• Role of CTLA-4: when CTLA-4 binds its ligands CD80 and CD86, it limits effector T-cell activation, mainly by limiting the co-stimulatory signal that passes through CD28.
• Blockade: tremelimumab is a selective antibody that blocks the interaction of CTLA-4 with CD80 and CD86. This enhances T-cell activation and proliferation, increases T-cell diversity and enhances anti-tumour activity.
• Laboratory findings: it binds human CTLA-4 with high selectivity and sub-nanomolar affinity. In blood-cell assays it raised interleukin-2 production in a dose-dependent way and increased the proliferation of effector T cells.
• With durvalumab: combining a CTLA-4 inhibitor with a PD-L1 inhibitor gave improved anti-tumour responses in metastatic non-small cell lung cancer and in hepatocellular carcinoma.

Pharmacokinetics

• Dose proportionality: studied at 75 mg to 750 mg or 10 mg/kg given intravenously every 4 or 12 weeks, and as a single 300 mg dose. Exposure rose in proportion to the dose (linear pharmacokinetics) at 75 mg and above, and steady state was reached after about 12 weeks.
• Distribution: in a population analysis of 1,605 patients, the estimated volume of distribution was 6.33 L.
• Elimination: estimated clearance 0.309 L/day and terminal half-life about 14.2 days. Like other antibodies, it is removed by protein catabolism through the reticuloendothelial system or by target-mediated disposition, so metabolic interactions are not expected.
• Special populations: age (18–87 years), body weight (34–149 kg), sex, race, ECOG/WHO status, tumour type, albumin, LDH and creatinine levels and anti-drug antibody status had no clinically significant effect on exposure. Mild and moderate renal impairment also had no clinically significant effect. The effect of severe renal impairment (creatinine clearance 15 to 29 mL/min) is unknown, but IgG antibodies are not mainly cleared by the kidney, so a change in renal function is not expected to alter exposure.
• Immunogenicity: in pooled data, 12.1% of 2,075 evaluable patients (252 patients) developed anti-drug antibodies during treatment. They had no apparent effect on pharmacokinetics or safety.

Both authorised uses are combinations that include durvalumab.

• Hepatocellular carcinoma (HCC): in combination with durvalumab, for the first-line treatment of adults with advanced or unresectable hepatocellular carcinoma.
• Non-small cell lung cancer (NSCLC): in combination with durvalumab and platinum-based chemotherapy, for the first-line treatment of adults with metastatic non-small cell lung cancer with no sensitising EGFR mutations or ALK-positive mutations.

• Hypersensitivity to the active substance or to any of the excipients.

The safety data come from 462 patients with hepatocellular carcinoma who received a single 300 mg dose of tremelimumab with durvalumab (HCC regimen) and 330 patients with metastatic non-small cell lung cancer who received 75 mg with durvalumab and platinum-based chemotherapy (NSCLC regimen). The most common reactions (more than 10%) were rash (32.5%), pruritus (25.5%), diarrhoea (25.3%) and abdominal pain (19.7%) with the HCC regimen, and anaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%) and decreased appetite (28.2%) with the NSCLC regimen. Where the two regimens fall into different frequency categories, the higher one is shown below, with the regimen in brackets when it applies to one only.

Very common (≥1/10): upper respiratory tract infections (NSCLC), pneumonia (NSCLC), anaemia (NSCLC), neutropenia (NSCLC), thrombocytopenia (NSCLC), leukopenia (NSCLC), hypothyroidism, decreased appetite (NSCLC), cough or productive cough, nausea (NSCLC), diarrhoea, constipation (NSCLC), vomiting (NSCLC), abdominal pain (HCC), increased aspartate or alanine aminotransferase, alopecia (NSCLC), rash, pruritus, arthralgia (NSCLC), fatigue (NSCLC), pyrexia, peripheral oedema (HCC).

Common (≥1/100 to <1/10): influenza, oral candidiasis (NSCLC), dental and oral soft-tissue infections (HCC), febrile neutropenia (NSCLC), pancytopenia (NSCLC), hyperthyroidism, adrenal insufficiency, hypophysitis or hypopituitarism (NSCLC), thyroiditis, peripheral neuropathy (NSCLC), pneumonitis, dysphonia (NSCLC), stomatitis (NSCLC), increased amylase, increased lipase, colitis, pancreatitis, hepatitis, dermatitis (HCC), night sweats (HCC), myalgia, increased blood creatinine, dysuria, infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): immune thrombocytopenia, type 1 diabetes mellitus, diabetes insipidus (NSCLC), uveitis (NSCLC), encephalitis (NSCLC), myasthenia gravis (HCC), meningitis (HCC), myocarditis, interstitial lung disease, large intestine perforation, pemphigoid, myositis, polymyositis, immune-mediated arthritis, polymyalgia rheumatica (HCC), nephritis, non-infective cystitis (NSCLC).

Rare (≥1/10,000 to <1/1,000): Guillain-Barré syndrome, intestinal perforation, coeliac disease.

Not known: transverse myelitis.

Serious immune-mediated reactions can occur. In pooled data from 2,280 patients treated with tremelimumab and durvalumab, immune-mediated pneumonitis occurred in 3.8% (fatal in 0.3%), hepatitis in 3.5%, colitis or diarrhoea in 7.3%, hypothyroidism in 9.2% and rash or dermatitis in 4.9%. Most of these reactions, including serious ones, resolved with appropriate medical treatment or withdrawal of tremelimumab. The most common serious reactions were colitis (2.6%), diarrhoea (2.4%) and pneumonia (2.2%) with the HCC regimen, and pneumonia (11.5%), anaemia (5.5%), thrombocytopenia (3%), colitis, diarrhoea and pyrexia (2.4% each) and febrile neutropenia (2.1%) with the NSCLC regimen. Adverse reactions led to permanent discontinuation in 6.5% of HCC patients (most often hepatitis, 1.5%) and in 4.5% of NSCLC patients (most often pneumonia, 1.2%, and colitis, 0.9%).

No formal pharmacokinetic interaction studies have been done with tremelimumab. Because it is eliminated by protein catabolism through the reticuloendothelial system or by target-mediated disposition, metabolic interactions are not expected.

• Systemic corticosteroids and immunosuppressants before treatment: not recommended before starting tremelimumab, except physiological doses of systemic corticosteroids (up to 10 mg/day prednisone or equivalent), because they may interfere with its pharmacodynamic activity and efficacy.
• After treatment has started: systemic corticosteroids and other immunosuppressants can be used to treat immune-related adverse reactions.
• Durvalumab and chemotherapy partners: in the POSEIDON study there were no clinically meaningful pharmacokinetic interactions between tremelimumab, durvalumab, nab-paclitaxel, gemcitabine, pemetrexed, carboplatin or cisplatin given together.

Treatment must be started and supervised by a physician experienced in the treatment of cancer. Tremelimumab is given only as an intravenous infusion over 1 hour, after dilution (preparation instructions are in section 6.6 of the SmPC). It is always combined with durvalumab and, in lung cancer, with platinum-based chemotherapy; the SmPCs of those medicines give their own dosing details.

Recommended Dose

• Advanced or unresectable hepatocellular carcinoma: 300 mg as a single dose, given with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab alone every 4 weeks until disease progression or unacceptable toxicity. Patients weighing 40 kg or less receive weight-based dosing equivalent to 4 mg/kg until their weight is above 40 kg.
• Metastatic non-small cell lung cancer: 75 mg with durvalumab 1,500 mg and platinum-based chemotherapy every 3 weeks (21 days) for 4 cycles (12 weeks). After the platinum chemotherapy, durvalumab 1,500 mg is given every 4 weeks together with histology-based pemetrexed maintenance every 4 weeks. A fifth dose of tremelimumab 75 mg is given at week 16 alongside durvalumab dose 6, up to a maximum of 5 doses. Patients may receive fewer than five doses if there is disease progression or unacceptable toxicity. Patients weighing 34 kg or less receive weight-based dosing equivalent to 1 mg/kg until their weight is above 34 kg.
• Notes for lung cancer: pemetrexed maintenance is considered for patients with non-squamous tumours who received pemetrexed with carboplatin or cisplatin in the chemotherapy stage. If doses are delayed, the fifth dose can be given after week 16 alongside durvalumab. If fewer than 4 cycles of platinum-based chemotherapy are given, the remaining tremelimumab doses (up to a total of 5) are given alongside durvalumab in the post-platinum phase.
• Durvalumab in low body weight: patients weighing 30 kg or less receive weight-based durvalumab dosing equivalent to 20 mg/kg until their weight is above 30 kg.

Order of Infusions

• Liver cancer: tremelimumab is given as a separate infusion before durvalumab on the same day.
• Lung cancer: tremelimumab first, then durvalumab, then the platinum-based chemotherapy (or the pemetrexed maintenance at week 16) on the day of dosing. Each is a separate infusion with its own infusion bag and filter; tremelimumab and durvalumab each run over 1 hour.
• Timing in cycle 1: durvalumab starts about 1 hour (maximum 2 hours) after the end of the tremelimumab infusion, and chemotherapy about 1 hour (maximum 2 hours) after the end of the durvalumab infusion. If there are no clinically significant concerns in cycle 1, later durvalumab doses can follow tremelimumab immediately at the physician’s discretion, and the gap before chemotherapy can be shortened to 30 minutes.

Dose Adjustments for Side Effects

Dose escalation or reduction is not recommended. Instead, treatment is withheld or stopped according to the type and grade of the reaction (Table 2 of the SmPC). In summary:

• Pneumonitis or interstitial lung disease: withhold for Grade 2; stop permanently for Grade 3 or 4.
• Hepatitis: withhold for ALT or AST above 3 and up to 5 times the upper limit of normal (ULN) or total bilirubin above 1.5 and up to 3 times ULN. For ALT or AST above 5 and up to 10 times ULN, withhold durvalumab and stop tremelimumab permanently where appropriate. Stop permanently for ALT or AST above 3 times ULN with bilirubin above 2 times ULN, or for ALT or AST above 10 times ULN or bilirubin above 3 times ULN. Separate thresholds based on baseline values apply in hepatocellular carcinoma or with liver involvement; see the SmPC.
• Colitis or diarrhoea: withhold for Grade 2; stop permanently for Grade 3 or 4 and for intestinal perforation of any grade. For Grade 3, tremelimumab is stopped permanently, but durvalumab can be resumed once the event has resolved.
• Endocrine reactions: for hyperthyroidism, thyroiditis, adrenal insufficiency and hypophysitis or hypopituitarism of Grades 2–4, withhold until clinically stable. No change is needed for hypothyroidism or type 1 diabetes mellitus.
• Nephritis: withhold for Grade 2 (serum creatinine above 1.5 and up to 3 times ULN or baseline); stop permanently for Grade 3 or 4.
• Rash or dermatitis (including pemphigoid): withhold for Grade 2 lasting more than 1 week or Grade 3; stop permanently for Grade 4.
• Myocarditis, myasthenia gravis, encephalitis, Guillain-Barré syndrome: stop permanently for Grades 2–4. Transverse myelitis: stop permanently at any grade. Meningitis: withhold for Grade 2, stop permanently for Grade 3 or 4.
• Myositis, polymyositis, rhabdomyolysis: withhold for Grade 2 or 3 (stop permanently if not resolved to Grade 1 within 30 days or if there are signs of respiratory insufficiency); stop permanently for Grade 4.
• Infusion-related reactions: interrupt or slow the infusion for Grade 1 or 2; stop permanently for Grade 3 or 4.
• Other immune-mediated reactions (including immune thrombocytopenia, pancreatitis, non-infective cystitis, immune-mediated arthritis, uveitis and polymyalgia rheumatica): withhold for Grade 2 or 3; stop permanently for Grade 4.
• Reactions not mediated by the immune system: withhold for Grade 2 or 3 until Grade 1 or baseline; stop permanently for Grade 4 (for Grade 4 laboratory abnormalities, the decision rests on accompanying clinical signs and judgement).
• Restarting: after withholding, tremelimumab and/or durvalumab can be resumed within 12 weeks if the reaction has improved to Grade 1 or below and the corticosteroid dose has been reduced to 10 mg/day prednisone or equivalent or less. Both are stopped permanently for recurrent Grade 3 reactions.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years and over. Data in patients aged 75 years or older with metastatic non-small cell lung cancer are limited.
• Renal impairment: no dose adjustment for mild or moderate impairment. Data in severe impairment are too limited to draw conclusions.
• Hepatic impairment: no dose adjustment for mild or moderate impairment. Tremelimumab has not been studied in severe hepatic impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established for hepatocellular carcinoma or non-small cell lung cancer, and no data are available. Outside its authorised indications, tremelimumab with durvalumab was studied in children aged 1 to 17 years with neuroblastoma, solid tumours and sarcoma, but the results did not allow a conclusion that the benefits outweigh the risks.

Immune-Mediated Adverse Reactions

Tremelimumab with durvalumab can cause immune-mediated reactions in many organs. For suspected reactions, the cause should be confirmed and other causes excluded. Depending on severity, treatment is withheld and corticosteroids are given; once the reaction has improved to Grade 1 or below, the corticosteroid is tapered over at least 1 month. If the reaction worsens or does not improve, a higher corticosteroid dose and/or an additional systemic immunosuppressant can be considered.

• Pneumonitis: monitor for symptoms; confirm with imaging and exclude infection. Grade 2: prednisone 1–2 mg/kg/day or equivalent, then taper. Grade 3 or 4: methylprednisolone 2–4 mg/kg/day or equivalent, then taper.
• Hepatitis: measure ALT, AST, total bilirubin and alkaline phosphatase before treatment and before each infusion. Corticosteroids (prednisone 1–2 mg/kg/day or equivalent, then taper) for all grades.
• Colitis and intestinal perforation: monitor for colitis, diarrhoea and perforation; corticosteroids (prednisone 1–2 mg/kg/day or equivalent, then taper) for Grades 2–4. A surgeon must be consulted immediately if intestinal perforation of any grade is suspected.
• Endocrine reactions: check thyroid function before and periodically during treatment; thyroid hormone replacement for hypothyroidism of Grades 2–4 and symptomatic management of hyperthyroidism or thyroiditis of Grades 2–4. Adrenal insufficiency and hypophysitis or hypopituitarism: corticosteroids followed by a taper, with hormone replacement as clinically indicated. Type 1 diabetes mellitus can first present as diabetic ketoacidosis, which can be fatal if not detected early; insulin is started as clinically indicated.
• Nephritis: monitor renal function before and periodically during treatment; corticosteroids for Grades 2–4.
• Rash and dermatitis: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with PD-1 and CTLA-4 inhibitors. Corticosteroids for Grade 2 lasting more than 1 week and for Grades 3–4.
• Myocarditis: can be fatal. Corticosteroids (prednisone 2–4 mg/kg/day or equivalent, then taper) for Grades 2–4; if there is no improvement within 2 to 3 days, additional immunosuppressive therapy is started promptly, and the taper begins on resolution and continues over at least 1 month.
• Pancreatitis: monitor for signs and symptoms.
• Other reactions: myasthenia gravis, transverse myelitis, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, non-infective cystitis, immune-mediated arthritis, uveitis and polymyalgia rheumatica have been observed. Corticosteroids (prednisone 1–2 mg/kg/day or equivalent, then taper) for Grades 2–4.

Infusion-Related Reactions

Monitor for signs and symptoms; severe infusion-related reactions have been reported. For Grade 1 or 2, pre-medication to prevent later reactions can be considered. Grade 3 or 4 reactions are managed according to institutional standards and clinical practice guidelines.

Traceability

To improve the traceability of biological medicinal products, the trade name and batch number of the product given must be clearly recorded.

Use in Specific Patient Groups

• Lung cancer, age 75 years and over: data on tremelimumab with durvalumab and platinum-based chemotherapy are limited; the potential benefit and risk should be weighed carefully for each patient.
• Hepatocellular carcinoma: patients with Child-Pugh B or C disease, main portal vein thrombosis, liver transplant, uncontrolled hypertension, current or past brain metastases, spinal cord compression, hepatitis B and C co-infection, gastrointestinal bleeding in the past 12 months, ascites needing non-pharmacological intervention in the past 6 months, hepatic encephalopathy in the past 12 months, or active or prior autoimmune or inflammatory disorders were excluded from the studies.
• Lung cancer: patients with active or prior autoimmune disease, active or untreated brain metastases, a history of immunodeficiency, systemic immunosuppression within 14 days before starting (other than physiological corticosteroid doses below 10 mg/day prednisone or equivalent), uncontrolled intercurrent illness, active tuberculosis, hepatitis B or C or HIV infection, or a live attenuated vaccine within 30 days before or after starting were excluded.
• In the absence of data, tremelimumab should be used with caution in these populations after careful consideration of the benefit and risk for the individual patient.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose.
• Pregnancy: there are no data in pregnant women. Based on its mechanism of action and the placental transfer of human IgG2, tremelimumab may affect the maintenance of pregnancy and may cause foetal harm. Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity. It is not recommended during pregnancy or in women of childbearing potential who are not using effective contraception.
• Breastfeeding: there is no information on excretion in human milk, but human IgG2 is excreted in milk and a risk to the breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment and for at least 3 months after the last dose.
• Fertility: there are no data on fertility in humans or animals. Mononuclear cell infiltration in the prostate and uterus was seen in repeat-dose toxicity studies; its clinical relevance for fertility is unknown.

Sodium Content

The medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is, it is essentially ‘sodium-free’.

Effect on Driving

Tremelimumab has no or negligible influence on the ability to drive and use machines.

Store the vials in a refrigerator at 2–8 °C and do not freeze. Keep them in the original package to protect from light. Maintain the cold chain from supply to the hospital pharmacy. For storage after dilution, see Shelf Life. The medicinal product is supplied in single-dose Type I glass vials: 1.25 mL (25 mg, violet flip-off seal) and 15 mL (300 mg, dark blue flip-off seal), one vial per pack. Not all pack sizes may be marketed.

• Unopened vial: 4 years at 2–8 °C.
• Diluted solution: chemical and physical in-use stability has been shown for up to 28 days at 2–8 °C and for up to 48 hours at room temperature (up to 25 °C) from the time of preparation. From a microbiological point of view, the prepared solution should be used immediately. If it is not, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C or 12 hours at room temperature (up to 25 °C), unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Treatment must be initiated and supervised by a physician experienced in the treatment of cancer. Tremelimumab is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.