Glofitamab

The initial release of cytokines associated with the start of glofitamab treatment could suppress CYP450 enzymes. The highest drug-drug interaction risk is during the period of one week following each of the first 2 doses of glofitamab (i.e., Cycle 1 Day 8 and 15) in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index (e.g., warfarin, cyclosporine). On initiation of glofitamab therapy, patients being treated with CYP450 substrates with a narrow therapeutic index should be monitored.

Caution should be exercised when considering the use of glofitamab in patients with a history of chronic or recurrent infection, those with underlying conditions that may predispose them to infections, or those who have had significant prior immunosuppressive treatment. Patients should be monitored before and during glofitamab treatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections and treated appropriately.

There are no data on the use of glofitamab in pregnant women. No reproductive toxicity studies have been performed in animals.

Glofitamab is an immunoglobulin G (IgG). IgG is known to cross the placenta. Based on its mechanism of action, glofitamab is likely to cause foetal B cell depletion when administered to a pregnant woman.

Glofitamab is not recommended during pregnancy and in women of childbearing potential not using contraception. Female patients receiving glofitamab should be advised of the potential harm to the foetus. Female patients should be advised to contact the treating physician, should pregnancy occur.

It is not known whether glofitamab is excreted in human milk. No studies have been conducted to assess the impact of glofitamab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. The potential for absorption of glofitamab and the potential for adverse reactions in the breast-feeding child is unknown. Women should be advised to discontinue breast-feeding during treatment with glofitamab and for 2 months after the final dose of glofitamab.

Women of childbearing potential / Contraception

Female patients of childbearing potential must use highly effective contraceptive methods during treatment with glofitamab and for at least 2 months following the last dose of glofitamab.

Fertility

No human data on fertility are available. No fertility assessments in animals have been performed to evaluate the effect of glofitamab on fertility.

Glofitamab has minor influence on the ability to drive and use machines. Patients experiencing symptoms of neurological adverse events and/or CRS (pyrexia, tachycardia, hypotension, chills, hypoxia) should be advised not to drive or use machines until symptoms resolve.

Summary of the safety profile

The most common adverse reactions (≥20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia, and rash.

The most common serious adverse reactions reported in ≥2% of patients were cytokine release syndrome (22.1%), sepsis (4.1%), COVID-19 (3.4%), tumour flare (3.4%), COVID-19 pneumonia (2.8%), febrile neutropenia (2.1%), neutropenia (2.1%), and pleural effusion (2.1%).

Permanent discontinuation of glofitamab due to an adverse reaction occurred in 5.5% of patients. The most common adverse reactions leading to permanent discontinuation of glofitamab were COVID-19 (1.4%) and neutropenia (1.4%).

Tabulated list of adverse reactions

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with glofitamab monotherapy (n=145) in study NP30179 are listed in the table below. Patients received a median of 5 cycles of glofitamab treatment (range: 1 to 13 cycles).

The adverse reactions are listed by MedDRA system organ class and categories of frequency. The following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions reported in patients with relapsed or refractory DLBCL treated with glofitamab monotherapy:

^* Grade 5 reactions reported. See serious infections in Description of selected adverse reactions.
^** No Grade 3-4 events were reported.
¹ Includes COVID-19, COVID-19 pneumonia, herpes zoster, influenza, and ophthalmic herpes zoster.
² Includes vascular device infection, bacterial infection, Campylobacter infection, biliary tract infection bacterial, urinary tract infection bacterial, Clostridium difficile infection, Escherichia infection, and peritonitis.
³ Includes upper respiratory tract infection, sinusitis, nasopharyngitis, chronic sinusitis, and rhinitis.
⁴ Includes sepsis and septic shock.
⁵ Includes lower respiratory tract infection and bronchitis.
⁶ Includes urinary tract infection and Escherichia urinary tract infection.
⁷ Includes oesophageal candidiasis and oral candidiasis.
⁸ Includes febrile neutropenia and neutropenic infection.
⁹ Based on ASTCT consensus grading (Lee 2019).
¹⁰ Myelitis occurred concurrently with CRS.
¹¹ Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.
¹² Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative,
erythema, palmar erythema, pruritis, and rash erythematous.

Description of selected adverse reactions

Cytokine release syndrome

In study NP30179, any grade CRS (by ASTCT criteria) occurred in 67.6% of patients, with Grade 1 CRS being reported in 50.3% of patients, Grade 2 CRS in 13.1% patients, Grade 3 CRS in 2.8% of patients and Grade 4 CRS in 1.4% of patients. CRS occurred more than once in 32.4% (47/145) of patients; 36/47 patients experienced multiple Grade 1 CRS events only. There were no fatal cases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (99.0%), tachycardia (25.5%), hypotension (23.5%), chills (14.3%) and hypoxia (12.2%). Grade 3 or higher events associated with CRS included hypotension (3.1%), hypoxia (3.1%), pyrexia (2.0%) and tachycardia (2.0%).

CRS of any grade occurred in 54.5% of patients following the first 2.5 mg dose of glofitamab at Cycle 1 Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 5.2 to 50.8 hours) and median duration of 31.8 hours (range: 0.5 to 316.7 hours); in 33.3% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 26.8 hours (range: 6.7 to 125.0 hours) and median duration of 16.5 hours (range: 0.3 to 109.2 hours); and in 26.8% of patients following the 30 mg dose at Cycle 2 with median time to onset of 28.2 hours (range: 15.0 to 44.2 hours) and median duration of 18.9 hours (range: 1.0 to 180.5 hours). CRS was reported in 0.9% of patients at Cycle 3 and in 2% of patients beyond Cycle 3.

Grade ≥ 2 CRS occurred in 12.4% of patients following the first glofitamab dose (2.5 mg) with median time to onset of 9.7 hours (range: 5.2 to 19.1 hours) and median duration of 50.4 hours (range: 6.5 to 316.7 hours). Following glofitamab 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥ 2 CRS decreased to 5.2% of patients with median time to onset of 26.2 hours (range: 6.7 to 144.2 hours) and median duration of 30.9 hours (range: 3.7 to 227.2 hours). Grade ≥ 2 CRS following glofitamab 30 mg dose at Cycle 2 Day 1 occurred in one patient (0.8%) with time to onset of 15.0 hours and duration of 44.8 hours. No Grade ≥ 2 CRS was reported beyond Cycle 2.

In 145 patients, 7 (4.8%) patients experienced elevated liver function tests (AST and ALT > 3 × ULN and/or total bilirubin > 2 × ULN) reported concurrently with CRS (n=6) or with disease progression (n=1).

Among the 25 patients who experienced Grade ≥ 2 CRS after glofitamab, 22 (88.0%) received tocilizumab, 15 (60.0%) received corticosteroids and 14 (56.0%) received both tocilizumab and corticosteroids. Ten patients (40.0%) received oxygen. All 6 patients (24.0%) with Grade 3 or 4 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following glofitamab administration occurred in 22.1% of patients and the reported median duration of hospitalisation was 4 days (range: 2 to 15 days).

Serious infections

In study NP30179, serious infections were reported in 15.9% of patients. The most frequent serious infections reported in ≥2% of patients were sepsis (4.1%), COVID-19 (3.4%), and COVID-19 pneumonia (2.8%). Infection-related deaths were reported in 4.8% of patients (due to sepsis, COVID-19 pneumonia and COVID-19). Four patients (2.8%) experienced serious infections concurrently with Grade 3 or 4 neutropenia.

Neutropenia

Neutropenia (including neutrophil count decreased) was reported in 40.0% of patients and severe neutropenia (Grade 3 or 4) was reported in 29.0% of patients. The median time to onset of the first neutropenia event was 29 days (range: 1 to 203 days). Prolonged neutropenia (lasting longer than 30 days) occurred in 11.7% of patients. The majority of patients with neutropenia (79.3%) were treated with G-CSF. Febrile neutropenia was reported in 3.4% of patients.

Tumour flare

Tumour flare was reported in 11.7% of patients, including Grade 2 tumour flare in 4.8% of patients and Grade 3 tumour flare in 2.8% of patients. Tumour flare was reported involving lymph nodes in the head and neck presenting with pain and involving lymph nodes in the thorax with symptoms of breathlessness due to development of pleural effusion. Most tumour flare events (16/17) occurred during Cycle 1, and no tumour flare events were reported beyond Cycle 2. The median time to onset of tumour flare of any grade was 2 days (range: 1 to 16 days), and the median duration was 3.5 days (range: 1 to 35 days).

Among the 11 patients who experienced Grade ≥ 2 tumour flare, 2 (18.2%) patients received analgesics, 6 (54.5%) patients received corticosteroids and analgesics including morphine derivatives, 1 (0.9%) patient received corticosteroids and anti-emetics, and 2 (18.2%) patients did not require treatment. All tumour flare events resolved except in one patient with a Grade ≥ 2 event. No patients discontinued treatment due to tumour flare.

Tumour lysis syndrome

TLS was reported in 2 patients (1.4%) and was Grade 3 in severity in both cases. The median time to onset of TLS onset was 2 days, and the median duration was 4 days (range: 3 to 5 days).