Atezolizumab

Atezolizumab is an immune checkpoint inhibitor. PD-L1, expressed on tumour cells and on tumour-infiltrating immune cells, binds the PD-1 and B7.1 receptors on T cells and antigen-presenting cells and so suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Atezolizumab binds PD-L1 directly and lifts this brake on the antitumour immune response.

Mechanism of Action

• Dual blockade: by occupying PD-L1, atezolizumab prevents it from engaging both PD-1 and B7.1, releasing PD-L1/PD-1-mediated inhibition and reactivating antitumour T-cell responses.
• Fc-engineered: the antibody does not trigger antibody-dependent cellular cytotoxicity against the cells it binds.
• PD-L2 spared: the PD-L2/PD-1 interaction is not blocked, so inhibitory signals through PD-L2 persist.
• Immune-mediated effects: releasing the immune brake can also cause inflammation in healthy organs, which explains the typical side effects.

Pharmacokinetics

• Absorption: given intravenously. Exposure is dose-proportional between 1 and 20 mg/kg, and the 840 mg two-weekly, 1,200 mg three-weekly and 1,680 mg four-weekly schedules give comparable exposure. Steady state is reached after 6 to 9 weeks, with 1.91-fold accumulation in AUC and 2.75-fold in trough concentration.
• Distribution: steady-state volume of distribution 6.91 L (central compartment 3.28 L).
• Metabolism: cleared by catabolism into small peptides and amino acids, not by cytochrome P450 enzymes.
• Elimination: clearance 0.200 L/day; typical terminal half-life 27 days. It is not excreted by the kidneys.
• Special populations: age (21–89 years), ethnicity, renal impairment, mild hepatic impairment, PD-L1 expression and ECOG status had no effect on exposure; body weight, gender, anti-drug antibodies, albumin and tumour burden had no clinically relevant effect. No dose adjustments are recommended.

Atezolizumab is used in adults. Where an indication sets a PD-L1 threshold, it must be confirmed by a validated test. The subcutaneous solution for injection has the same indications.

• Urothelial carcinoma (monotherapy): locally advanced or metastatic disease after prior platinum-containing chemotherapy, or in patients considered ineligible for cisplatin whose tumours have PD-L1 expression ≥5%.
• Early-stage non-small cell lung cancer (NSCLC; monotherapy): adjuvant treatment after complete resection and platinum-based chemotherapy, for NSCLC at high risk of recurrence with PD-L1 on ≥50% of tumour cells and without EGFR-mutant or ALK-positive disease.
• Metastatic non-squamous NSCLC, first line: with bevacizumab, paclitaxel and carboplatin (in EGFR-mutant or ALK-positive NSCLC only after failure of appropriate targeted therapies), or with nab-paclitaxel and carboplatin in patients without EGFR-mutant or ALK-positive NSCLC.
• Metastatic NSCLC, first line, monotherapy: PD-L1 on ≥50% of tumour cells or ≥10% of tumour-infiltrating immune cells, without EGFR-mutant or ALK-positive NSCLC.
• Advanced NSCLC, first line, monotherapy: patients ineligible for platinum-based therapy.
• Previously treated NSCLC (monotherapy): locally advanced or metastatic disease after prior chemotherapy; patients with EGFR-mutant or ALK-positive NSCLC should also have received targeted therapies.
• Extensive-stage small cell lung cancer (ES-SCLC): first-line treatment with carboplatin and etoposide.
• Triple-negative breast cancer (TNBC): with nab-paclitaxel, for unresectable locally advanced or metastatic TNBC with PD-L1 expression ≥1%, in patients who have not had chemotherapy for metastatic disease.
• Hepatocellular carcinoma (HCC): with bevacizumab, for advanced or unresectable HCC in patients without prior systemic therapy.

• Hypersensitivity to atezolizumab or to any of the excipients.

With atezolizumab alone (pooled data, 5,039 patients), the most common side effects were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%) and nausea (18.8%). Frequencies with monotherapy:

Very common (≥1/10): urinary tract infection, anaemia, decreased appetite, headache, dyspnoea, cough, nausea, vomiting, diarrhoea, rash, pruritus, arthralgia, back pain, pyrexia, fatigue, asthenia.

Common (≥1/100 to <1/10): thrombocytopenia, neutropenia, infusion-related reaction, hypothyroidism, hyperthyroidism, hypokalaemia, hyponatraemia, hyperglycaemia, hypoalbuminaemia, hypophosphataemia, hypocalcaemia, peripheral neuropathy, pericardial disorders, hypotension, pneumonitis, hypoxia, nasopharyngitis, colitis, abdominal pain, dysphagia, oropharyngeal pain, dry mouth, hepatitis, increased AST and ALT, dry skin, musculoskeletal pain, arthritis, increased blood creatinine, influenza-like illness, chills, increased gamma-glutamyl transferase.

Uncommon (≥1/1,000 to <1/100): diabetes mellitus, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, meningoencephalitis, uveitis, pancreatitis, severe cutaneous adverse reactions, psoriasis, lichen disorders, myositis, tenosynovitis, nephritis, increased blood creatine phosphokinase.

Rare (≥1/10,000 to <1/1,000): cytomegalovirus infection, haemophagocytic lymphohistiocytosis, autoimmune haemolytic anaemia, sarcoidosis, myasthenic syndrome, facial paresis, myelitis, myocarditis, coeliac disease, pemphigoid.

Not known: noninfective cystitis.

With monotherapy, hypothyroidism occurred in 8.5% of patients, pneumonitis in 3.0% and hepatitis in 1.7% (three fatal cases each), hyperthyroidism in 2.4% and colitis in 1.2%.

In combination therapy (4,535 patients), the most common side effects (20% or more) were anaemia (36.8%), neutropenia (36.6%), nausea, fatigue, alopecia, rash, diarrhoea, thrombocytopenia, constipation, decreased appetite and peripheral neuropathy; reactions of the partner medicines can also occur. In first-line NSCLC, adding bevacizumab to atezolizumab, paclitaxel and carboplatin increased grade 3–4 events (63.6% compared with 57.5%) and fatal events (6.1% compared with 2.5%), with more epistaxis, haemoptysis and cerebrovascular accident. Immune-mediated reactions were more frequent in the adjuvant NSCLC study (51.7%) than in advanced disease (38.4%).

• No metabolic interactions expected: no formal studies have been done; atezolizumab is cleared by catabolism, so metabolic drug–drug interactions are not expected.
• Systemic corticosteroids and immunosuppressants: avoid them before starting treatment, as they may interfere with the pharmacodynamic activity and efficacy of atezolizumab. Once treatment has started, they can be used to treat immune-mediated reactions.
• Combination partners: the interactions and warnings of bevacizumab, paclitaxel, nab-paclitaxel, carboplatin and etoposide also apply (see their SmPCs).

Treatment must be started and supervised by a physician experienced in cancer treatment, and the infusions are given by healthcare professionals.

Recommended Dose

• 840 mg every 2 weeks, 1,200 mg every 3 weeks or 1,680 mg every 4 weeks by intravenous infusion, alone or in any of the combinations. When the medicines are given on the same day, atezolizumab is given first; the partner medicines are dosed according to their own SmPCs.
• Solution for injection (subcutaneous): 1,875 mg every 3 weeks by subcutaneous injection, for the same indications and alone or with the same partner medicines. As with the infusion, atezolizumab is given first when the medicines are given on the same day.
• With bevacizumab, paclitaxel and carboplatin (NSCLC): bevacizumab, paclitaxel and then carboplatin every 3 weeks for four or six induction cycles, then maintenance with bevacizumab every 3 weeks.
• With nab-paclitaxel and carboplatin (NSCLC): both on day 1, with nab-paclitaxel also on days 8 and 15 of each 3-weekly cycle, for four or six induction cycles.
• With carboplatin and etoposide (ES-SCLC): both on day 1, with etoposide also on days 2 and 3 of each 3-weekly cycle, for four induction cycles.
• With nab-paclitaxel (TNBC): nab-paclitaxel 100 mg/m² on days 1, 8 and 15 of each 28-day cycle.
• With bevacizumab (HCC): bevacizumab 15 mg/kg body weight every 3 weeks.

Duration of Treatment

• Until disease progression or unmanageable toxicity: first-line urothelial carcinoma, first-line NSCLC monotherapy (including platinum-ineligible patients), the NSCLC and ES-SCLC combinations, and TNBC.
• Until loss of clinical benefit or unmanageable toxicity: previously treated urothelial carcinoma and NSCLC, and HCC.
• Adjuvant early-stage NSCLC: 1 year, unless the disease recurs or toxicity is unacceptable; longer treatment has not been studied.
• In the NSCLC and ES-SCLC combinations, atypical responses (initial progression, then tumour shrinkage) have been seen, so treatment beyond progression may be considered at the physician’s discretion.

Dose Changes and Missed Doses

• Dose reductions are not recommended. Depending on the type and severity of an adverse reaction, treatment is withheld or stopped permanently (Table 2 of the SmPC; see Special Instructions).
• A missed dose should be given as soon as possible, and the schedule adjusted to keep the correct interval between doses.

Special Populations

• Elderly (65 years or older): no dose adjustment.
• Asian patients: in the bevacizumab, paclitaxel and carboplatin regimen, the recommended starting dose of paclitaxel is 175 mg/m² every 3 weeks, because haematological toxicity was higher in the IMpower150 study.
• Renal impairment: no adjustment in mild or moderate impairment; data in severe impairment are too limited.
• Hepatic impairment: no adjustment in mild or moderate impairment; not studied in severe impairment.
• ECOG performance status ≥2: such patients were excluded from the trials in TNBC, ES-SCLC, previously treated urothelial carcinoma and HCC.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Method of Administration

The concentrate is given by intravenous infusion only, after dilution to a final concentration of 3.2–16.8 mg/mL, and never as an intravenous push or bolus. The first infusion is given over 60 minutes and, if well tolerated, later infusions over 30 minutes. The concentrate is not for subcutaneous use.

The solution for injection is for subcutaneous use only and must not be given intravenously. A volume of 15 mL is injected into the thigh over about 7 minutes, preferably through a subcutaneous infusion set (winged or butterfly type); the small volume left in the tubing is not given to the patient. The injection site is alternated between the left and right thigh only, each new injection is given at least 2.5 cm from the previous one, and it is never given where the skin is red, bruised, tender or hard. During the course, other medicines for subcutaneous use should preferably be injected at different sites.

Patients can switch from the infusion to the solution for injection and back, so the label must be checked to make sure the prescribed formulation is given.

Immune-Mediated Adverse Reactions

These can affect any organ, several at once, and can occur after the last dose. Most were reversible with interruption of treatment and corticosteroids and/or supportive care.

• Suspected reactions need evaluation to confirm the cause or rule out others. Depending on severity, atezolizumab is withheld and corticosteroids are given (usually prednisone 1–2 mg/kg per day or equivalent), tapered over at least 1 month once the reaction has improved to grade 1 or lower; other immunosuppressants may be considered if corticosteroids fail.
• Treatment can usually resume if the reaction improves to grade 1 or lower within 12 weeks and the corticosteroid dose is 10 mg prednisone (or equivalent) per day or less.
• Treatment is stopped permanently for a grade 3 reaction that recurs and for any grade 4 reaction, except endocrinopathies controlled with replacement hormones.
• Patients receive a patient card to carry at all times and should report new symptoms promptly, such as cough, breathlessness, diarrhoea, abdominal pain, yellowing of the skin, unusual tiredness, headache, muscle weakness, chest pain or rash.

Pneumonitis, Hepatitis and Colitis

• Pneumonitis (including fatal cases): withhold for grade 2; stop permanently for grade 3 or 4.
• Hepatitis (some fatal): AST, ALT and bilirubin are checked before treatment and periodically. Without HCC, withhold if a grade 2 event (ALT or AST more than 3 to 5 times the upper limit of normal, or bilirubin more than 1.5 to 3 times) lasts more than 5 to 7 days, and stop permanently for grade 3 or 4 (ALT or AST more than 5 times, or bilirubin more than 3 times the upper limit). In HCC, the withholding thresholds depend on baseline values, and treatment is stopped if ALT or AST exceeds 10 times the upper limit or bilirubin 3 times.
• Colitis: withhold for grade 2 or 3 diarrhoea (4 or more stools a day above baseline) or symptomatic colitis, with corticosteroids (intravenous for grade 3); stop permanently for grade 4. Gastrointestinal perforation is a possible complication.

Endocrine Disorders

Thyroid function is checked before and periodically during treatment; abnormal tests without symptoms do not prevent treatment. Symptomatic hypothyroidism or hyperthyroidism is treated with hormone replacement or an anti-thyroid medicine while atezolizumab is withheld. Adrenal insufficiency and grade 2 or 3 hypophysitis are managed by withholding treatment and giving intravenous corticosteroids and hormone replacement as needed; grade 4 hypophysitis requires permanent discontinuation. In type 1 diabetes, insulin is started and atezolizumab is withheld for grade 3 or higher hyperglycaemia (fasting glucose above 13.9 mmol/L) until metabolic control is achieved.

Other Immune-Mediated Reactions

• Permanent discontinuation: any grade of meningoencephalitis, myasthenic syndrome or Guillain-Barré syndrome; grade 2–4 myelitis; grade 2 or higher myocarditis or pericardial disorders; suspected haemophagocytic lymphohistiocytosis; confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis.
• Withholding first: grade 2 nephritis, grade 2 or 3 myositis, grade 2 or 3 pancreatitis (or amylase or lipase above 2 times the upper limit), grade 3 skin reactions and grade 1 or 2 facial paresis; higher grades or recurrence lead to permanent discontinuation.
• Overlap syndrome: myocarditis, myositis and myasthenia gravis can occur together, sometimes fatally, so a patient with one is monitored for the other two.
• Uveitis, noninfective cystitis and autoimmune haemolytic anaemia may also occur.

Infusion-Related Reactions

Infusion-related reactions, including anaphylaxis, can occur. For grade 1 or 2 reactions the infusion is slowed or interrupted, and premedication with an antipyretic and antihistamines may be considered; grade 3 or 4 reactions require permanent discontinuation.

Precautions in Specific Settings

• With bevacizumab, paclitaxel and carboplatin: the combined risks of the four-drug regimen should be weighed. Patients with clear tumour infiltration into the great vessels of the chest or clear cavitation of lung lesions were excluded from the pivotal trial after fatal pulmonary haemorrhages.
• With bevacizumab in HCC: bleeding risk is increased, including fatal gastrointestinal haemorrhage, so oesophageal varices are screened for and treated before starting, and blood glucose is monitored. Data in Child-Pugh B liver disease are very limited, and there are none in Child-Pugh C.
• First-line monotherapy in NSCLC: the effect starts with a delay; more deaths occurred in the first 2.5 months than with chemotherapy, followed by a long-term survival benefit.
• Cisplatin-ineligible urothelial carcinoma: use with caution in patients unfit for any chemotherapy.
• Autoimmune disease: observational data suggest a higher risk of immune-mediated reactions with checkpoint inhibitors, and flares of the underlying disease were frequent, though mostly mild and manageable. Patients with autoimmune disease, prior pneumonitis, active brain metastases, HIV or hepatitis B or C infection (outside HCC) or significant cardiovascular disease were excluded from the trials.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for 5 months after it.
• Pregnancy: there are no human data. In mouse pregnancy models, blocking the PD-L1/PD-1 pathway caused immune-mediated rejection of the foetus and foetal death, and IgG1 antibodies cross the placenta. Atezolizumab could cause foetal harm, including miscarriage or stillbirth, and should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: as an antibody, it is expected in the first milk and at low levels afterwards; a decision is made between stopping breastfeeding and stopping treatment.
• Fertility: no clinical data are available. In a 26-week animal toxicity study, atezolizumab reversibly affected menstrual cycles at about 6 times the human exposure; male reproductive organs were not affected.

Polysorbate 20 and Traceability

Each 840 mg vial contains 5.6 mg and each 1,200 mg vial 8 mg of polysorbate 20 (0.4 mg/mL), and each 1,875 mg vial of solution for injection contains 9 mg; polysorbate 20 may cause allergic reactions. As for all biological medicines, the product name and batch number should be recorded.

Effect on Driving

Atezolizumab has a minor influence on the ability to drive and use machines. Patients who feel tired should not drive or use machines until the symptoms have passed.

Store unopened Tecentriq vials (both the infusion concentrate and the solution for injection) in a refrigerator at 2–8 °C, in the outer carton to protect them from light. Do not freeze. The vials travel in an unbroken cold chain to the pharmacy that prepares the infusion.

After dilution, in-use stability has been shown for up to 24 hours at up to 30 °C and up to 30 days at 2–8 °C. Microbiologically, the solution should be used immediately; otherwise it would normally be kept no longer than 24 hours at 2–8 °C or 8 hours at room temperature (up to 25 °C), unless diluted under controlled and validated aseptic conditions.

Once the solution for injection has been drawn from the vial into the syringe, it is physically and chemically stable for up to 30 days at 2–8 °C and for up to 8 hours at up to 30 °C in diffuse daylight. Because it contains no antimicrobial preservative, it should be used immediately; otherwise in-use storage is the user’s responsibility and would not normally exceed 24 hours at 2–8 °C, unless the syringe was prepared under controlled and validated aseptic conditions.

Unopened vial: 3 years (concentrate and solution for injection). Do not use after the expiry date on the carton.

Prescription only (Rx). Treatment is started and supervised by a physician experienced in cancer treatment. Atezolizumab is given as an intravenous infusion by healthcare professionals, so it is supplied to the hospital or clinic that administers it, in a refrigerated cold chain (2–8 °C). Each pack of the concentrate contains one 14 mL or 20 mL vial.