Polatuzumab Vedotin

Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate. A humanised IgG1 monoclonal antibody carries the potent anti-mitotic agent monomethyl auristatin E (MMAE), attached by a cleavable linker, to B cells, where it kills the malignant cells. CD79b is a surface component of the B-cell receptor and is found on normal cells of the B-cell lineage (except plasma cells) and on malignant B cells.

Mechanism of Action

• Targeting CD79b: the antibody binds CD79b with high affinity and selectivity. CD79b is expressed in about 95% of diffuse large B-cell lymphomas, and its expression in normal tissue is restricted to B-lineage cells (plasma cells excepted).
• Internalisation and release: after binding, the conjugate is rapidly internalised and lysosomal proteases cleave the linker, releasing MMAE inside the cell.
• Cytotoxic action: MMAE binds to microtubules (tubulin), blocks cell division and induces apoptosis in dividing cells.
• Preclinical activity: in vitro, polatuzumab vedotin was cytotoxic to most diffuse large B-cell lymphoma cell lines, whatever their cell-of-origin subtype and whether or not they carried CD79B mutations.
• Cardiac electrophysiology: at the recommended dose, it did not prolong the mean QTc interval to a clinically relevant extent in two open-label studies in patients with previously treated B-cell malignancies.

Pharmacokinetics

• Dose proportionality: exposure of antibody-conjugated MMAE (acMMAE) rose in proportion to dose over 0.1 to 2.4 mg/kg. After the first 1.8 mg/kg dose, acMMAE peak concentration was 803 ng/mL (± 233) and AUC to infinity was 1,860 day·ng/mL (± 966).
• Accumulation: the Cycle 3 acMMAE AUC was about 30% above Cycle 1 and reached more than 90% of the Cycle 6 AUC. The concentration at the end of Cycle 6 is predicted to be about 80% of the theoretical steady state.
• Unconjugated MMAE: the cytotoxic component. After the first 1.8 mg/kg dose its peak concentration was 6.82 ng/mL (± 4.73), reached at about 2.5 days, with a terminal half-life of about 4 days. Its plasma exposure is below 3% of acMMAE exposure and falls with repeated three-weekly dosing. In patients over 100 kg, exposure to unconjugated MMAE is predicted to be increased by not more than 55%.
• Absorption: given only by intravenous infusion; other routes have not been studied.
• Distribution: central volume of distribution of acMMAE 3.15 L, close to plasma volume. In vitro, MMAE is 71–77% bound to plasma proteins with a blood-to-plasma ratio of 0.79 to 0.98; it is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations.
• Metabolism: the antibody is expected to be broken down into small peptides, amino acids, unconjugated MMAE and MMAE-related catabolites. MMAE itself is metabolised by CYP3A4/5.
• Elimination: terminal half-life of acMMAE about 12 days at Cycle 6 (95% confidence interval 8.1 to 19.5 days); predicted clearance about 0.9 L/day. Elimination is mainly in faeces, with some in urine.
• Special populations: in mild hepatic impairment, unconjugated MMAE exposure rose by not more than 40%, which was not considered clinically significant. No dose adjustment is needed in patients aged 65 or over or with creatinine clearance of at least 30 mL/min.

• Previously untreated diffuse large B-cell lymphoma (DLBCL): in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP), for adults.
• Relapsed or refractory DLBCL: in combination with bendamustine and rituximab, for adults who are not candidates for haematopoietic stem cell transplant.

• Hypersensitivity to polatuzumab vedotin or to any of the excipients.
• Active severe infections.

The safety profile comes from 586 patients treated with Polivy: 435 with previously untreated DLBCL (study POLARIX, Polivy plus R-CHP) and 151 with relapsed or refractory DLBCL (study GO29365, Polivy plus bendamustine and rituximab).

• Previously untreated DLBCL (Polivy plus R-CHP): the most frequent reactions (at least 30%) were peripheral neuropathy (52.9%), nausea (41.6%), neutropenia (38.4%) and diarrhoea (30.8%). Serious adverse reactions occurred in 24.1%, most commonly febrile neutropenia (10.6%) and pneumonia (5.3%). Pneumonia (1.1%) was the only reaction that led to stopping the regimen in more than 1% of patients.
• Relapsed or refractory DLBCL (Polivy plus bendamustine and rituximab): the most frequent reactions (at least 30%) were neutropenia (45.7%), diarrhoea (35.8%), nausea (33.1%), thrombocytopenia (32.5%), anaemia (31.8%) and peripheral neuropathy (30.5%). Serious adverse reactions occurred in 41.7%, most commonly febrile neutropenia (10.6%), sepsis (9.9%), pneumonia (8.6%) and pyrexia (7.9%). Thrombocytopenia (7.9%) led to stopping the regimen in more than 5% of patients.

Very common (≥1/10): pneumonia, upper respiratory tract infection, febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leukopenia, hypokalaemia, decreased appetite, peripheral neuropathy, cough, diarrhoea, nausea, constipation, vomiting, mucositis, abdominal pain, alopecia, pyrexia, fatigue, asthenia, weight loss, infusion-related reaction.

Common (≥1/100 to <1/10): sepsis, herpes infection, cytomegalovirus infection, urinary tract infection, lymphopenia, pancytopenia, hypocalcaemia, hypoalbuminaemia, dizziness, pneumonitis, dyspnoea, pruritus, skin infection, rash, dry skin, arthralgia, myalgia, peripheral oedema, chills, increased lipase, hypophosphataemia, increased transaminases.

Uncommon (≥1/1,000 to <1/100): blurred vision, infusion-site extravasation.

No rare or very rare reactions are listed. Pneumonia, sepsis and herpes infection have been associated with fatal outcomes. Mucositis, alopecia, urinary tract infection, dyspnoea, skin infection, rash, dry skin, myalgia and peripheral oedema were seen only in previously untreated DLBCL; blurred vision and increased lipase only in relapsed or refractory DLBCL. Progressive multifocal leukoencephalopathy has also been reported (see Special Instructions).

No dedicated clinical interaction studies have been done with polatuzumab vedotin. The statements below rest on modelling and on the properties of MMAE, which is a CYP3A4 and P-gp substrate.

• Strong CYP3A4 and P-gp inhibitors (for example ketoconazole): modelling suggests they may raise the AUC of unconjugated MMAE by 48%. Use with caution. Patients taking strong CYP3A4 inhibitors (boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicity.
• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenobarbital, phenytoin, St John’s wort): may lower exposure to unconjugated MMAE.
• CYP3A4 substrates: unconjugated MMAE is not predicted to change their exposure.
• Rituximab, bendamustine, cyclophosphamide and doxorubicin: their pharmacokinetics are not affected by polatuzumab vedotin. Rituximab raised the AUC of antibody-conjugated MMAE by 24% and lowered that of unconjugated MMAE by 37%, and bendamustine had no effect on either. No dose adjustment is needed.
• Live or live-attenuated vaccines: should not be given during treatment.
• Grapefruit: grapefruit products may raise MMAE concentrations because MMAE is a CYP3A4 substrate; use caution.

Polivy must only be given under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients. It is for intravenous use only.

Recommended Dose

• Previously untreated DLBCL: 1.8 mg/kg as an intravenous infusion every 21 days with R-CHP for 6 cycles. Polivy, rituximab, cyclophosphamide and doxorubicin can be given in any order on day 1, after prednisone. Prednisone is given on days 1–5 of each cycle. Cycles 7 and 8 consist of rituximab alone. The doses of the other medicines are in their own SmPCs.
• Relapsed or refractory DLBCL: 1.8 mg/kg as an intravenous infusion every 21 days with bendamustine and rituximab for 6 cycles. The three can be given in any order on day 1 of each cycle. With Polivy, bendamustine is given at 90 mg/m² per day on days 1 and 2 of each cycle and rituximab at 375 mg/m² on day 1. Because clinical experience is limited, the Polivy dose should not exceed 240 mg per cycle.
• Premedication: an antihistamine and an antipyretic before Polivy, if the patient is not already premedicated.
• Delayed or missed dose: give it as soon as possible and adjust the schedule to keep a 21-day interval between doses.

Method of Administration

• The first dose is given as a 90-minute infusion. Patients are monitored for infusion-related and hypersensitivity reactions during the infusion and for at least 90 minutes afterwards.
• If the previous infusion was well tolerated, later doses may be given over 30 minutes, with monitoring during the infusion and for at least 30 minutes afterwards.
• Polivy is reconstituted and diluted with aseptic technique under the supervision of a healthcare professional. It is given through a dedicated infusion line with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2 or 0.22 micrometre pore size) and a catheter. It must not be given as an intravenous push or bolus.
• Polivy contains a cytotoxic component attached to the antibody, so handling and disposal follow the procedures in section 6.6 of the SmPC.

Dose Modifications for Peripheral Neuropathy

• Previously untreated DLBCL, grade 2 sensory neuropathy: reduce Polivy to 1.4 mg/kg. If grade 2 persists or recurs on day 1 of a later cycle, reduce to 1.0 mg/kg. If already at 1.0 mg/kg and grade 2 occurs on day 1 of a later cycle, stop Polivy.
• Previously untreated DLBCL, grade 2 motor neuropathy: withhold Polivy until improvement to grade 1 or less, then restart at the next cycle at 1.4 mg/kg. If already at 1.4 mg/kg and grade 2 occurs on day 1 of a later cycle, withhold until grade 1 or less and restart at 1.0 mg/kg. If already at 1.0 mg/kg and grade 2 occurs, stop Polivy.
• Previously untreated DLBCL, grade 3 sensory neuropathy: withhold until improvement to grade 2 or less, then reduce to 1.4 mg/kg; if already at 1.4 mg/kg reduce to 1.0 mg/kg; if already at 1.0 mg/kg stop Polivy.
• Previously untreated DLBCL, grade 3 motor neuropathy: withhold until grade 1 or less and restart at the next cycle at 1.4 mg/kg. If already at 1.4 mg/kg and grade 2–3 occurs, withhold until grade 1 or less and restart at 1.0 mg/kg; if already at 1.0 mg/kg and grade 2–3 occurs, stop Polivy.
• Concurrent sensory and motor neuropathy: follow the most severe restriction. Grade 4: stop Polivy. R-CHP may continue to be given.
• Relapsed or refractory DLBCL, grade 2–3: withhold until improvement to grade 1 or less. If recovery to grade 1 or less happens on or before day 14, restart at a permanently reduced dose of 1.4 mg/kg. If a dose reduction to 1.4 mg/kg has already occurred, or recovery is not reached by day 14, stop Polivy. Grade 4: stop Polivy.

Dose Modifications for Myelosuppression

• Previously untreated DLBCL, grade 3–4 neutropenia: withhold all treatment until ANC recovers to above 1,000/µL. If this happens on or before day 7, resume all treatment without dose reduction. If after day 7, resume all treatment and consider reducing cyclophosphamide and/or doxorubicin by 25–50%; if they are already reduced by 25%, consider reducing one or both to 50%.
• Previously untreated DLBCL, grade 3–4 thrombocytopenia: the same approach, withholding all treatment until platelets recover to above 75,000/µL.
• Relapsed or refractory DLBCL, grade 3–4 neutropenia: withhold all treatment until ANC recovers to above 1,000/µL. If this happens on or before day 7, resume without further reductions. If after day 7, restart all treatment with bendamustine reduced from 90 to 70 mg/m² or from 70 to 50 mg/m²; if bendamustine is already at 50 mg/m², stop all treatment.
• Relapsed or refractory DLBCL, grade 3–4 thrombocytopenia: the same approach, with platelets recovering to above 75,000/µL. For both neutropenia and thrombocytopenia in this setting, if the primary cause is the lymphoma, the bendamustine dose may not need to be reduced.

Dose Modifications for Infusion-Related Reactions

• Grade 1–3: interrupt the infusion and give supportive treatment. Stop Polivy permanently after a first grade 3 wheezing, bronchospasm or generalised urticaria, after recurrent grade 2 wheezing or urticaria, or after recurrence of any grade 3 symptom. Otherwise, once symptoms have resolved completely, resume at 50% of the rate reached before the interruption, and if there are no symptoms increase the rate in steps of 50 mg/hour every 30 minutes. At the next cycle, infuse over 90 minutes and, if no reaction occurs, over 30 minutes afterwards. Give premedication at every cycle.
• Grade 4: stop the infusion immediately, give supportive treatment and stop Polivy permanently.
• A life-threatening reaction means immediate and permanent discontinuation.

Special Populations

• Elderly: no dose adjustment in patients aged 65 or over.
• Renal impairment: no adjustment when creatinine clearance is at least 30 mL/min. No dose has been determined below 30 mL/min because data are limited.
• Hepatic impairment: avoid Polivy in moderate or severe impairment (bilirubin above 1.5 times the upper limit of normal). No adjustment of the starting dose in mild impairment (bilirubin above the upper limit of normal up to 1.5 times it, or AST above the upper limit).
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Traceability

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

Myelosuppression

Serious and severe neutropenia and febrile neutropenia have been reported from the first cycle. Prophylactic granulocyte colony stimulating factor (G-CSF) was required in clinical development and should be considered. Grade 3 or 4 thrombocytopenia or anaemia can also occur. Complete blood counts should be checked before each dose, and more frequent testing, delays or discontinuation considered for grade 3 or 4 neutropenia or thrombocytopenia.

Peripheral Neuropathy

Neuropathy has been reported from the first cycle, and the risk rises with later doses. Existing neuropathy may worsen. It is mainly sensory, but motor and sensorimotor neuropathy also occur. Patients should be monitored for hypoaesthesia, hyperaesthesia, paraesthesia, dysaesthesia, neuropathic pain, burning sensation, muscle weakness or gait disturbance, and new or worsening neuropathy may need a delay, dose reduction or discontinuation.

Infections

Serious, life-threatening and fatal infections, including opportunistic infections, have been reported: pneumonia (including Pneumocystis jirovecii and other fungal pneumonia), bacteraemia, sepsis, herpes infection and cytomegalovirus infection. Latent infections can reactivate. Patients should be monitored closely, and anti-infective prophylaxis should be considered throughout treatment. Polivy must not be given during an active severe infection, and it and any concomitant chemotherapy should be stopped in patients who develop a serious infection. Polivy has not been evaluated in patients with HIV; several strong CYP3A inhibitors are HIV medicines (see Drug Interactions).

Vaccination

Live or live-attenuated vaccines should not be given during treatment. No studies have been done in patients who recently received live vaccines.

Progressive Multifocal Leukoencephalopathy

PML has been reported. Patients should be monitored closely for new or worsening neurological, cognitive or behavioural changes. Polivy and any concomitant chemotherapy are withheld if PML is suspected and stopped permanently if it is confirmed.

Tumour Lysis Syndrome

Patients with a high tumour burden and rapidly proliferating tumour may be at higher risk. Appropriate measures or prophylaxis according to local guidelines should be taken before treatment, and patients monitored closely.

Infusion-Related Reactions

Reactions can be severe, and delayed reactions as late as 24 hours after the infusion have occurred. An antihistamine and an antipyretic are given beforehand, patients are monitored closely during the infusion, and if a reaction occurs the infusion is interrupted and managed medically.

Hepatic Toxicity

Serious cases consistent with hepatocellular injury, including raised transaminases and/or bilirubin, have occurred. Existing liver disease, high baseline liver enzymes and other medicines may increase the risk. Liver enzymes and bilirubin should be monitored.

Extravasation at the Infusion Site

Skin and soft tissue injury has been seen from hours to weeks after extravasation. Good venous access should be ensured before starting and the infusion site watched during administration. If extravasation occurs, stop the infusion, monitor for tissue damage and manage according to local guidelines; the rest of the dose may be given in another limb if clinically appropriate.

Older Patients

Among 435 previously untreated patients given Polivy with R-CHP, 227 (52.2%) were 65 or older; serious adverse reactions occurred in 39.2% of those aged 65 or over and 28.4% of younger patients, with a similar pattern on R-CHOP. Among 151 relapsed or refractory patients, 103 (68%) were 65 or older, and serious reactions were similar in both age groups (55% and 56%). The studies did not include enough patients aged 65 or over to show whether they respond differently.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 9 months after the last dose. Male patients with female partners of childbearing potential should do so during treatment and for at least 6 months after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies showed reproductive toxicity, and polatuzumab vedotin can harm the foetus. The pregnancy status of women of childbearing potential should be checked before treatment. Polivy is not recommended in pregnancy, or in women of childbearing potential who do not use contraception, unless the potential benefit to the mother outweighs the risk to the foetus.
• Breastfeeding: it is not known whether polatuzumab vedotin or its metabolites pass into human milk and a risk cannot be excluded. Breastfeeding should be stopped during treatment and for at least 3 months after the last dose.
• Fertility: testicular toxicity was seen in nonclinical studies, and male reproductive function and fertility may be impaired. Men are advised to have sperm samples preserved and stored before treatment and not to father a child during treatment and for up to 6 months after the last dose.

Excipients

Polivy contains less than 1 mmol sodium (23 mg) per dose, that is, it is essentially sodium-free. It contains polysorbate 20 (1.8 mg per 30 mg vial and 8.4 mg per 140 mg vial), which may cause allergic reactions.

Effect on Driving

Polivy has a minor influence on the ability to drive and use machines. Infusion-related reactions, peripheral neuropathy, fatigue and dizziness may occur during treatment.

Store Polivy vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. It is a cold-chain product from dispatch to the hospital pharmacy. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 30 months.
• Reconstituted solution: it 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, unless reconstitution took place under controlled and validated aseptic conditions. Chemical and physical in-use stability has been shown for up to 72 hours at 2–8 °C and up to 24 hours at room temperature (9–25 °C).
• Diluted solution: it should be used immediately; section 6.3 of the SmPC gives the in-use conditions.

Prescription only (Rx), a medicinal product subject to restricted medical prescription, for use under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer. Polivy is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, as a cold-chain product at 2–8 °C.