Zolbetuximab

No dose recommendation has been established in patients with severe renal impairment (CrCL ≥15 to <30 mL/min).

No dose recommendation has been established in patients with moderate (TB >1.5 to 3 × ULN and any AST) or severe (TB >3 to 10 × ULN and any AST) hepatic impairment.

There are no data on the use of zolbetuximab in pregnant women. No adverse effects were observed in an animal reproductive and developmental study with intravenous administration of zolbetuximab to pregnant mice during organogenesis. Zolbetuximab should only be given to a pregnant woman if the benefit outweighs the potential risk.

There are no data on the presence of zolbetuximab in human milk, the effects on the breast-fed child, or the effects on milk production. Since it is known that antibodies can be excreted in human milk, and because of the potential for serious adverse reactions in a breast-fed child, breast-feeding is not recommended during treatment with zolbetuximab.

Women of childbearing potential

As a precautionary measure, women of childbearing potential should be advised to use effective contraception to prevent pregnancy during treatment.

Fertility

Studies to evaluate the effect of zolbetuximab on fertility have not been performed. Thus, the effect of zolbetuximab on male and female fertility is unknown.

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

Summary of the safety profile

The most common adverse reactions with zolbetuximab were nausea (77.2%), vomiting (66.9%), decreased appetite (42%), neutropenia (30.7%), neutrophil count decreased (28.4%), weight decreased (21.9%), pyrexia (17.4%), hypoalbuminaemia (17.1%), oedema peripheral (13.9%), hypertension (9%), dyspepsia (7.8%), chills (5.2%), salivary hypersecretion (3.8%), infusion related reaction (3.2%) and drug hypersensitivity (1.6%).

Serious adverse reactions occurred in 45% of patients treated with zolbetuximab. The most common serious adverse reactions were vomiting (6.8%), nausea (4.9%), and decreased appetite (1.9%).

Twenty percent of patients permanently discontinued zolbetuximab for adverse reactions; the most common adverse reactions leading to dose discontinuation were vomiting (3.8%) and nausea (3.3%).

Adverse reactions leading to dose interruption of zolbetuximab occurred in 60.9% of patients; the most common adverse reactions leading to dose interruption were vomiting (26.6%), nausea (25.5%), neutropenia (9.8%), neutrophil count decreased (5.9%), hypertension (3.2%), chills (2.2%), infusion related reaction (1.6%), decreased appetite (1.6%) and dyspepsia (1.1%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on two phase 2 studies and two phase 3 studies in 631 patients who received at least one dose of zolbetuximab 800 mg/m² as a loading dose followed by 600 mg/m² maintenance doses every 3 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy. Patients were exposed to zolbetuximab for a median duration of 174 days (range: 1 to 1791 days).

Adverse reactions observed during clinical studies are listed in this section by frequency category. Frequency categories are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

Description of selected adverse reactions

Hypersensitivity reactions

In the integrated safety analysis, all grade anaphylactic reaction and drug hypersensitivity occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 0.5% and 1.6%, respectively.

Severe (Grade 3) anaphylactic reaction and drug hypersensitivity occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 0.5% and 0.2%.

Anaphylactic reaction led to permanent discontinuation of zolbetuximab in 0.3% of patients. Dose interruption of zolbetuximab was experienced due to drug hypersensitivity in 0.3% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum-containing chemotherapy in 0.2% of patients due to drug hypersensitivity.

Infusion related reaction

In the integrated safety analysis, all grade IRR occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 3.2%.

Severe (Grade 3) IRR occurred in 0.5% of patients treated with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy.

An IRR led to permanent discontinuation of zolbetuximab in 0.5% of patients, and dose interruption in 1.6% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum- containing chemotherapy in 0.3% of patients due to an IRR.

Nausea and vomiting

In the integrated safety analysis, all grade nausea and vomiting occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 77.2% and 66.9%, respectively. Nausea and vomiting occurred more often during the first cycle of treatment but decreased in incidence with subsequent cycles of treatment. The median time to onset of nausea and vomiting was 1 day each with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy. The median duration of nausea and vomiting was 3 days and 1 day, respectively, with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy.

Severe (Grade 3) nausea and vomiting occurred with zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 11.6% and 13.6%.

Nausea led to permanent discontinuation of zolbetuximab in 3.3% of patients, and dose interruption in 25.5% of patients. Vomiting led to permanent discontinuation of zolbetuximab in 3.8% of patients, and dose interruption in 26.6% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum-containing chemotherapy in 9.7% of patients due to nausea and in 7.8% of patients due to vomiting.