Durvalumab

Durvalumab is a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that selectively blocks programmed death-ligand 1 (PD-L1). Many tumours use PD-L1 to escape the immune system; by blocking it, durvalumab restores the activity of T cells against the tumour.

Mechanism of Action

• Immune escape through PD-L1: PD-L1 expression is an adaptive immune response. Inflammatory signals such as interferon gamma induce it on tumour cells and on tumour-associated immune cells.
• Checkpoint signalling: PD-L1 binds PD-1 and CD80 (B7.1) on T cells, which lowers cytotoxic T-cell activity, proliferation and cytokine production.
• Blockade: durvalumab blocks the interaction of PD-L1 with PD-1 and with CD80, which enhances anti-tumour immune responses and increases T-cell activation. It acts on PD-L1 selectively and does not target PD-L2.
• No cell killing by the antibody: durvalumab does not induce antibody-dependent cell-mediated cytotoxicity.
• With tremelimumab: tremelimumab, a CTLA-4 inhibitor, adds to the effect at a different stage of the immune response; dual PD-L1 and CTLA-4 blockade enhanced anti-tumour activity in mouse tumour models.
• Dose schedules: modelling of exposure, safety and efficacy found no expected clinically significant difference between 10 mg/kg every 2 weeks, 1,120 mg every 3 weeks and 1,500 mg every 4 weeks.

Pharmacokinetics

• Absorption and exposure: given intravenously. Across 0.1–20 mg/kg exposure rises more than in proportion to the dose below 3 mg/kg and in proportion to the dose from 3 mg/kg upwards. Steady state is reached after about 16 weeks.
• Distribution: steady-state volume of distribution about 5.64 L.
• Metabolism and elimination: removed mainly by protein breakdown in the reticuloendothelial system and by target-mediated disposition. Clearance falls over time to about 8.16 mL/h at day 365, a change that is not clinically relevant. The terminal half-life is about 18 days.
• Combinations: the pharmacokinetics were not clinically different when given alone or with chemotherapy, tremelimumab or olaparib.
• Special populations: age (19–96 years), body weight (31–149 kg), sex, anti-drug antibodies, albumin, LDH, creatinine, soluble PD-L1, tumour type, race and ECOG status had no clinically significant effect. Mild and moderate renal impairment did not change exposure; severe impairment has not been studied, but a change in renal function is not expected to affect exposure, because IgG antibodies are not cleared mainly by the kidney.

Durvalumab is indicated in adults:

• Non-small cell lung cancer (NSCLC):
  • in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by durvalumab alone as adjuvant treatment, for resectable NSCLC at high risk of recurrence with no EGFR mutations or ALK rearrangements;
  • as monotherapy for locally advanced, unresectable NSCLC whose tumours express PD-L1 on at least 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation therapy;
  • in combination with tremelimumab and platinum-based chemotherapy as first-line treatment of metastatic NSCLC with no sensitising EGFR mutations or ALK-positive mutations.
• Small cell lung cancer (SCLC):
  • as monotherapy for limited-stage SCLC (LS-SCLC) whose disease has not progressed after platinum-based chemoradiation therapy;
  • in combination with etoposide and either carboplatin or cisplatin as first-line treatment of extensive-stage SCLC (ES-SCLC).
• Biliary tract cancer (BTC): in combination with gemcitabine and cisplatin as first-line treatment of unresectable or metastatic disease.
• Hepatocellular carcinoma (HCC): as first-line treatment of advanced or unresectable HCC, either as monotherapy or in combination with tremelimumab.
• Endometrial cancer: in combination with carboplatin and paclitaxel as first-line treatment of primary advanced or recurrent endometrial cancer in patients who are candidates for systemic therapy, followed by maintenance treatment with durvalumab alone in mismatch repair deficient (dMMR) disease, or with durvalumab plus olaparib in mismatch repair proficient (pMMR) disease.
• Muscle invasive bladder cancer (MIBC): in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by durvalumab alone as adjuvant treatment after radical cystectomy, for resectable MIBC.
• Gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJC): in combination with FLOT chemotherapy as neoadjuvant and adjuvant treatment, followed by adjuvant durvalumab alone, for resectable disease.

• Hypersensitivity to durvalumab or to any of the excipients.

With durvalumab alone (4,642 patients across tumour types), the most common reactions (more than 10%) were cough or productive cough (18.1%), diarrhoea (15.1%), rash (15.0%), pyrexia (12.5%), arthralgia (12.4%), abdominal pain (11.8%), upper respiratory tract infections (11.8%), hypothyroidism (11.6%) and pruritus (11.1%). The most common reactions of grade 3 or higher (more than 2%) were pneumonia (3.4%) and raised AST or ALT (2.5%). Treatment was stopped for adverse reactions in 3.9% of patients, most often for pneumonitis (1.1%) and pneumonia (0.8%). In hepatocellular carcinoma, raised AST or ALT (20.3%) and abdominal pain (17.9%) were the most common.

With chemotherapy (2,244 patients), the most common reactions were neutropenia (44.6%), nausea (42.4%), fatigue (41.2%) and anaemia (37.4%), and treatment was stopped in 6.2%. With tremelimumab and platinum-based chemotherapy (330 patients), they were anaemia (49.7%), nausea (41.5%), neutropenia (41.2%) and fatigue (36.1%). With a single dose of tremelimumab 300 mg in liver cancer (462 patients), they were rash (32.5%), pruritus (25.5%), diarrhoea (25.3%) and abdominal pain (19.7%). With olaparib maintenance in endometrial cancer, they were anaemia (61.8%), nausea (54.6%), fatigue (54.2%) and peripheral neuropathy (51.7%).

Very common (≥1/10): upper respiratory tract infections, hypothyroidism, cough or productive cough, diarrhoea, abdominal pain, rash, pruritus, arthralgia, pyrexia. In combination regimens, also anaemia, neutropenia, thrombocytopenia, leukopenia, decreased appetite, peripheral neuropathy, nausea, vomiting, constipation, raised AST or ALT, alopecia, fatigue and peripheral oedema.

Common (≥1/100 to <1/10): pneumonia, influenza, oral candidiasis, dental and oral soft-tissue infections, hyperthyroidism, pneumonitis, dysphonia, hepatitis, raised AST or ALT (alone), night sweats, myalgia, raised blood creatinine, dysuria, peripheral oedema, infusion-related reaction. In combination regimens, also febrile neutropenia, stomatitis, colitis, dermatitis, adrenal insufficiency, thyroiditis, raised amylase and lipase and pancreatitis.

Uncommon (≥1/1,000 to <1/100): immune thrombocytopenia, thyroiditis, adrenal insufficiency, hypophysitis or hypopituitarism, type 1 diabetes mellitus, myasthenia gravis, encephalitis, myocarditis, interstitial lung disease, colitis, pancreatitis, dermatitis, psoriasis, pemphigoid, myositis, immune-mediated arthritis, nephritis, non-infective cystitis. With combinations also pancytopenia, acute myocardial infarction and pulmonary embolism.

Rare (≥1/10,000 to <1/1,000): diabetes insipidus, uveitis, meningitis, coeliac disease, exocrine pancreatic insufficiency, polymyositis, polymyalgia rheumatica; with chemotherapy also deep vein thrombosis and Guillain-Barré syndrome.

Not known: Guillain-Barré syndrome and transverse myelitis (post-marketing); with tremelimumab also intestinal and large intestine perforation.

Immune-mediated reactions with durvalumab alone (pooled data): pneumonitis 3.2% (grade 3 in 0.8%, fatal in 0.2%), hepatitis 2.6%, colitis or diarrhoea 1.7%, hypothyroidism 8.3%, hyperthyroidism 1.6%, thyroiditis 0.5%, adrenal insufficiency 0.5%, nephritis 0.4%, rash or dermatitis 1.6%, type 1 diabetes mellitus 0.1% and infusion-related reactions 1.5%. Most are managed with corticosteroids and treatment modification. With tremelimumab, colitis or diarrhoea (7.3%) and hepatitis (3.5%) were more frequent, and in the liver cancer group hepatitis occurred in 7.4%. Immune-mediated pneumonitis was more frequent in patients who had just completed chemoradiation: 9.9% in the PACIFIC study (locally advanced NSCLC) and 11.8% in the ADRIATIC study (limited-stage SCLC), against 6.0% and 3.0% on placebo.

• Systemic corticosteroids and immunosuppressants before starting: not recommended, except a physiological dose (10 mg/day prednisone or equivalent, or less), because they may interfere with the activity and efficacy of durvalumab. After treatment has started, corticosteroids and other immunosuppressants can be used to treat immune-mediated reactions.
• Pharmacokinetic interactions: no formal studies. Because durvalumab is cleared by protein breakdown, no metabolic interactions are expected, and no clinically meaningful interactions were found in combination studies.
• Live attenuated vaccines: patients who received one within 30 days before or after the start of treatment were excluded from the studies; use with caution after weighing benefit and risk.

Treatment should be started and supervised by a physician experienced in cancer treatment. For locally advanced NSCLC, PD-L1 expression must be confirmed by a validated test; for endometrial cancer, mismatch repair status must be confirmed by a validated test. Durvalumab is given as an intravenous infusion over 1 hour, diluted before use (see the SmPC), using separate bags and filters for each infusion. With chemotherapy, durvalumab is given before chemotherapy on the same day; with tremelimumab, tremelimumab is given first, then durvalumab, then chemotherapy if used. Refer to the SmPC of each partner medicine for its dosing.

Recommended Dose by Indication

• Locally advanced NSCLC (monotherapy): 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks, up to a maximum of 12 months.
• Limited-stage SCLC (monotherapy): 1,500 mg every 4 weeks, up to a maximum of 24 months.
• HCC (monotherapy): 1,500 mg every 4 weeks until disease progression or unacceptable toxicity.
• HCC with tremelimumab: 1,500 mg together with a single dose of tremelimumab 300 mg at cycle 1, day 1, then durvalumab alone every 4 weeks.
• Resectable NSCLC: 1,500 mg with platinum-based chemotherapy every 3 weeks for up to 4 cycles before surgery, then 1,500 mg alone every 4 weeks for up to 12 cycles after surgery.
• Metastatic NSCLC: 1,500 mg with tremelimumab 75 mg and platinum-based chemotherapy every 3 weeks for 4 cycles (12 weeks), then 1,500 mg every 4 weeks with histology-based pemetrexed maintenance every 4 weeks; a fifth dose of tremelimumab 75 mg is given at week 16 alongside durvalumab.
• Extensive-stage SCLC: 1,500 mg with etoposide and carboplatin or cisplatin every 3 weeks for 4 cycles, then 1,500 mg alone every 4 weeks.
• Biliary tract cancer: 1,500 mg with gemcitabine and cisplatin every 3 weeks for up to 8 cycles, then 1,500 mg alone every 4 weeks.
• Endometrial cancer: 1,120 mg with carboplatin and paclitaxel every 3 weeks for at least 4 and up to 6 cycles, then 1,500 mg every 4 weeks, alone in dMMR patients or with olaparib 300 mg twice daily in pMMR patients.
• Muscle invasive bladder cancer: 1,500 mg with gemcitabine and cisplatin every 3 weeks for 4 cycles before surgery, then 1,500 mg alone every 4 weeks for up to 8 cycles after surgery.
• Gastric or gastro-oesophageal junction adenocarcinoma: 1,500 mg with FLOT chemotherapy every 4 weeks for up to 2 cycles before surgery, then 1,500 mg with FLOT every 4 weeks for 2 cycles and 1,500 mg alone every 4 weeks for up to 10 cycles, for a total of up to 12 cycles after surgery.
• Duration: until disease progression (or recurrence in the adjuvant phase) or unacceptable toxicity, within the maximum periods above. In locally advanced NSCLC, clinically stable patients with initial evidence of progression are advised to continue until progression is confirmed.
• Low body weight: patients weighing 30 kg or less receive weight-based dosing (10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks alone; 20 mg/kg in combination regimens) until their weight rises above 30 kg. The SmPC gives other weight thresholds for biliary tract cancer and for tremelimumab doses.

Dose Modifications for Side Effects

Dose escalation or reduction is not recommended; treatment is instead withheld or stopped according to the type and grade of the reaction.

• Pneumonitis or interstitial lung disease: grade 2, withhold; grade 3 or 4, discontinue permanently.
• Hepatitis: AST or ALT above 3 and up to 5 times the upper limit of normal (ULN), or bilirubin above 1.5 and up to 3 times ULN, withhold. AST or ALT above 5 and up to 10 times ULN, withhold durvalumab and permanently stop tremelimumab. AST or ALT above 10 times ULN, bilirubin above 3 times ULN, or AST or ALT above 3 times with bilirubin above 2 times ULN, discontinue permanently. Different thresholds apply in liver cancer.
• Colitis or diarrhoea: grade 2, withhold; grade 3 on durvalumab alone, withhold; grade 3 with tremelimumab, stop tremelimumab permanently (durvalumab can be resumed once resolved); grade 4, discontinue permanently. Intestinal perforation of any grade: discontinue permanently.
• Endocrine reactions (grade 2 to 4): hyperthyroidism or thyroiditis, and adrenal insufficiency or hypophysitis/hypopituitarism, call for withholding until clinically stable; hypothyroidism needs no change in treatment. Hormone replacement is given as indicated.
• Nephritis, rash or dermatitis, and other immune-mediated reactions: withhold for moderate reactions (for example grade 2 nephritis with creatinine above 1.5 and up to 3 times ULN, grade 2 rash lasting more than 1 week, or grade 3 rash); discontinue permanently for grade 4 reactions and for severe nephritis.
• Myocarditis, myasthenia gravis, encephalitis, Guillain-Barré syndrome and transverse myelitis: discontinue permanently.
• Infusion-related reactions: grade 1 or 2, interrupt or slow the infusion; grade 3 or 4, discontinue permanently.
• Resuming treatment: after a delay, treatment can be resumed within 12 weeks if the reaction has improved to grade 1 or less and the corticosteroid dose is 10 mg prednisone or equivalent per day or less. Recurrent grade 3 and any grade 4 immune-mediated reaction require permanent discontinuation, except endocrine reactions controlled with replacement hormones.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; data in severe impairment are too limited to draw conclusions.
• Hepatic impairment: no adjustment in mild or moderate impairment; data in severe impairment are too limited to draw conclusions.
• Children and adolescents: safety and efficacy below 18 years have not been established for the authorised indications; no data are available.

Immune-Mediated Reactions

Durvalumab can cause immune-mediated reactions in almost any organ. For suspected reactions the cause should be confirmed or other causes excluded. Depending on severity, durvalumab (and tremelimumab) is withheld or permanently stopped and corticosteroids or endocrine therapy started; once the reaction improves to grade 1 or less, the corticosteroid is tapered over at least 1 month. If the reaction worsens or does not improve, a higher corticosteroid dose or additional immunosuppressants can be considered.

Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease has occurred, and pneumonitis can be hard to tell from radiation pneumonitis. In the PACIFIC study, pneumonitis or radiation pneumonitis occurred in 33.9% of patients on durvalumab and 24.8% on placebo, and in ADRIATIC in 38.2% and 30.2%. Suspected pneumonitis should be confirmed with imaging and other causes excluded. Grade 2 events need prednisone 1–2 mg/kg/day or equivalent, and grade 3 or 4 events methylprednisolone 2–4 mg/kg/day or equivalent, each followed by a taper.

Hepatitis, Colitis and Intestinal Perforation

ALT, AST, total bilirubin and alkaline phosphatase should be checked before treatment and before each infusion. Hepatitis and colitis are treated with prednisone 1–2 mg/kg/day or equivalent followed by a taper. Intestinal perforation has been reported with the tremelimumab combination, and a surgeon should be consulted at once if it is suspected at any grade.

Endocrine Reactions

Hypothyroidism, hyperthyroidism and thyroiditis, adrenal insufficiency, type 1 diabetes mellitus (which can first present as diabetic ketoacidosis) and hypophysitis or hypopituitarism can occur. Thyroid function should be checked before and during treatment, and patients monitored for symptoms of the other conditions. Treatment includes hormone replacement, insulin or corticosteroids as indicated.

Nephritis, Skin Reactions and Myocarditis

Renal function should be checked before and during treatment. Immune-mediated rash or dermatitis, including pemphigoid, has occurred; Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with PD-1 inhibitors. Immune-mediated myocarditis can be fatal; if there is no improvement within 2 to 3 days on corticosteroids, further immunosuppression should be started promptly.

Other Immune-Mediated Reactions

Myasthenia gravis, transverse myelitis, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, immune-mediated arthritis, pancreatitis, uveitis, non-infective cystitis and polymyalgia rheumatica have been seen.

Infusion-Related Reactions

Severe infusion-related reactions have been reported. For grade 1 or 2, premedication can be considered before later infusions.

Pre-Existing Autoimmune Disease

In patients with existing autoimmune disease, observational data suggest a higher risk of immune-related reactions after checkpoint inhibitors; flares of the underlying disease were frequent but mostly mild and manageable.

Disease- and Treatment-Specific Precautions

• Biliary tract cancer: cholangitis and biliary tract infections are not uncommon, mostly with biliary stents (14.5% against 8.2% on placebo plus chemotherapy in TOPAZ-1). Monitor closely before and during treatment.
• Endometrial cancer with olaparib: pure red cell aplasia and autoimmune haemolytic anaemia were reported with olaparib maintenance. If either is confirmed, durvalumab and olaparib should be stopped.
• Metastatic NSCLC in patients aged 75 or over: data are limited for the tremelimumab and chemotherapy regimen; weigh benefit and risk individually.
• Patients excluded from studies: ECOG performance score of 2 or more, active or prior autoimmune disease within 2 years, immunodeficiency, a history of severe immune-mediated reactions, a need for systemic immunosuppression, uncontrolled illness, active tuberculosis, hepatitis B or C or HIV infection. Use with caution after weighing benefit and risk. The safety of prophylactic cranial irradiation given at the same time in extensive-stage SCLC is unknown.

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: no human data. Disrupted PD-L1 signalling increased foetal loss in a mouse pregnancy model, and IgG1 crosses the placenta, so durvalumab may cause foetal harm. It is not recommended in pregnancy or in women of childbearing potential not using effective contraception.
• Breastfeeding: not known whether it passes into human milk; low levels were found in monkey milk. A risk to the breast-fed child cannot be excluded, so a decision must be made between stopping breastfeeding and stopping or abstaining from treatment.
• Fertility: no data in humans or animals.

Traceability

To improve traceability of biological medicines, the trade name and batch number of the administered product should be clearly recorded.

Effect on Driving

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

Store vials in a refrigerator at 2–8 °C. Do not freeze. Keep in the original package to protect from light. Keep the cold chain unbroken during transport and handling. For storage after dilution, see Shelf Life.

• Unopened vial: 3 years.
• Diluted solution: chemical and physical in-use stability has been shown for up to 30 days at 2–8 °C and up to 24 hours at room temperature (up to 25 °C) from preparation. From a microbiological point of view the prepared solution should be used immediately. If it is not, the user is responsible for storage, which would normally not exceed 24 hours at 2–8 °C or 12 hours at room temperature (up to 25 °C), unless dilution was done under controlled and validated aseptic conditions.

Prescription only (Rx); treatment is started and supervised by a physician experienced in cancer treatment. Durvalumab is given as an intravenous infusion in hospital or clinic, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions at 2–8 °C.