VYLOY 300mg powder for concentrate infusion solution medication leaflet

Vyloy 100 mg powder for concentrate for solution for infusion.

Vyloy 300 mg powder for concentrate for solution for infusion.

Vyloy 100 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 100 mg zolbetuximab.

Vyloy 300 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 300 mg zolbetuximab.

After reconstitution, each mL of solution contains 20 mg of zolbetuximab.

Zolbetuximab is produced in Chinese hamster ovary cells by recombinant DNA technology.

Each mL of concentrate contains 0.21 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

Vyloy, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated forthe first-line treatment of adult patients with locally advanced unresectable or metastatic

HER2-negative gastric or gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours are

Claudin (CLDN) 18.2 positive (see section 4.2).

Treatment should be prescribed, initiated and supervised by a physician experienced in the use ofanti-cancer therapies. Resources for the management of hypersensitivity reactions and/or anaphylacticreactions should be available.

Patient selection

Eligible patients should have CLDN18.2 positive tumour status defined as ≥75% of tumour cellsdemonstrating moderate to strong membranous CLDN18 immunohistochemical staining, assessed by a

CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, analternative validated test should be used.

Prior to administration

If a patient is experiencing nausea and/or vomiting prior to administration of zolbetuximab, thesymptoms should be resolved to Grade ≤1 before administering the first infusion.

Prior to each infusion of zolbetuximab, patients should be pre-medicated with a combination ofantiemetics (e.g., NK-1 receptor blockers and 5-HT3 receptor blockers, as well as other medicinalproducts as indicated).

Pre-medication with a combination of antiemetics is important for the management of nausea andvomiting to prevent early treatment discontinuation of zolbetuximab (see section 4.4). Pre-medicationwith systemic corticosteroids per local treatment guidelines may also be considered particularly beforethe first infusion of zolbetuximab.

Recommended dose

The recommended dose should be calculated according to body surface area (BSA) for thezolbetuximab loading dose and maintenance doses as provided in Table 1.

Table 1. Recommended zolbetuximab dose based on BSA

Single loading dose Maintenance doses Duration of therapy

On Cycle 1, Day 1a, Beginning 3 weeks after Until disease progression or800 mg/m2 intravenously the single loading dose, unacceptable toxicity.600 mg/m2 intravenouslyevery 3 weeksor

Beginning 2 weeks afterthe single loading dose,400 mg/m2 intravenously

Administer zolbetuximab in every 2 weekscombination withfluoropyrimidine- andplatinum-containing Administer zolbetuximab inchemotherapy (see combination withsection 5.1).b fluoropyrimidine- andplatinum-containingchemotherapy (see section 5.1).b

a. The cycle duration of zolbetuximab is determined based on the respective chemotherapybackbone (see section 5.1).

b. Refer to the fluoropyrimidine- or platinum-containing chemotherapy prescribing informationregarding the dosing information for chemotherapy.

No dose reduction for zolbetuximab is recommended. Adverse reactions for zolbetuximab aremanaged by infusion rate reduction, interruption, and/or discontinuation as presented in Table 2.

Table 2. Dose modifications for zolbetuximab

Adverse reaction Severitya Dose modification

Hypersensitivity reactions Anaphylactic Immediately stop the infusion andreaction, permanently discontinue.suspectedanaphylaxis,

Grade 3 or 4

Grade 2 Interrupt the infusion until Grade ≤1, thenresume at a reduced infusion rateb for theremaining infusion.

For the next infusion, premedicate withantihistamines and administer per the infusionrates in Table 3.

Infusion related reaction Grade 3 or 4 Immediately stop the infusion andpermanently discontinue.

Grade 2 Interrupt the infusion until Grade ≤1, thenresume at a reduced infusion rateb for theremaining infusion.

For the next infusion, premedicate withantihistamines and administer per the infusionrates in Table 3.

Nausea Grade 2 or 3 Interrupt the infusion until Grade ≤1, thenresume at a reduced infusion rateb for theremaining infusion.

For the next infusion, administer per theinfusion rates in Table 3.

Vomiting Grade 4 Permanently discontinue.

Grade 2 or 3 Interrupt the infusion until Grade ≤1, thenresume at a reduced infusion rateb for theremaining infusion.

For the next infusion, administer per theinfusion rates in Table 3.

a. Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse

Events Version 4.03 (NCI-CTCAE v4.03) where Grade 1 is mild, Grade 2 is moderate,

Grade 3 is severe, Grade 4 is life-threatening.

b. Reduced infusion rate should be determined per physician’s clinical judgment based on patienttolerability, severity of toxicity, and previously tolerated infusion rate (see section 4.4 forpatient monitoring recommendations).

No dose adjustment is required in patients ≥65 years of age (see section 5.2). Data for patients aged75 years and older who received zolbetuximab are limited.

No dose adjustment is required in patients with mild (creatinine clearance [CrCL] ≥60 to <90 mL/min)or moderate (CrCL ≥30 to <60 mL/min) renal impairment. No dose recommendation has beenestablished in patients with severe renal impairment (CrCL ≥15 to <30 mL/min) (see section 5.2).

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin [TB] ≤ upperlimit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or TB >1 to 1.5 × ULN and any

AST). No dose recommendation has been established in patients with moderate (TB >1.5 to 3 × ULNand any AST) or severe (TB >3 to 10 × ULN and any AST) hepatic impairment (see section 5.2).

There is no relevant use of zolbetuximab in the paediatric population in the treatment of gastric orgastro-oesophageal junction adenocarcinoma.

Zolbetuximab is for intravenous use. The recommended dose is administered by intravenous infusionover a minimum of 2 hours. The medicinal product must not be administered as an intravenous push orbolus injection.

If zolbetuximab and fluoropyrimidine- and platinum-containing chemotherapy are administered on thesame day, zolbetuximab must be administered first.

To help minimise potential adverse reactions, it is recommended that each infusion is started at aslower rate for 30-60 minutes, and gradually increased as tolerated during the course of the infusion(see Table 3).

If the infusion time exceeds the recommended storage time at room temperature (≤ 25 °C for 8 hoursfrom end of preparation of infusion solution), the infusion bag must be discarded and a new infusionbag prepared to continue the infusion (see section 6.3 for recommended storage times).

Table 3. Infusion rates recommended for each zolbetuximab infusion

Infusion rate

Zolbetuximab dose First 30-60 minutes Remaining infusiontimeb

Single loadingdose (Cycle 1, 800 mg/m2 75 mg/m2/hr 150-300 mg/m2/hr

Day 1)a

Maintenance 600 mg/m2 every 3 weeks 75 mg/m2/hr 150-300 mg/m2/hrdoses Or or or400 mg/m2 every 2 weeks 50 mg/m2/hr 100-200 mg/m2/hr

a. The cycle duration of zolbetuximab is determined based on the respective chemotherapybackbone (see section 5.1).

b. In the absence of adverse reactions after 30-60 minutes, the infusion rate can be increased astolerated.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity reactions, including anaphylactic reaction and drug hypersensitivity, occurred inpatients treated with zolbetuximab in combination with fluoropyrimidine and platinum-containingchemotherapy during clinical studies (see section 4.8).

Patients should be monitored during and after infusion with zolbetuximab (at least 2 hours, or longer ifclinically indicated) for hypersensitivity reactions with symptoms and signs that are highly suggestiveof anaphylaxis (urticaria, repetitive cough, wheeze and throat tightness/change in voice).

Hypersensitivity reactions should be managed according to the dose modifications as recommended in

Table 2.

Infusion-related reactions (IRRs) have occurred during clinical studies with zolbetuximab incombination with fluoropyrimidine and platinum-containing chemotherapy (see section 4.8).

Patients should be monitored for signs and symptoms of infusion-related reactions including nausea,vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough,and hypertension. These signs and symptoms are usually reversible with the interruption of theinfusion.

Infusion-related reactions should be managed according to the dose modifications as recommended in

Table 2.

Nausea and vomiting

During clinical studies, nausea and vomiting were the most frequently observed gastrointestinaladverse reactions with zolbetuximab in combination with fluoropyrimidine and platinum-containingchemotherapy (see section 4.8).

To prevent nausea and vomiting, pre-treatment with a combination of antiemetics is recommendedprior to each infusion of zolbetuximab (see section 4.2).

During and after infusion, patients should be monitored and managed using standard of care, includingantiemetics or fluid replacement, as clinically indicated.

Nausea and vomiting should be managed according to the dose modifications as recommended in

Table 2.

Mitigation measures before initiating treatment with zolbetuximab

Prior to treatment with zolbetuximab in combination with fluoropyrimidine- and platinum-containingchemotherapy, prescribers should evaluate the individual patient’s risk of gastrointestinal toxicities. Itis important to proactively manage nausea and vomiting to mitigate the potential risk of reducedexposure to zolbetuximab and/or chemotherapy.

To prevent nausea and vomiting, pre-treatment with a combination of antiemetics is recommendedprior to each infusion of zolbetuximab. During infusion, it is important to closely monitor patients andmanage gastrointestinal toxicities by infusion interruption and/or infusion rate reduction to minimizethe risk of severe adverse reactions or early treatment discontinuation. During and after infusion,patients should be monitored and managed using standard of care, including antiemetics or fluidreplacement, as clinically indicated.

Patients were excluded from clinical studies if they had a complete or partial gastric outlet syndrome,positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B or Cinfection, significant cardiovascular disease (e.g., congestive heart failure per New York Heart

Association Class III or IV, history of significant ventricular arrhythmias, QTc interval >450 msec formales; >470 msec for females) or history of central nervous system metastases.

This medicinal product contains 1.05 mg and 3.15 mg of polysorbate 80 in each 100 mg and 300 mgvial, respectively. Polysorbates may cause allergic reactions.

This medicinal product does not contain sodium, however, sodium chloride 9 mg/mL (0.9%) solutionfor infusion is used for the dilution of zolbetuximab prior to administration and this should be takeninto consideration in the context of the daily sodium intake of the patient.

No formal pharmacokinetic drug interaction studies have been conducted with zolbetuximab. Sincezolbetuximab is cleared from the circulation through catabolism, no metabolic drug-drug interactionsare expected.

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

There are no data on the use of zolbetuximab in pregnant women. No adverse effects were observed inan animal reproductive and developmental study with intravenous administration of zolbetuximab topregnant mice during organogenesis (see section 5.3). Zolbetuximab should only be given to apregnant 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, andbecause of the potential for serious adverse reactions in a breast-fed child, breast-feeding is notrecommended during treatment with zolbetuximab.

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

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

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 commonserious 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 mostcommon 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 mostcommon 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%), infusionrelated reaction (1.6%), decreased appetite (1.6%) and dyspepsia (1.1%).

The frequencies of adverse reactions are based on two phase 2 studies and two phase 3 studies in631 patients who received at least one dose of zolbetuximab 800 mg/m2 as a loading dose followed by600 mg/m2 maintenance doses every 3 weeks in combination with fluoropyrimidine- andplatinum-containing chemotherapy. Patients were exposed to zolbetuximab for a median duration of174 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 arepresented in order of decreasing seriousness.

Table 4. Adverse reactions

MedDRA System organ class Adverse reaction Frequency category

Blood and lymphatic system disorders Neutropenia Very common

Neutrophil count decreased

Immune system disorders Drug hypersensitivity Common

Anaphylactic reaction Uncommon

Metabolism and nutrition disorders Hypoalbuminaemia Very common

Decreased appetite

Vascular disorders Hypertension Common

Gastrointestinal disorders Vomiting Very common

Nausea

Dyspepsia Common

Salivary hypersecretion

General disorders and administration site Pyrexia Very commonconditions Oedema peripheral

Chills Common

Investigations Weight decreased Very common

Injury, poisoning and procedural Infusion related reaction Commoncomplications

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

Severe (Grade 3) anaphylactic reaction and drug hypersensitivity occurred with zolbetuximab incombination with fluoropyrimidine and platinum-containing chemotherapy at a frequency of 0.5% and0.2%.

Anaphylactic reaction led to permanent discontinuation of zolbetuximab in 0.3% of patients. Doseinterruption of zolbetuximab was experienced due to drug hypersensitivity in 0.3% of patients. Theinfusion rate was reduced for zolbetuximab or fluoropyrimidine and platinum-containingchemotherapy 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 withfluoropyrimidine 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 withfluoropyrimidine and platinum-containing chemotherapy.

An IRR led to permanent discontinuation of zolbetuximab in 0.5% of patients, and dose interruption in1.6% of patients. The infusion rate was reduced for zolbetuximab or fluoropyrimidine andplatinum-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 incombination 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 treatmentbut decreased in incidence with subsequent cycles of treatment. The median time to onset of nauseaand vomiting was 1 day each with zolbetuximab in combination with fluoropyrimidine andplatinum-containing chemotherapy. The median duration of nausea and vomiting was 3 days and1 day, respectively, with zolbetuximab in combination with fluoropyrimidine and platinum-containingchemotherapy.

Severe (Grade 3) nausea and vomiting occurred with zolbetuximab in combination withfluoropyrimidine 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 in25.5% of patients. Vomiting led to permanent discontinuation of zolbetuximab in 3.8% of patients, anddose interruption in 26.6% of patients. The infusion rate was reduced for zolbetuximab orfluoropyrimidine and platinum-containing chemotherapy in 9.7% of patients due to nausea and in7.8% of patients due to vomiting.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, the patient should be closely monitored for adverse reactions, and supportivetreatment should be administered, as appropriate.

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drugconjugates, ATC code: L01FX31

Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tightjunction molecule CLDN18.2. Nonclinical data suggest zolbetuximab binds selectively to cell linestransfected with CLDN18.2 or those that endogenously express CLDN18.2. Zolbetuximab depletes

CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) andcomplement-dependent cytotoxicity (CDC). Cytotoxic medicinal products were shown to increase

CLDN18.2 expression on human cancer cells and to improve zolbetuximab-induced ADCC and CDCactivities.

Based on the exposure-response analyses of efficacy and safety in patients with locally advancedunresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are

CLDN18.2 positive, there are no anticipated clinically significant differences in efficacy or safetybetween zolbetuximab doses of 800/400 mg/m2 every 2 weeks and 800/600 mg/m2 every 3 weeks.

Based on a pooled analysis of data from two phase 3 studies, the overall immunogenicity incidencewas 4.4% (21 of 479 total patients treated with zolbetuximab 800/600 mg/m² every 3 weeks incombination with mFOLFOX6/CAPOX were tested positive for anti-drug antibodies [ADAs]).

Because of the low occurrence of ADAs, the effect of these antibodies on the pharmacokinetics, safetyand/or effectiveness of zolbetuximab is unknown.

Gastric or GEJ adenocarcinoma

SPOTLIGHT (8951-CL-0301) and GLOW (8951-CL-0302)

The safety and efficacy of zolbetuximab in combination with chemotherapy was evaluated in twophase 3, double-blind, randomised, multicentre studies that enrolled 1072 patients whose tumourswere CLDN18.2 positive, HER2-negative, with locally advanced unresectable or metastatic gastric or

GEJ adenocarcinoma. CLDN18.2 positivity (defined as ≥75% of tumour cells demonstrating moderateto strong membranous CLDN18 staining) was determined by immunohistochemistry on gastric or GEJtumour tissue specimens from all patients with the VENTANA CLDN18 (43-14A) RxDx Assayperformed in a central laboratory.

Patients were randomised 1:1 to receive either zolbetuximab in combination with chemotherapy(n=283 in SPOTLIGHT, n=254 in GLOW) or placebo in combination with chemotherapy (n=282 in

SPOTLIGHT, n=253 in GLOW). Zolbetuximab was administered intravenously at a loading dose of800 mg/m2 (Day 1 of cycle 1) followed by maintenance doses of 600 mg/m2 every 3 weeks incombination with either mFOLFOX6 (oxaliplatin, folinic acid and fluorouracil), or CAPOX(oxaliplatin and capecitabine).

Patients in the SPOTLIGHT study received between 1-12 treatments of mFOLFOX6 [oxaliplatin85 mg/m2, folinic acid (leucovorin or local equivalent) 400 mg/m2, fluorouracil 400 mg/m2 given as abolus and fluorouracil 2400 mg/m2 given as a continuous infusion] administered on Days 1, 15 and 29of a 42-day cycle. After 12 treatments, patients were allowed to continue treatment with zolbetuximab,5-fluorouracil and folinic acid (leucovorin or local equivalent) at the discretion of the investigator,until progression of disease or unacceptable toxicity.

Patients in the GLOW study received between 1-8 treatments of CAPOX administered on Day 1(oxaliplatin 130 mg/m2) and on Days 1 to 14 (capecitabine 1000 mg/m2) of a 21-day cycle. After8 treatments of oxaliplatin, patients were allowed to continue treatment of zolbetuximab andcapecitabine at the discretion of the investigator, until progression of disease or unacceptable toxicity.

Baseline characteristics were generally similar between studies, except for the proportion of Asianversus non-Asian patients in each study.

In the SPOTLIGHT study, the median age was 61 years (range: 20 to 86); 62% were male; 53% were

Caucasian, 38% were Asian; 31% were from Asia and 69% were not from Asia. Patients had abaseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (43%) or 1 (57%).

Patients had a mean body surface area of 1.7 m2 (range: 1.1 to 2.5). The median time from diagnosiswas 56 days (range: 2 to 5366); 36% of tumour types were diffuse, 24% were intestinal; 76% hadgastric adenocarcinoma, 24% had GEJ adenocarcinoma; 16% had locally advanced disease and 84%had metastatic disease.

In the GLOW study, the median age was 60 years (range: 21 to 83); 62% were male; 37% were

Caucasian, 63% were Asian; 62% were from Asia and 38% were not from Asia. Patients had abaseline ECOG performance status of 0 (43%) or 1 (57%). Patients had a mean body surface area of1.7 m2 (range: 1.1 to 2.3). The median time from diagnosis was 44 days (range: 2 to 6010); 37% oftumour types were diffuse, 15% were intestinal; 84% had gastric adenocarcinoma, 16% had GEJadenocarcinoma; 12% had locally advanced disease and 88% had metastatic disease.

The primary efficacy outcome was progression-free survival (PFS) as assessed per RECIST v1.1 by anindependent review committee (IRC). The key secondary efficacy outcome was overall survival (OS).

Other secondary efficacy outcomes were objective response rate (ORR) and duration of response(DOR) as assessed per RECIST v1.1 by IRC.

In the primary analysis (final PFS and interim OS), the SPOTLIGHT study demonstrated a statisticallysignificant benefit in PFS (as assessed by IRC) and OS for patients who received zolbetuximab incombination with mFOLFOX6 compared with patients who received placebo in combination withmFOLFOX6 treatment. The PFS HR was 0.751 (95% CI: 0.598, 0.942; 1-sided P = 0.0066) and the

OS HR was 0.750 (95% CI: 0.601, 0.936; 1-sided P = 0.0053).

The updated PFS and final OS analysis for SPOTLIGHT are presented in table 5 and Figures 1-2 showthe Kaplan- Meier curves.

In the primary analysis (final PFS and interim OS), the GLOW study demonstrated a statisticallysignificant benefit in PFS (as assessed by IRC) and OS for patients who received zolbetuximab incombination with CAPOX compared with patients who received placebo in combination with CAPOXtreatment. The PFS HR was 0.687 (95% CI: 0.544, 0.866; 1-sided P = 0.0007) and the OS HR was0.771 (95% CI: 0.615, 0.965; 1-sided P = 0.0118).

The updated PFS and final OS analysis for GLOW are presented in table 5 and Figures 3-4 show the

Kaplan- Meier curves.

Table 5. Efficacy results in SPOTLIGHT and GLOW

SPOTLIGHTa GLOWb

Zolbetuximab Placebo Zolbetuximab Placebowith with with withmFOLFOX6 mFOLFOX6 CAPOX CAPOX

Endpoint n=283 n=282 n=254 n=253

Progression-free survival

Number (%) ofpatients with events 159 (56.2) 187 (66.3) 153 (60.2) 182 (71.9)

Median in months 11.0 8.9 8.2 6.8(95% CI)c (9.7, 12.5) (8.2, 10.4) (7.3, 8.8) (6.1, 8.1)

Hazard ratio (95%

CI)d,e 0.734 (0.591, 0.910) 0.689 (0.552, 0.860)

Overall survival

Number (%) ofpatients with events 197 (69.6) 217 (77.0) 180 (70.9) 207 (81.8)

Median in months 18.2 15.6 14.3 12.2(95% CI)c (16.1, 20.6) (13.7, 16.9) (12.1, 16.4) (10.3, 13.7)

Hazard ratio (95%

CI)d,e 0.784 (0.644, 0.954) 0.763 (0.622, 0.936)

Objective response rate (ORR), Duration of response (DOR)

ORR (%) (95% CI)f 39.1 (33.1,48.1 (42.1, 54.1) 47.5 (41.6, 53.5) 42.5 (36.4, 48.9) 45.4)

DOR Median inmonths (95% CI)f 9.0 (7.5, 10.4) 8.1 (6.5, 11.4) 6.3 (5.4, 8.3) 6.1 (4.4, 6.3)

a. SPOTLIGHT data cut-off: 08-Sep-2023, median follow-up time of zolbetuximab incombination with mFOLFOX6 arm was 18.0 months.

b. GLOW data cut-off: 12-Jan-2024, median follow-up time of zolbetuximab in combinationwith CAPOX arm 20.6 months.

c. Based on Kaplan-Meier estimate.

d. Stratification factors were region, number of metastatic sites, prior gastrectomy frominteractive response technology and study ID (SPOTLIGHT/GLOW).

e. Based on Cox proportional hazards model with treatment, region, number of organs withmetastatic sites, prior gastrectomy as the explanatory variables and study ID(SPOTLIGHT/GLOW).

f. Based on IRC assessment and unconfirmed responses.

A combined efficacy analysis of SPOTLIGHT and GLOW of the final OS and updated PFS resulted ina median PFS (as assessed by IRC) of 9.2 months (95% CI: 8.4, 10.4) for zolbetuximab incombination with mFOLFOX6/CAPOX versus 8.2 months (95% CI: 7.6, 8.4) for placebo withmFOLFOX6/CAPOX [HR 0.712, 95% CI: 0.610, 0.831] and a median OS for zolbetuximab incombination with mFOLFOX6/CAPOX of 16.4 months (95% CI: 15.0, 17.9) versus 13.7 months(95% CI: 12.3, 15.3) for placebo with mFOLFOX6/CAPOX [HR 0.774, 95% CI: 0.672, 0.892].

Figure 1. Kaplan Meier plot of progression-free survival, SPOTLIGHT

Figure 2. Kaplan Meier plot of overall survival, SPOTLIGHT

Figure 3. Kaplan Meier plot of progression-free survival, GLOW

Figure 4. Kaplan Meier plot of overall survival, GLOW

Exploratory subgroup analyses of efficacy for SPOTLIGHT and GLOW showed a difference in PFSand OS for Caucasian versus Asian patients.

For SPOTLIGHT, in Caucasian patients this resulted in a PFS (as assessed by IRC) with a HR of0.872 [95% CI: 0.653, 1.164] and an OS HR of 0.940 [95% CI: 0.718, 1.231] for zolbetuximab incombination with mFOLFOX6 versus placebo with mFOLFOX6. In Asian patients, this resulted in a

PFS (as assessed by IRC) with a HR of 0.526 [95% CI: 0.354, 0.781] and an OS HR of 0.636 [95% CI:0.450, 0.899] for zolbetuximab in combination with mFOLFOX6 versus placebo with mFOLFOX6.

For GLOW, in Caucasian patients this resulted in a PFS (as assessed by IRC) with a HR of 0.891[95% CI: 0.622, 1.276] and an OS HR of 0.805 [95% CI: 0.579, 1.120] for zolbetuximab incombination with CAPOX versus placebo with CAPOX. In Asian patients, this resulted in a PFS (asassessed by IRC) with a HR of 0.616 [95% CI: 0.467, 0.813] and an OS HR of 0.710 [95% CI: 0.549,0.917] for zolbetuximab in combination with CAPOX versus placebo with CAPOX.

The European Medicines Agency has waived the obligation to submit the results of studies withzolbetuximab in all subsets of the paediatric population in gastric or GEJ adenocarcinoma (seesection 4.2 for information on paediatric use).

Following intravenous administration, zolbetuximab exhibited dose-proportional pharmacokinetics atdoses ranging from 33 mg/m2 to 1000 mg/m2. When administered at 800/600 mg/m2 every 3 weeks,steady state was achieved by 24 weeks with a mean (SD) Cmax and AUCtau at 453 (82) µg/mL and 4125(1169) day*µg/mL, respectively, based on a population pharmacokinetic analysis. When administeredat 800/400 mg/m2 every 2 weeks, steady state is expected to be achieved by 22 weeks with a mean(SD) Cmax and AUCtau at 359 (68) µg/mL and 2758 (779) day*µg/mL, respectively, based on apopulation pharmacokinetics analysis.

The estimated mean steady state volume of distribution of zolbetuximab was 5.5 L.

Zolbetuximab is expected to be catabolised into small peptides and amino acids.

Zolbetuximab clearance (CL) decreased over time, with a maximal reduction from baseline values of57.6% resulting in a population mean steady-state clearance (CLss) of 0.0117 L/h. The half-life ofzolbetuximab ranged from 7.6 to 15.2 days during treatment.

Population pharmacokinetic analysis indicates that age [range: 22 to 83 years; 32.2% (230/714) were>65 years, 5.0% (36/714) were >75 years] did not have a clinically meaningful effect on thepharmacokinetics of zolbetuximab.

Based on the population pharmacokinetic analysis, no clinically significant differences in thepharmacokinetics of zolbetuximab were identified based on gender [62.3% male, 37.7% female] orrace [50.1% Caucasian, 42.2% Asian, 4.2% Missing, 2.7% Others, and 0.8% Black].

Based on the population pharmacokinetic analysis using data from clinical studies in patients withgastric or GEJ adenocarcinoma, no clinically significant differences in the pharmacokinetics ofzolbetuximab were identified in patients with mild (CrCL ≥60 to <90 mL/min; n=298) to moderate(CrCL ≥30 to <60 mL/min; n=109) renal impairment based on CrCL estimated by the Cockcroft-Gaultformula. Zolbetuximab has only been evaluated in a limited number of patients with severe renalimpairment (CrCL ≥15 to <30 mL/min; n=1). The effect of severe renal impairment on thepharmacokinetics of zolbetuximab is unknown.

Based on the population pharmacokinetic analysis using data from clinical studies in patients withgastric or GEJ adenocarcinoma, no clinically significant differences in the pharmacokinetics ofzolbetuximab were identified in patients with mild hepatic impairment as measured by TB and AST(TB ≤ ULN and AST > ULN, or TB > 1 to 1.5 × ULN and any AST; n=108). Zolbetuximab has onlybeen evaluated in a limited number of patients with moderate hepatic impairment(TB > 1.5 to 3 × ULN and any AST; n=4) and has not been evaluated in patients with severe hepaticimpairment (TB > 3 to 10 × ULN and any AST). The effect of moderate or severe hepatic impairmenton the pharmacokinetics of zolbetuximab is unknown.

No studies in animals have been performed to evaluate carcinogenicity or mutagenicity.

No toxicity or other zolbetuximab-related adverse effects on the cardiovascular, respiratory or centralnervous systems was observed in mice administered zolbetuximab for 13 weeks at systemic exposuresup to 7.0-fold the human exposure at the recommended dose of 600 mg/m2 (based on AUC) or incynomolgus monkeys administered zolbetuximab for 4 weeks at systemic exposures up to 6.1-fold thehuman exposure at the recommended dose of 600 mg/m2 (based on AUC).

In an embryo-foetal development toxicity study, where zolbetuximab was administered to pregnantmice during the period of organogenesis at systemic exposures up to approximately 6.2-fold the humanexposure at the recommended dose of 600 mg/m2 (based on AUC), zolbetuximab crossed the placentalbarrier. The resulting concentration of zolbetuximab in foetal serum at Day 18 of gestation was higherthan that in the maternal serum at Day 16 of gestation. Zolbetuximab did not result in any external orvisceral foetal abnormalities (malformations or variations).

Arginine

Phosphoric acid (E 338)

Sucrose

Polysorbate 80 (E 433)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial4 years.

Reconstituted solution in the vial

Reconstituted vials may be stored at room temperature (≤ 25 °C) for up to 6 hours. Do not freeze themnor expose them to direct sunlight. Discard unused vials with reconstituted solution beyond therecommended storage time.

Diluted solution in the infusion bag

From a microbiological point of view, the diluted solution in the bag should be administeredimmediately. If not administered immediately, the prepared infusion bag should be stored:

* under refrigeration (2 °C to 8 °C) for no longer than 24 hours, including infusion time, from theend of the preparation of the infusion bag. Do not freeze.

* at room temperature (≤ 25 °C) for no longer than 8 hours, including infusion time, from whenthe prepared infusion bag is removed from the refrigerator.

Do not expose to direct sunlight. Discard unused prepared infusion bags beyond the recommendedstorage time.

Store in a refrigerator (2 ºC - 8 ºC).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Vyloy 100 mg powder for concentrate for solution for infusion vial20 mL Type I glass vial with European blow-back feature, grey bromobutyl rubber stopper withethylene tetrafluoroethylene film, and aluminum seal with a green cap.

Vyloy 300 mg powder for concentrate for solution for infusion vial50 mL Type I glass vial with European blow-back feature, grey bromobutyl rubber stopper withethylene tetrafluoroethylene film, and aluminum seal with a violet cap.

Pack sizes 100 mg: one carton containing 1 or 3 vials.

Pack size 300 mg: one carton containing 1 vial.

Not all pack sizes may be marketed.

Instructions for preparation and administration

Reconstitution in single-dose vial

* Follow procedures for proper handling and disposal of anticancer medicinal products.

* Use appropriate aseptic technique for reconstitution and preparation of solutions.

* Calculate the recommended dose based on the patient’s body surface area to determine thenumber of vials needed.

* Reconstitute each vial as follows. If possible, direct the stream of sterile water for injections(SWFI) along the walls of the vial and not directly onto the lyophilised powder:

a. 100 mg vial: Slowly add 5 mL of SWFI, resulting in 20 mg/mL zolbetuximab.

b. 300 mg vial: Slowly add 15 mL of SWFI, resulting in 20 mg/mL zolbetuximab.

* Slowly swirl each vial until the contents are completely dissolved. Allow the reconstitutedvial(s) to settle. Visually inspect the solution until the bubbles are gone. Do not shake the vial.

* Visually inspect the solution for particulate matter and discolouration. The reconstituted solutionshould be clear to slightly opalescent, colourless to slight yellow and free of visible particles.

Discard any vial with visible particles or discolouration.

* Based upon the calculated dose amount, the reconstituted solution from the vial(s) should beadded to the infusion bag immediately. This product does not contain a preservative. If not usedimmediately, refer to section 6.3 for storage of reconstituted vials.

Dilution in infusion bag

* Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer intoan infusion bag.

* Dilute with sodium chloride 9 mg/mL (0.9%) solution for infusion. The infusion bag size shouldallow enough diluent to achieve a final concentration of 2 mg/mL zolbetuximab.

The diluted dosing solution of zolbetuximab is compatible with intravenous infusion bags composedof polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with either plasticizer[Di-(2-ethylhexyl) phthalate (DEHP) or trioctyl trimellitate (TOTM)], ethylene propylene copolymer,ethylene-vinyl acetate (EVA) copolymer, PP and styrene-ethylene-butylene-styrene copolymer, orglass (bottle for administration use), and infusion tubing composed of PE, polyurethane (PU), PVCwith either plasticizer [DEHP, TOTM or Di(2-ethylhexyl) terephthalate], polybutadiene (PB), orelastomer modified PP with in-line filter membranes (pore size 0.2 μm) composed of polyethersulfone(PES) or polysulfone.

* Mix the diluted solution by gentle inversion. Do not shake the bag.

* Visually inspect the infusion bag for any particulate matter prior to use. The diluted solutionshould be free of visible particles. Do not use the infusion bag if particulate matter is observed.

* Discard any unused portion left in the single-dose vials.

* Do not co-administer other medicinal products through the same infusion line.

* Administer the infusion immediately over a minimum of 2 hours through an intravenous line.

Do not administer as an intravenous push or bolus.

No incompatibilities have been observed with closed system transfer device composed of PP, PE,stainless steel, silicone (rubber/oil/resin), polyisoprene, PVC or with plasticizer [TOTM],acrylonitrile-butadiene-styrene (ABS) copolymer, methyl methacrylate-ABS copolymer, thermoplasticelastomer, polytetrafluoroethylene, polycarbonate, PES, acrylic copolymer, polybutylene terephthalate,

PB, or EVA copolymer.

No incompatibilities have been observed with central port composed of silicone rubber, titanium alloyor PVC with plasticizer [TOTM].

* In-line filters (pore size of 0.2 μm with materials listed above) are recommended to be usedduring administration.

* If not administered immediately, refer to section 6.3 for storage of the prepared infusion bag.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

EU/1/24/1856/001

EU/1/24/1856/002

EU/1/24/1856/003

Date of first authorisation: 19 September 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.