Brentuximab Vedotin

Brentuximab vedotin is an antibody-drug conjugate (ADC). It joins a chimeric human–murine IgG1 antibody directed against CD30, produced in Chinese hamster ovary cells, to the antimicrotubule agent monomethyl auristatin E (MMAE) through a protease-cleavable linker. Classical Hodgkin lymphoma, systemic anaplastic large cell lymphoma (sALCL) and subtypes of cutaneous T-cell lymphoma (CTCL), including mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, carry CD30 on the surface of their malignant cells, whatever the stage of disease, the line of therapy or the transplant status. Because CD30 stays present in disease that no longer responds to multi-agent chemotherapy, it provides the biological rationale for use in relapsed and refractory disease.

Mechanism of Action

• Targeting: the antibody part binds CD30 on the tumour cell surface. The ADC–CD30 complex is then taken into the cell and carried to the lysosomal compartment.
• Release of MMAE: inside the cell, proteolytic cleavage of the linker frees MMAE, the single defined active species.
• Microtubule disruption: MMAE binds tubulin and breaks down the microtubule network of the cell. The cell cycle stops (at the transition from G2 to mitosis) and the CD30-expressing cell dies by apoptosis.
• Other antibody functions: a contribution from other antibody-associated functions has not been excluded.
• Cardiac electrophysiology: in an open-label study of 46 patients with CD30-expressing haematological malignancies given 1.8 mg/kg, the mean QTc interval did not rise by more than 10 ms from baseline.

Pharmacokinetics

• Exposure: the product is infused, so absorption does not apply. Conjugate concentrations peak at or near the end of the infusion and then fall in a multi-exponential pattern. Exposure is roughly proportional to dose, there is minimal or no accumulation of the conjugate on the 3-weekly schedule, and steady state is reached within 21 days. After a single 1.8 mg/kg dose in a phase 1 study, the typical conjugate Cmax was about 31.98 µg/mL and the AUC about 79.41 µg × day/mL.
• MMAE: MMAE is the major metabolite. After a single 1.8 mg/kg dose, median Cmax was about 4.97 ng/mL, AUC about 37.03 ng × day/mL and Tmax about 2 days. With repeated doses MMAE exposure falls to about 50–80% of the first-dose exposure. In the first cycle, higher MMAE exposure went with a larger absolute fall in neutrophil count.
• Distribution: in vitro, 68–82% of MMAE is bound to human plasma proteins; it is unlikely to displace, or be displaced by, highly protein-bound medicines. MMAE is a substrate of P-glycoprotein but not a potent inhibitor of it.
• Metabolism: only a small fraction of the released MMAE is metabolised, mainly by CYP3A4/5 oxidation in vitro. The main further metabolite is equally potent but its exposure is about ten times lower, so it adds little. In vitro, MMAE inhibits CYP3A4/5 but no other CYP isoform, and does not induce the major CYP450 enzymes.
• Elimination: the conjugate has a terminal half-life of about 4–6 days. About 24% of the MMAE given as part of the conjugate was recovered in urine and faeces over 7 days, about 72% of it in faeces and mostly unchanged; the liver is the main route of MMAE clearance. With 1.2 mg/kg every 2 weeks (AVD regimen), half-lives were about 4–5 days for the conjugate and 3–4 days for MMAE, and steady-state trough levels were reached by cycle 3.
• Special populations: MMAE exposure (AUC) was about 2.2 times higher in patients with hepatic impairment than in those with normal liver function. In a small study at 1.2 mg/kg, grade 3 or higher reactions occurred in all 6 patients with moderate or severe hepatic impairment, against 3 of 8 with normal liver function (see Administration and Dosage for the reduced starting dose).

Brentuximab vedotin is authorised for adults only.

• Previously untreated Hodgkin lymphoma (with AVD): adults with previously untreated CD30-positive Stage III or IV Hodgkin lymphoma (HL), in combination with doxorubicin, vinblastine and dacarbazine (AVD).
• Previously untreated Hodgkin lymphoma (with BrECADD): adults with previously untreated CD30-positive Stage IIB with risk factors, Stage III or Stage IV HL, in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (BrECADD).
• Hodgkin lymphoma at increased risk of relapse or progression: adults with CD30-positive HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT).
• Relapsed or refractory Hodgkin lymphoma: adults with relapsed or refractory CD30-positive HL (1) following ASCT, or (2) following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
• Systemic anaplastic large cell lymphoma (sALCL): adults with previously untreated sALCL, in combination with cyclophosphamide, doxorubicin and prednisone (CHP); and adults with relapsed or refractory sALCL.
• Cutaneous T-cell lymphoma (CTCL): adults with CD30-positive CTCL after at least one prior systemic therapy.

• Hypersensitivity to brentuximab vedotin or to any of the excipients (citric acid monohydrate, sodium citrate dihydrate, α,α-trehalose dihydrate, polysorbate 80).
• Combined use with bleomycin, because the combination causes pulmonary toxicity.

The safety profile comes from clinical trials, a named patient programme and post-marketing experience. In the pooled monotherapy data, the most frequent reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, neutropenia, upper respiratory tract infection, arthralgia, rash, cough, vomiting, pruritus, peripheral motor neuropathy, infusion-related reactions, constipation, dyspnoea, myalgia, weight decreased and abdominal pain. Serious adverse drug reactions occurred in 12% of patients on monotherapy, and adverse events led to discontinuation in 24%. With chemotherapy combinations (AVD or CHP), serious adverse reactions occurred in 34% of patients, most often febrile neutropenia (15%), pyrexia (5%) and neutropenia (3%), and adverse events led to discontinuation in 10%. The groups below describe monotherapy; differences in combination therapy are noted.

Very common (≥1/10): infection, upper respiratory tract infection, neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, cough, dyspnoea, nausea, diarrhoea, vomiting, constipation, abdominal pain, rash, pruritus, arthralgia, myalgia, fatigue, pyrexia, infusion-related reactions, weight decreased. With chemotherapy combinations, anaemia, febrile neutropenia, decreased appetite, insomnia, dizziness, stomatitis, alopecia, bone pain and back pain are also very common, while pruritus and infusion-related reactions are common.

Common (≥1/100 to <1/10): herpes zoster, pneumonia, herpes simplex, oral candidiasis, anaemia, thrombocytopenia, hyperglycaemia, dizziness, increased alanine and aspartate aminotransferase, alopecia, back pain, chills. With chemotherapy combinations, sepsis or septic shock, pruritus and infusion-related reactions are common as well.

Uncommon (≥1/1,000 to <1/100): Pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, cytomegalovirus infection or reactivation, sepsis or septic shock, febrile neutropenia, anaphylactic reaction, tumour lysis syndrome, demyelinating polyneuropathy, acute pancreatitis, Stevens-Johnson syndrome or toxic epidermal necrolysis. With chemotherapy combinations, herpes simplex and Pneumocystis jiroveci pneumonia are uncommon, as are anaphylactic reaction, tumour lysis syndrome, acute pancreatitis and Stevens-Johnson syndrome (toxic epidermal necrolysis was not reported in the combination setting).

Not known: progressive multifocal leukoencephalopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), and infusion site extravasation (which can cause redness, pain, swelling, blistering, exfoliation or cellulitis at or around the infusion site).

Important serious reactions:

• Peripheral neuropathy: with monotherapy, treatment-emergent neuropathy occurred in 57% of patients (peripheral motor neuropathy in 13%), with a median onset of 12 weeks. It led to discontinuation in 15%, dose reduction in 15% and dose delay in 16%. With combinations, neuropathy occurred in 67% (AVD) and 52% (CHP) of patients, and sensory neuropathy in 38.8% with BrECADD. Among patients followed after treatment, most had improvement or resolution (82–85% after monotherapy, 86% after AVD).
• Neutropenia: with monotherapy, grade 3 neutropenia occurred in 13% and grade 4 in 5%. With AVD or CHP, grade 3 occurred in 17% and grade 4 in 41%; febrile neutropenia occurred in 20% of patients without primary G-CSF prophylaxis and 13% with it. With BrECADD (all patients on G-CSF prophylaxis), febrile neutropenia occurred in 26.5%.
• Infections: serious and opportunistic infections occurred in 10% of patients on monotherapy (sepsis or septic shock in under 1%) and in 15% on AVD or CHP (sepsis, neutropenic sepsis, septic shock or bacteraemia in 4%). Herpes zoster and herpes simplex were the most common opportunistic infections.
• Infusion-related reactions: reported in 12% (monotherapy) and 8% (AVD or CHP) of patients; anaphylactic reactions have been reported. Reactions were more frequent in patients with persistently positive antibodies to the conjugate.
• BrECADD regimen: serious adverse reactions occurred in 39.4% of patients (36.4% with the comparator eBEACOPP), most often febrile neutropenia (19.3%), pyrexia (3.9%) and neutropenia (3.2%). Serious cardiac reactions occurred in 2.7%.
• Older patients: on monotherapy, elderly patients may be more susceptible to pneumonia, neutropenia and febrile neutropenia. With combinations, patients aged 60 years or older had more serious events and dose modifications, and advanced age was a risk factor for febrile neutropenia.

Interactions concern MMAE, the active payload released from the conjugate.

• Strong CYP3A4 and P-glycoprotein inhibitors (for example ketoconazole): MMAE exposure rose by about 73% without any change in exposure to the conjugate, so neutropenia may become more frequent. If neutropenia develops, follow the neutropenia dosing recommendations (see Administration and Dosage).
• Strong CYP3A4 inducers (for example rifampicin): exposure to the conjugate did not change; limited data suggest lower concentrations of the MMAE metabolites that could be measured.
• Medicines metabolised by CYP3A4: a study with a CYP3A4 probe substrate showed no change in its metabolism, so brentuximab vedotin is not expected to alter exposure to such medicines.
• Bleomycin: contraindicated, because combined use causes pulmonary toxicity.
• AVD (doxorubicin, vinblastine, dacarbazine) and CHP (cyclophosphamide, doxorubicin, prednisone): the pharmacokinetics of the conjugate and of MMAE were similar to those on monotherapy. Brentuximab vedotin did not affect exposure to AVD and is not expected to affect exposure to CHP.
• Grapefruit and St John’s wort: grapefruit inhibits CYP3A4 and may raise MMAE concentrations; St John’s wort induces CYP3A4 and may lower them. Caution is advised with both.

Treatment must be given under the supervision of a physician experienced in the use of anti-cancer agents. The dose is calculated from body weight (above 100 kg, 100 kg is used in the calculation) and infused intravenously over 30 minutes through a dedicated line. It must not be given as an intravenous push or bolus and must not be mixed with other medicinal products. The powder is reconstituted and diluted before use (see SmPC section 6.6). Complete blood counts are checked before each dose, and patients are observed during and after the infusion.

Recommended Dose

• Previously untreated HL with AVD: 1.2 mg/kg on days 1 and 15 of each 28-day cycle, for 6 cycles. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) from the first dose is recommended.
• Previously untreated HL with BrECADD: 1.8 mg/kg every 3 weeks, for up to 6 cycles. G-CSF primary prophylaxis must be given from day 5 of each cycle, and antibiotic prophylaxis 3 times a week throughout chemotherapy. Dexamethasone for 4 days before the first cycle is recommended for patients over 40 years or at the physician’s discretion.
• HL at increased risk of relapse or progression: 1.8 mg/kg every 3 weeks, starting after recovery from ASCT on clinical judgement, for up to 16 cycles.
• Relapsed or refractory HL or sALCL: 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Patients who reach stable disease or better receive a minimum of 8 and up to 16 cycles (about 1 year). For retreatment of patients who responded before, the starting dose is 1.8 mg/kg, or alternatively the last tolerated dose.
• Previously untreated sALCL with CHP: 1.8 mg/kg every 3 weeks for 6 to 8 cycles, with G-CSF primary prophylaxis from the first dose recommended.
• CTCL: 1.8 mg/kg every 3 weeks, for up to 16 cycles.
• Partner chemotherapy is given as set out in its own SmPC; the SmPC of Adcetris lists the BrECADD dose levels.

Dose Adjustments

• Neutropenia on monotherapy: grade 1 or 2 (neutrophils down to 1,000/mm³) needs no change. For grade 3 or 4 (below 1,000/mm³), withhold the dose until recovery to grade 2 or baseline, then resume at the same dose and schedule; G-CSF or GM-CSF can be considered in later cycles. Grade 3 or 4 lymphopenia does not require interruption.
• Neutropenia with AVD or CHP: primary G-CSF prophylaxis is recommended from the first dose, and the dose and schedule continue unchanged.
• Blood counts with BrECADD: treatment is withheld when counts fall below the SmPC thresholds, until recovery, and may then be resumed at a reduced 1.2 mg/kg (maximum 120 mg) every 3 weeks. The partner drugs are reduced one dose level after a cycle with specified events (for example leukopenia for more than 4 days, thrombocytopenia, grade 4 infection or other grade 4 toxicity, or a delay of more than 2 weeks for blood-count recovery) and to the lowest level if events occur in two successive cycles.
• Peripheral neuropathy on monotherapy: grade 1 needs no change. For grade 2 or 3, withhold the dose until recovery to grade 1 or baseline, then restart at 1.2 mg/kg (maximum 120 mg) every 3 weeks. Grade 4: discontinue.
• Peripheral neuropathy with combinations: each regimen has its own steps (for example, with AVD, grade 2 calls for a reduction to 0.9 mg/kg, maximum 90 mg, every 2 weeks). Grade 4 requires discontinuation in every regimen.

Special Populations

• Renal impairment: on monotherapy, the starting dose in severe impairment is 1.2 mg/kg every 3 weeks, with close monitoring. In combination with chemotherapy, use should be avoided in severe impairment (no trial experience with serum creatinine of 2.0 mg/dL or more, or creatinine clearance of 40 mL/min or less).
• Hepatic impairment: on monotherapy, the starting dose is 1.2 mg/kg every 3 weeks, with close monitoring. In combination, mild impairment calls for a starting dose of 0.9 mg/kg every 2 weeks with AVD or 1.2 mg/kg every 3 weeks with CHP; use with chemotherapy should be avoided in moderate or severe impairment.
• Elderly: the same dosing as for other adults. Safety and efficacy as part of BrECADD have not been established in patients aged 60 years and older.
• Children and adolescents: safety and efficacy below 18 years have not been established. The SmPC describes the available data but no dose recommendation can be made.

Traceability

Because this is a biological medicinal product, the name and batch number of each administered dose should be clearly recorded.

Progressive Multifocal Leukoencephalopathy

Reactivation of the John Cunningham virus (JCV) can cause PML, a rare and often fatal demyelinating disease of the central nervous system, in treated patients. Cases were reported in people who had received multiple earlier chemotherapy regimens. Patients should be monitored closely for new or worsening neurological, cognitive or behavioural signs and symptoms, some of which the patient may not notice. Treatment is held for any suspected case. Evaluation can include neurology consultation, gadolinium-enhanced MRI of the brain, and cerebrospinal fluid testing for JCV DNA by PCR or a brain biopsy; a negative PCR does not exclude PML. Treatment is permanently discontinued if PML is confirmed.

Peripheral Neuropathy

Peripheral sensory and motor neuropathy is among the most frequent toxicities (see Side Effects). Patients should report new or worsening numbness, tingling, pain or weakness to the treating team. New or worsening neuropathy is managed by delaying a dose, reducing it or stopping treatment, depending on the grade (see Administration and Dosage).

Neutropenia and Infections

Severe and prolonged (1 week or longer) neutropenia can occur and may raise the risk of serious infection. Blood counts are checked before every dose. Serious and opportunistic infections have been reported, including pneumonia, staphylococcal bacteraemia, sepsis or septic shock (with fatal outcomes), herpes zoster, cytomegalovirus reactivation, Pneumocystis jiroveci pneumonia and oral candidiasis. Patients should be monitored carefully for them during treatment.

Infusion-Related Reactions

Immediate and delayed infusion-related reactions and anaphylactic reactions have been reported. Patients are observed closely during and after each infusion. If an anaphylactic reaction occurs, the infusion is stopped immediately and permanently and appropriate medical treatment is given.

Acute Pancreatitis

Acute pancreatitis, sometimes fatal, has been observed. Patients should be monitored for new or worsening abdominal pain. Evaluation can include examination, serum amylase and lipase, and abdominal imaging. Treatment is held for any suspected case and discontinued if the diagnosis is confirmed.

Pulmonary Toxicity

Pneumonitis, interstitial lung disease and acute respiratory distress syndrome, some with fatal outcomes, have been reported. A causal link has not been established but the risk cannot be ruled out. New or worsening respiratory symptoms (for example cough or dyspnoea) need prompt evaluation, and dosing can be held during evaluation and until symptoms improve. Combined use with bleomycin is contraindicated.

Other Serious Reactions

The SmPC also lists tumour lysis syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis, DRESS, hyperglycaemia and raised liver enzymes among reported reactions (see Side Effects).

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use two methods of effective contraception during treatment and for 6 months afterwards.
• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Brentuximab vedotin should not be used in pregnancy unless the benefit to the mother outweighs the possible risk to the foetus; a pregnant woman who needs treatment should be clearly advised of that risk.
• Breastfeeding: it is not known whether brentuximab vedotin or its metabolites pass into human milk, and a risk to the infant cannot be excluded. A decision is made whether to stop breastfeeding or to stop or avoid the treatment.
• Fertility: animal studies showed testicular toxicity, so male fertility may be affected, and MMAE has aneugenic properties. Men are advised to have sperm samples frozen and stored before treatment, and not to father a child during treatment and for up to 6 months after the last dose.

Excipients

Each vial contains about 13.2 mg of sodium and about 2 mg of polysorbate 80.

Effect on Driving

Brentuximab vedotin may have a moderate influence on the ability to drive and use machines, for example through dizziness.

Adcetris vials are stored in a refrigerator at 2–8 °C and must not be frozen. Keep the vial in the original carton to protect it from light. The cold chain applies from dispatch to administration: the product stays at 2–8 °C during transport and hospital storage. After reconstitution and dilution (see SmPC section 6.6), the solution should be used immediately; chemical and physical stability in use has been shown for 24 hours at 2–8 °C.

4 years for the unopened vial stored as above. After reconstitution and dilution, the product should be used immediately from a microbiological point of view; in-use stability has been demonstrated for 24 hours at 2–8 °C.

Prescription only (Rx), on restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in the use of anti-cancer agents. Brentuximab vedotin is given as an infusion in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.