Glofitamab

Glofitamab is a humanised anti-CD20/anti-CD3 bispecific antibody produced in Chinese hamster ovary cells by recombinant DNA technology. It engages the patient’s own T cells against CD20-expressing B cells, including lymphoma cells. Because the antibody redirects T cells, it also triggers a release of cytokines, which explains its main toxicities and the careful step-up dosing used to start treatment.

Mechanism of Action

• Dual binding: glofitamab binds bivalently to CD20 on the surface of B cells and monovalently to CD3 in the T-cell receptor complex on T cells.
• Immunological synapse: by binding both cells at once it forms an immunological synapse, which leads to T-cell activation and proliferation, secretion of cytokines and release of cytolytic proteins, and so to lysis of the CD20-expressing B cells.
• B-cell depletion: in study NP30179, 84% of patients were already B-cell depleted (below 70 cells/µL) before obinutuzumab pre-treatment; after it, all 94 evaluable patients were depleted, and B-cell counts stayed low during treatment. In study STARGLO the proportion rose from 63.9% to 79.4%.
• Cytokines: during step-up dosing in cycle 1, plasma IL-6 rose briefly, about 6 hours after the infusion, stayed raised at 20 hours and returned to baseline before the next infusion.
• Cardiac electrophysiology: a post-baseline QTc above 450 ms occurred in 16 of 145 patients (monotherapy study) and 16 of 172 patients (combination study); one case was judged clinically significant and no patient stopped treatment for this reason.

Pharmacokinetics

• Absorption: given by intravenous infusion; the peak concentration is reached at the end of the infusion. Pharmacokinetics are linear and dose-proportional over 0.005 to 30 mg and do not change with time.
• Distribution: central volume of distribution 3.34 L, close to the total serum volume; peripheral volume 2.35 L.
• Metabolism: not studied. As with other antibodies, it is expected to be cleared mainly by catabolism into small peptides and amino acids.
• Elimination: a two-compartment model describes the serum data, with a time-independent clearance of 0.633 L/day and an initial time-varying clearance of 0.814 L/day that decays quickly (decay half-life 0.471 days). The effective half-life in the linear phase is 7.92 days (geometric mean).
• Special populations: exposure is the same in patients aged 65 and over as in younger patients. Mild or moderate renal impairment (creatinine clearance 30 to below 90 mL/min) and mild hepatic impairment do not change exposure. There are no data in severe renal impairment or in moderate or severe hepatic impairment.

• Combination with gemcitabine and oxaliplatin: adults with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) who are not eligible for autologous stem cell transplant (ASCT).
• Monotherapy: adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Data are limited in CD20-negative DLBCL, where benefit may be smaller; the risks and benefits should be weighed before treating such patients.

• Hypersensitivity to glofitamab, to obinutuzumab or to any of the excipients.
• For contraindications of obinutuzumab (given as pre-treatment), see the obinutuzumab prescribing information.

With monotherapy (145 patients) the most common reactions (≥20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia and rash. With gemcitabine and oxaliplatin (172 patients) they were thrombocytopenia, cytokine release syndrome, neutropenia, anaemia, nausea, peripheral neuropathy, diarrhoea, raised AST and ALT, rash, lymphopenia, pyrexia and vomiting. The frequencies below refer to all grades.

Very common (≥1/10)

• Monotherapy: viral infections, tumour flare, neutropenia, anaemia, thrombocytopenia, cytokine release syndrome, hypophosphataemia, hypomagnesaemia, hypocalcaemia, hypokalaemia, headache, constipation, diarrhoea, nausea, rash, pyrexia.
• With gemcitabine and oxaliplatin: COVID-19, respiratory tract infections, pneumonia, thrombocytopenia, neutropenia, anaemia, lymphopenia, cytokine release syndrome, hypokalaemia, hyponatraemia, peripheral neuropathy, nausea, diarrhoea, vomiting, abdominal pain, constipation, rash, musculoskeletal pain, pyrexia, raised AST, ALT, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase.

Common (≥1/100 to <1/10)

• Monotherapy: bacterial, upper and lower respiratory tract, urinary tract and fungal infections, sepsis, pneumonia, lymphopenia, febrile neutropenia, hyponatraemia, tumour lysis syndrome, confusional state, ICANS, somnolence, tremor, gastrointestinal haemorrhage, vomiting, raised ALT, AST, alkaline phosphatase, gamma-glutamyltransferase, bilirubin and other liver enzymes.
• With gemcitabine and oxaliplatin: cytomegalovirus and herpes viral infections, urinary tract infection, sepsis, Candida infections, tumour flare, febrile neutropenia, hypomagnesaemia, hypocalcaemia, hypophosphataemia, tumour lysis syndrome, ICANS, headache, pneumonitis, colitis, pancreatitis, raised bilirubin.

Uncommon (≥1/1,000 to <1/100)

• Monotherapy: myelitis, colitis.
• With gemcitabine and oxaliplatin: Pneumocystis jirovecii pneumonia, tremor, raised liver enzymes.

Serious reactions occurring in at least 2% of patients included cytokine release syndrome (22.1% with monotherapy, 20.3% with the combination), sepsis, COVID-19, pneumonia, pyrexia, thrombocytopenia and febrile neutropenia. Serious infections occurred in 15.9% of patients on monotherapy and 22.7% on the combination; infection-related deaths were reported in 4.8% and 3.5%. Two patients (1.2%) on the combination had fatal pneumonitis. Treatment was stopped permanently because of an adverse reaction in 5.5% (monotherapy) and 20.9% (combination), mostly because of COVID-19.

No interaction studies have been done, and interactions through cytochrome P450 enzymes, other metabolising enzymes or transporters are not expected.

• CYP450 substrates with a narrow therapeutic index (for example warfarin, ciclosporin): the cytokine release at the start of treatment can temporarily suppress CYP450 enzymes. The risk is highest in the week after each of the first two doses (cycle 1, days 8 and 15), so these patients should be monitored when treatment begins.
• Gemcitabine and oxaliplatin: they do not change the pharmacokinetics of glofitamab.
• Obinutuzumab: given as pre-treatment 7 days before the first glofitamab dose; see its own prescribing information.

Glofitamab must be given only under the supervision of a healthcare professional experienced in diagnosing and treating cancer, with access to medical support for severe cytokine release syndrome and ICANS. At least one dose of tocilizumab must be on hand before each infusion in cycles 1 and 2, and a further dose must be obtainable within 8 hours of the previous one. It is for intravenous use only: a healthcare professional dilutes it using aseptic technique and gives it as an infusion through a dedicated line, never as an intravenous push or bolus.

Pre-treatment and Premedication

• Obinutuzumab: a single 1,000 mg intravenous dose on cycle 1, day 1, 7 days before the first glofitamab dose, to lower circulating and lymphoid B cells. It is infused at 50 mg/h, raised by 50 mg/h every 30 minutes to a maximum of 400 mg/h.
• Hydration and CRS premedication: patients should be well hydrated. For the infusions on cycle 1 (days 8 and 15), cycle 2 (day 1) and cycle 3 (day 1), all patients receive 20 mg intravenous dexamethasone (finished at least 1 hour before the infusion), an oral analgesic/antipyretic (for example 1,000 mg paracetamol) and an antihistamine (for example 50 mg diphenhydramine), both at least 30 minutes before. If dexamethasone cannot be used, 100 mg prednisone/prednisolone or 80 mg methylprednisolone is given instead.
• Later infusions: all patients receive the analgesic/antipyretic and antihistamine; dexamethasone is added for patients who had cytokine release syndrome with the previous dose.
• Infection prophylaxis: recommended; consider prophylaxis against cytomegalovirus, herpes, Pneumocystis jirovecii pneumonia and other opportunistic infections in patients at increased risk.

Recommended Dose: Monotherapy

Each cycle lasts 21 days.

• Cycle 1: day 1 obinutuzumab 1,000 mg; day 8 glofitamab 2.5 mg; day 15 glofitamab 10 mg (4-hour infusions).
• Cycle 2, day 1: 30 mg over 4 hours.
• Cycles 3 to 12, day 1: 30 mg over 2 hours, at the physician’s discretion if the previous infusion was well tolerated; after cytokine release syndrome with the previous dose the infusion stays at 4 hours.
• Duration: a maximum of 12 cycles, or until disease progression or unmanageable toxicity.

Recommended Dose: With Gemcitabine and Oxaliplatin

• Cycle 1: day 1 obinutuzumab 1,000 mg; day 2 gemcitabine 1,000 mg/m² then oxaliplatin 100 mg/m²; day 8 glofitamab 2.5 mg and day 15 glofitamab 10 mg (4 hours each).
• Cycle 2: day 1 glofitamab 30 mg over 4 hours, then gemcitabine and oxaliplatin at the same doses.
• Cycles 3 to 8: glofitamab 30 mg over 2 hours before gemcitabine and oxaliplatin, which may be given on day 1 or 2 (gemcitabine first).
• Cycles 9 to 12: glofitamab 30 mg alone over 2 hours.
• Duration: 8 cycles with the combination, then 4 cycles of glofitamab alone, 12 in total, or until progression or unmanageable toxicity.

Monitoring During Treatment

• On monotherapy, patients are monitored during all infusions and for at least 10 hours after the first infusion (2.5 mg, cycle 1 day 8). With the combination, monitoring continues for 4 hours after that first infusion.
• Patients who had cytokine release syndrome of grade 2 or higher with the previous infusion are monitored after the next infusion as well.
• All patients are counselled on the signs of cytokine release syndrome and ICANS and told to contact their healthcare provider immediately if they appear.

Dose Modifications and Delayed Doses

• No dose reductions of glofitamab are recommended.
• Cytokine release syndrome: managed by grade. Grade 1: treat symptoms (corticosteroids or tocilizumab can be considered if it lasts more than 48 hours). Grade 2: stop the infusion if it occurs during it, treat symptoms and give corticosteroids; tocilizumab can be considered. Grade 3: stop the infusion, give corticosteroids and tocilizumab; if grade 3 or higher recurs at a later infusion, treatment is stopped permanently. Grade 4: stop permanently, with corticosteroids and tocilizumab. Before the next infusion the symptoms must have resolved for at least 72 hours, and the infusion may be slowed (up to 8 hours). Tocilizumab is given at 8 mg/kg (maximum 800 mg), with no more than 3 doses in 6 weeks.
• ICANS: at the first sign, consider supportive care and a neurology review, and withhold glofitamab until it resolves. Dexamethasone 10 mg intravenously every 6 hours is used for grade 2 and higher, and non-sedating anti-seizure medicine such as levetiracetam can be considered. For grade 3 ICANS that does not improve within 7 days, consider stopping permanently; grade 4 requires permanent discontinuation.
• Missed doses in step-up dosing: if the 2.5 mg dose is delayed by more than 1 week after obinutuzumab, obinutuzumab is repeated. If 2 to 6 weeks pass after the 2.5 mg or 10 mg dose, the last tolerated dose is repeated and step-up resumes. After more than 6 weeks, obinutuzumab and the whole step-up are repeated.
• After cycle 2: if more than 6 weeks pass between cycles, obinutuzumab and step-up dosing are repeated before returning to the 30 mg dose.

Special Populations

• Elderly: no dose adjustment in patients aged 65 and over.
• Renal impairment: no adjustment in mild or moderate impairment; not studied in severe impairment.
• Hepatic impairment: no adjustment in mild impairment; not studied in moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Cytokine Release Syndrome

Cytokine release syndrome, including life-threatening reactions, has been reported. Its most common signs are pyrexia, tachycardia, hypotension, chills and hypoxia, and infusion-related reactions can look the same. Most events follow the first dose: any grade occurred in 54.5% of monotherapy patients after the 2.5 mg dose, with a median onset of about 12.6 hours. Overall, any-grade cytokine release syndrome occurred in 67.6% (monotherapy) and 44.2% (combination) of patients, with grade 3 or higher in 4.2% and 2.3%. Raised liver tests have occurred together with it. Other causes of fever, hypoxia and hypotension, such as infection or sepsis, must be ruled out. Patients carry a patient card and must seek immediate medical help if symptoms appear at any time.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Serious, potentially life-threatening or fatal ICANS has occurred. It can start together with cytokine release syndrome, after it has resolved, or without it. Signs include confusion, depressed level of consciousness, disorientation, seizure, aphasia and dysgraphia; most cases began 1 to 7 days (median 2 days) after the latest dose.

Infections, Neutropenia and Tumour Lysis

Serious infections, including fatal ones, have occurred, and prophylaxis is recommended. With monotherapy, neutropenia occurred in 40.0% of patients (grade 3 or 4 in 29.0%), starting a median of 29 days into treatment and lasting more than 30 days in 11.7%. Tumour flare occurred in 11.7% of monotherapy patients, mostly in cycle 1, with pain in affected lymph nodes or breathlessness from a pleural effusion. Tumour lysis syndrome occurred in 1.4%. Colitis and, with the combination, pneumonitis have also been reported.

Traceability

To keep biological medicines traceable, the name and batch number of the product given must be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception during treatment and for at least 2 months after the last dose.
• Pregnancy: there are no data in pregnant women and no animal reproductive studies. Glofitamab is an IgG antibody, and IgG crosses the placenta, so it is likely to deplete foetal B cells. It is not recommended in pregnancy or in women of childbearing potential who do not use contraception. Patients should tell their doctor if they become pregnant.
• Breastfeeding: it is not known whether glofitamab passes into breast milk. Breastfeeding should be stopped during treatment and for 2 months after the final dose.
• Fertility: there are no human or animal data on fertility.

Polysorbate 20

Each 2.5 mL vial contains 1.25 mg and each 10 mL vial 5 mg of polysorbate 20 (0.5 mg/mL).

Effect on Driving

Glofitamab has a major influence on the ability to drive and use machines because of the risk of ICANS and a depressed level of consciousness. Patients should avoid driving or operating machines for 48 hours after each of the first two doses during step-up dosing, and if symptoms of ICANS or cytokine release syndrome appear.

Store the vials in a refrigerator at 2–8 °C, in the outer carton to protect them from light. Do not freeze. The product needs cold-chain handling from the manufacturer to the point of use. After dilution, use immediately; if it is not used at once, the in-use stability is 72 hours at 2–8 °C or 24 hours at 30 °C followed by an infusion time of up to 8 hours, and the user is responsible for storage times, which would normally not exceed 24 hours at 2–8 °C unless dilution took place under controlled and validated aseptic conditions.

30 months for the unopened vial. For the diluted solution, see Storage Conditions.

Prescription only (Rx). Glofitamab is subject to restricted medical prescription (Annex II B) and is used under the supervision of a specialist experienced in cancer treatment. It is infused in hospital, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions at 2–8 °C.