VYLOY (zolbetuximab-clzb) for Injection, 2024 PDF

HIGHLIGHTS OF PRESCRIBING INFORMATION based on severity and type of reaction. Premedicate with antihistamines These highlights do not include all the information needed to use VYLOY for subsequent infusions after a hyper...

HIGHLIGHTS OF PRESCRIBING INFORMATION based on severity and type of reaction. Premedicate with antihistamines These highlights do not include all the information needed to use VYLOY for subsequent infusions after a hypersensitivity reaction. (2.4, 5.1) safely and effectively. See full prescribing information for VYLOY. Severe nausea and vomiting: Premedicate patients with antiemetics prior to each infusion. Interrupt or permanently discontinue VYLOY based on VYLOY® (zolbetuximab-clzb) for injection, for intravenous use the severity of the nausea and/or vomiting. Manage patients during and Initial U.S. Approval: 2024 after infusion with antiemetics or fluid replacement. (2.4, 5.2) ------------------------------ ADVERSE REACTIONS ----------------------------- --------------------------- INDICATIONS AND USAGE -------------------------- The most common adverse reactions (≥15%) for VYLOY in combination with VYLOY is a claudin 18.2-directed cytolytic antibody and is indicated in mFOLFOX6 or CAPOX were nausea, vomiting, fatigue, decreased appetite, combination with fluoropyrimidine- and platinum-containing chemotherapy diarrhea, peripheral sensory neuropathy, abdominal pain, constipation, for the first-line treatment of adults with locally advanced unresectable or decreased weight, hypersensitivity reactions, and pyrexia. metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are claudin The most common laboratory abnormalities (≥15%) for VYLOY in (CLDN) 18.2 positive as determined by an FDA-approved test (1). combination with mFOLFOX6 or CAPOX were decreased neutrophil count, decreased leucocyte count, decreased albumin, increased creatinine, decreased ---------------------- DOSAGE AND ADMINISTRATION ---------------------- hemoglobin, increased glucose, decreased lymphocyte count, increased Administer by intravenous infusion only. Do not administer VYLOY as aspartate aminotransferase, decreased platelets, increased alkaline an intravenous push or bolus. (2.6) phosphatase, increased alanine aminotransferase, decreased glucose, The recommended first dose of VYLOY is 800 mg/m2 followed by decreased sodium, increased phosphate, decreased potassium, and decreased 600 mg/m2 every 3 weeks or 400 mg/m2 every 2 weeks. (2.3) magnesium (6.1). --------------------- DOSAGE FORMS AND STRENGTHS -------------------- To report SUSPECTED ADVERSE REACTIONS, contact Astellas For injection: 100 mg lyophilized powder in a single-dose vial. (3) Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or ------------------------------ CONTRAINDICATIONS ----------------------------- www.fda.gov/medwatch. None. (4) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- ----------------------- WARNINGS AND PRECAUTIONS ---------------------- Lactation: Advise not to breastfeed. (8.2) Hypersensitivity reactions including serious anaphylaxis reactions and serious and fatal infusion-related reactions have occurred. Monitor See 17 for PATIENT COUNSELING INFORMATION and FDA- patients during and for at least 2 hours after infusion with VYLOY. approved patient labeling. Interrupt, slow the rate of infusion or permanently discontinue VYLOY Revised: 10/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Patient Selection 8.3 Females and Males of Reproductive Potential 2.2 Prior to Administration 8.4 Pediatric Use 2.3 Recommended Dosage 8.5 Geriatric Use 2.4 Dosage Modifications for Adverse Reactions 11 DESCRIPTION 2.5 Preparation 12 CLINICAL PHARMACOLOGY 2.6 Administration 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 12.6 Immunogenicity 5.1 Hypersensitivity reactions, including anaphylaxis reactions, and 13 NONCLINICAL TOXICOLOGY infusion related reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Severe Nausea and Vomiting 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION 8 USE IN SPECIFIC POPULATIONS *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5464272  FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE VYLOY, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive as determined by an FDA-approved test [see Dosage and Administration (2.1) and Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select adult patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 immunohistochemical staining) for treatment with VYLOY in combination with fluoropyrimidine- and platinum-containing chemotherapy using an FDA-approved test [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of CLDN18.2 is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Prior to Administration If a patient is experiencing nausea and/or vomiting prior to administration of VYLOY, the symptoms should be resolved to Grade ≤1 before administering the first infusion. Premedication Prior to each infusion of VYLOY, premedicate patients with a combination of antiemetics (e.g., NK-1 receptor blockers and/or 5-HT3 receptor blockers, as well as other drugs as indicated) for the prevention of nausea and vomiting [see Warnings and Precautions (5.2)]. 2.3 Recommended Dosage Administer VYLOY in combination with fluoropyrimidine- and platinum-containing chemotherapy as follows: First dose: 800 mg/m2 intravenously Subsequent doses: o 600 mg/m2 intravenously every 3 weeks, or o 400 mg/m2 intravenously every 2 weeks Continue treatment until disease progression or unacceptable toxicity. 2.4 Dosage Modifications for Adverse Reactions No dose reduction for VYLOY is recommended. Adverse reactions for VYLOY are managed by reducing the infusion rate, interruption of the infusion, withholding the dose, and/or permanently discontinuing VYLOY as described in Table 1. Reference ID: 5464272  Table 1. Recommended Dose Modifications for VYLOY for Adverse Reactions Adverse Reaction Severity1 Dose Modification Hypersensitivity or Grade 2 Interrupt the infusion until Grade ≤1, then Infusion-related resume at a reduced infusion rate for the reactions remaining infusion. [see Warnings and Premedicate and administer the next infusion Precautions (5.1)]. per the infusion rates in Table 2. Grade 32 or 4 or Immediately stop the infusion and anaphylaxis permanently discontinue. 1. Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) 2. Follow Grade 2 management for Grade 3 infusion-related nausea and vomiting 2.5 Preparation Reconstitution Calculate the recommended dose based on the patient’s body surface area as described in Section 2.3 to determine the total volume and number of vials needed. Reconstitute each vial by slowly adding 5 mL of Sterile Water For Injection, directing the stream along the walls of the vial and not directly onto the lyophilized powder. The reconstituted solution contains 20 mg/mL of VYLOY. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle until the bubbles are gone. Do not shake the vial. Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution should be clear to slightly opalescent, colorless to slight yellow and free of visible particles. Discard any vial with visible particles or discoloration. Store reconstituted vial(s) at room temperature 15°C to 30°C (59°F to 86°F) for up to 5 hours if not used immediately. This product does not contain a preservative. Dilution Withdraw the required volume of reconstituted VYLOY vial(s) and transfer into an infusion bag containing 0.9% Sodium Chloride Injection, to a final concentration of 5 mg/mL. o The diluted solution of VYLOY is compatible with intravenous infusion bags composed of polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) [with either Di(2-ethylhexyl) phthalate (DEHP) or, Trioctyl trimellitate (TOTM) plasticizers], ethylene propylene copolymer, ethylene-vinyl acetate (EVA) copolymer, PP and styrene-ethylene-butylene-styrene copolymer, o The diluted solution of VYLOY is compatible with infusion tubing composed of PE, PVC [with DEHP, TOTM or Di(2-ethylhexyl) terephthalate plasticizers], polybutadiene (PB), or elastomer modified polypropylene with in-line filter membranes composed of polyethersulfone (PES) or polysulfone. Mix diluted solution by gentle inversion. Do not shake the bag. Visually inspect the infusion bag for any particulate matter prior to use. The diluted solution should 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. Storage of diluted infusion Store the prepared infusion bag: a. At room temperature 15°C to 30°C (59°F to 86°F) for no longer than 6 hours from the end of the preparation of the infusion bag to the completion of the infusion. b. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 16 hours from the end of the preparation of the infusion bag to the completion of the infusion. Do not freeze. Reference ID: 5464272  2.6 Administration Administer VYLOY as an intravenous infusion only. Do NOT administer as an intravenous push or bolus. If VYLOY and fluoropyrimidine- and platinum-containing chemotherapy are administered on the same day, VYLOY must be administered first. No incompatibilities have been observed with o closed system transfer devices composed of PP, PE, stainless steel, silicone (rubber/oil/resin), polyisoprene, PVC with TOTM plasticizer, acrylonitrile-butadiene-styrene (ABS) copolymer, methyl methacrylate-ABS copolymer, thermoplastic elastomer, polytetrafluoroethylene, polycarbonate, PES, acrylic copolymer, polybutylene terephthalate, PB, or EVA copolymer. o central ports composed of silicone rubber, titanium alloy or PVC with TOTM plasticizer. In-line filters (pore size of 0.2 μm composed of materials listed above) are recommended to be used during administration. Do NOT co-administer other drugs through the same infusion line. Immediately administer the infusion as described in Table 2. To minimize the risk of adverse reactions, begin each infusion at a slower rate for 30 to 60 minutes; if tolerated, gradually increase the rate as described in Table 2. If the infusion time exceeds the recommended storage time (6 hours from end of preparation of infusion solution at room temperature or 16 hours from end of preparation of infusion solution under refrigeration), the infusion bag must be discarded and a new infusion bag prepared to continue the infusion. Infusion Rate Recommendations Table 2. Infusion Rates Recommended for Each VYLOY Infusion Initial Infusion Rate Subsequent Infusion VYLOY Dose (first 30-60 minutes)1 Rate 800 mg/m2 100 mg/m2/hr 200-265 mg/m2/hr First Dose 600 mg/m2 every 3 weeks 75 mg/m2/hr 150-265 mg/m2/hr Subsequent Doses or or or 400 mg/m2 every 2 weeks 50 mg/m2/hr 100-200 mg/m2/hr 1. In the absence of adverse reactions after 30 to 60 minutes, the infusion rate can be increased to the subsequent infusion rate as tolerated. 3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg of zolbetuximab-clzb as a white to off-white lyophilized powder in a single-dose vial for reconstitution. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity reactions, including anaphylaxis reactions, and infusion related reactions Hypersensitivity reactions, including serious anaphylaxis reactions, and serious and fatal infusion-related reactions (IRR) have been reported in clinical studies when VYLOY has been administered. Any grade hypersensitivity reactions, including anaphylactic reactions, occurring with VYLOY in combination with mFOLFOX6 or CAPOX was 18%. Severe (Grade 3 or 4) hypersensitivity reactions, including anaphylactic reactions, Reference ID: 5464272  occurred in 2% of patients. Seven patients (1.3%) permanently discontinued VYLOY for hypersensitivity reactions, including two patients (0.4%) who permanently discontinued VYLOY due to anaphylactic reactions. Seventeen (3.2%) patients required dose interruption, and three patients (0.6%) required infusion rate reduction due to hypersensitivity reactions. All grade IRRs occurred in 3.2% in patients administered VYLOY in combination with mFOLFOX6 or CAPOX. Severe (Grade 3) IRRs occurred in 2 (0.4%) patients who received VYLOY. An IRR led to permanent discontinuation of VYLOY in 2 (0.4%) patients and dose interruption in 7 (1.3%) patients. The infusion rate was reduced for VYLOY for 2 (0.4%) patients due to an IRR. Monitor patients during infusion with VYLOY and for 2 hours after completion of infusion or longer if clinically indicated, for hypersensitivity reactions with symptoms and signs that are highly suggestive of anaphylaxis (urticaria, repetitive cough, wheeze and throat tightness/change in voice). Monitor patients for signs and symptoms of IRRs including nausea, vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough and hypertension. If a severe or life-threatening hypersensitivity or IRR reaction occurs, discontinue VYLOY permanently, treat symptoms according to standard medical care, and monitor until symptoms resolve. For any Grade 2 hypersensitivity or IRR, interrupt the VYLOY infusion until Grade ≤1, then resume at a reduced infusion rate for the remaining infusion. Premedicate the patient with antihistamines for the subsequent infusions, administer per the infusion rates in Table 2 and closely monitor the patient for symptoms and signs of a hypersensitivity reaction. The infusion rate may be gradually increased as tolerated [see Dosage and Administration (2.4)]. 5.2 Severe Nausea and Vomiting VYLOY is emetogenic. Nausea and vomiting occurred more often during the first cycle of treatment. All grade nausea and vomiting occurred in 82% and 67% respectively of patients treated with VYLOY in combination with mFOLFOX6 and 69% and 66% in combination with CAPOX, respectively. Severe (Grade 3) nausea occurred in 16% and 9% of patients treated with VYLOY in combination with mFOLFOX6 or CAPOX respectively. Severe (Grade 3) vomiting occurred in 16% and 12% of patients treated with VYLOY in combination with mFOLFOX6 or CAPOX. Nausea led to permanent discontinuation of VYLOY in combination with mFOLFOX6 or CAPOX in 18 (3.4%) patients and dose interruption in 147 (28%) patients. Vomiting led to permanent discontinuation of VYLOY in combination with mFOLFOX6 or CAPOX in 20 (3.8%) patients and dose interruption in 150 (28%) patients. Pretreat with antiemetics prior to each infusion of VYLOY [see Dosage and Administration (2.2)]. Manage patients during and after infusion with antiemetics or fluid replacement. Interrupt the infusion, or permanently discontinue VYLOY based on severity [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions, including anaphylaxis, and infusion related reactions [see Warnings and Precautions (5.1)] Severe Nausea and Vomiting [see Warnings and Precautions (5.2)] Reference ID: 5464272  6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to VYLOY in 533 patients at an 800 mg/m2 initial dose followed by subsequent doses of 600 mg/m2 every 3 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy in the SPOTLIGHT (279) and GLOW (254) studies. Among 533 patients who received VYLOY in these studies, 47% were exposed for ≥6 months and 20% were exposed for ≥12 months. In this pooled population, the most common (>15%) adverse reactions, were nausea, vomiting, fatigue, decreased appetite, diarrhea, peripheral sensory neuropathy, abdominal pain, constipation, decreased weight, hypersensitivity reactions, and pyrexia. The most common (≥15%) laboratory abnormalities in the pooled population were decreased neutrophil count, decreased leucocyte count, decreased albumin, increased creatinine, decreased hemoglobin, increased glucose, decreased lymphocyte count, increased aspartate aminotransferase, decreased platelets, increased alkaline phosphatase, increased alanine aminotransferase, decreased glucose, decreased sodium, increased phosphate, decreased potassium, and decreased magnesium. SPOTLIGHT The safety of VYLOY was evaluated in SPOTLIGHT in patients with locally advanced unresectable or metastatic gastric or GEJ cancer who received at least one dose of VYLOY at an 800 mg/m2 initial dose followed by 600 mg/m2 subsequent doses every 3 weeks in combination with mFOLFOX6 [see Clinical Studies (14)]. The median duration of exposure to VYLOY in combination with mFOLFOX6 was 6.2 months (range: 1 day to 40.9 months). Serious adverse reactions occurred in 45% of patients treated with VYLOY in combination with mFOLFOX6; the most common serious adverse reactions (≥2%) were vomiting (8%), nausea (7%), neutropenia (2.9%), febrile neutropenia (2.9%), diarrhea (2.9%), intestinal obstruction (3.2%), pyrexia (2.5%), pneumonia (2.5%), respiratory failure (2.2%), pulmonary embolism (2.2%), decreased appetite (2.1%) and sepsis (2.0%). Fatal adverse reactions occurred in 5% of patients who received VYLOY in combination with mFOLFOX6 including sepsis (1.4%), pneumonia (1.1%), respiratory failure (1.1%), intestinal obstruction (0.7%), acute hepatic failure (0.4%), acute myocardial infarction (0.4%), death (0.4%), disseminated intravascular coagulation (0.4%), encephalopathy (0.4%), and upper gastrointestinal hemorrhage (0.4%). Permanent discontinuation of VYLOY due to an adverse reaction occurred in 20% of patients; the most common adverse reactions leading to discontinuation (≥2%) were nausea and vomiting. Dosage interruptions of VYLOY due to an adverse reaction occurred in 75% of patients; the most common adverse reactions leading to dose interruption (≥5%) were nausea, vomiting, neutropenia, abdominal pain, fatigue, and hypertension. Tables 3 and 4 summarize the most common (≥15%) adverse reactions and laboratory abnormalities with a difference between arms of ≥5%, respectively, compared to placebo in SPOTLIGHT. Reference ID: 5464272  Table 3. Adverse Reactions (≥15%) in Patients Treated with VYLOY in SPOTLIGHT with a Difference Between Arms of ≥5% Compared to Placebo VYLOY Placebo with mFOLFOX6 with mFOLFOX6 n=279 n=278 All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction % % % % Gastrointestinal disorders Nausea 82 16 61 7 Vomiting 67 16 36 6 Metabolism and nutrition disorders Decreased appetite 47 6 34 3.2 General disorders and administration site conditions Peripheral edema 18 0.7 9 0 Table 4. Laboratory Abnormalities (≥ 15%) in SPOTLIGHT with a Difference Between Arms of ≥ 5% Compared to Placebo VYLOY with mFOLFOX61 Placebo with mFOLFOX61 All Grades Grade 3 or 4 All Grades Grade 3 or 4 Laboratory Abnormality % % % % Albumin decreased 78 4.4 47 1.1 Potassium decreased 28 11 21 6 Glucose decreased 45 0.4 35 0.4 Sodium decreased 29 5 21 2.9 1. The denominator used to calculate the rate varied from 271 to 272 based on the number of patients with a baseline value and at least one post-treatment value. GLOW The safety of VYLOY was evaluated in GLOW in patients with locally advanced unresectable or metastatic gastric/GEJ cancer who received at least one dose of VYLOY at an 800 mg/m2 initial dose followed by 600 mg/m2 subsequent doses every 3 weeks in combination with CAPOX [see Clinical Studies (14)]. The median duration of exposure to VYLOY in combination with CAPOX was 4.4 months (range: 0.03 to 30.7 months). Serious adverse reactions occurred in 47% of patients treated with VYLOY in combination with CAPOX; the most common serious adverse reactions (≥2%) were vomiting (6%), nausea (4.3%), decreased appetite (3.9%), decreased platelet count (3.1%), upper gastrointestinal hemorrhage (2.8%), diarrhea (2.8%), pneumonia (2.4%), pulmonary embolism (2.3%), and pyrexia (2.0%). Fatal adverse reactions occurred in 8% of patients who received VYLOY in combination with CAPOX including sepsis (1.2%), pneumonia (0.4%), death (0.8%), upper gastrointestinal hemorrhage (0.8%), cerebral hemorrhage (0.8%), abdominal infection (0.4%), acute respiratory distress syndrome (0.4%), cardio-respiratory arrest (0.4%), decreased platelet count (0.4%), disseminated intravascular coagulation (0.4%), dyspnea (0.4%), gastric perforation (0.4%), hemorrhagic ascites (0.4%), procedural complication (0.4%), sudden death (0.4%), and syncope (0.4%). Permanent discontinuation of VYLOY due to an adverse reaction occurred in 19% of patients; the most common adverse reaction leading to discontinuation (≥2%) was vomiting. Dosage interruption of VYLOY due to an adverse reaction occurred in 55% of patients; the most common adverse reactions leading to dose interruption (≥2%) were nausea, vomiting, neutropenia, thrombocytopenia, anemia, fatigue, infusion-related reaction, and abdominal pain. Reference ID: 5464272  Tables 5 and 6 summarize the most common (≥15%) adverse reactions and laboratory abnormalities with a difference between arms of ≥5%, respectively compared to placebo in GLOW. Table 5. Adverse Reactions (≥15%) in Patients Treated with VYLOY in GLOW with a Difference Between Arms of ≥5% Compared to Placebo VYLOY Placebo with CAPOX with CAPOX n=254 n=249 All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction % % % % Gastrointestinal disorders Nausea 69 9 50 2.4 Vomiting 66 12 31 3.6 Metabolism and nutrition disorders Decreased appetite 41 7 34 1.6 Blood and lymphatic system disorders Neutropenia 20 7 14 2.8 Investigations Weight decreased 20 0.4 10 0.4 Other clinically relevant adverse reactions (1 to 1.5 x ULN and any AST). The effect of severe renal impairment, and moderate to severe hepatic impairment is unknown. 12.6 Immunogenicity There is insufficient information to characterize the anti-drug antibody response to zolbetuximab-clzb and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety or efficacy of zolbetuximab products. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies in animals have been performed with zolbetuximab-clzb to evaluate carcinogenicity, mutagenicity, or impairment of fertility. Reference ID: 5464272  14 CLINICAL STUDIES SPOTLIGHT The efficacy of VYLOY in combination with mFOLFOX6 was evaluated in SPOTLIGHT (NCT03504397), a double-blind, randomized, multicenter study that enrolled 565 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. CLDN18.2 positivity (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining) was determined by immunohistochemistry on gastric or GEJ tumor tissue specimens from all patients with the VENTANA CLDN18 (43-14A) RxDx Assay performed in a central laboratory. Patients were excluded from the study if they had a complete or partial gastric outlet syndrome, or history of central nervous system metastases. Patients were randomized 1:1 to receive VYLOY in combination with mFOLFOX6 (n=283) or placebo in combination with mFOLFOX6 (n=282). VYLOY was administered intravenously at an initial dose of 800 mg/m2 (Day 1 of cycle 1) followed by subsequent doses of 600 mg/m2 every 3 weeks in combination with up to 12 treatments (4 cycles) of mFOLFOX6 (oxaliplatin 85 mg/m2, folinic acid (leucovorin or local equivalent) 400 mg/m2, fluorouracil 400 mg/m2 given as a bolus and fluorouracil 2400 mg/m2 given as a continuous infusion) administered on Days 1, 15 and 29 of a 42-day cycle. After 12 treatments, patients were allowed to continue treatment with VYLOY, 5-fluorouracil and folinic acid (leucovorin or local equivalent) at the discretion of the investigator, until progression of disease or unacceptable toxicity. Treatment with VYLOY continued until RECIST v1.1-defined progression of disease as determined by an independent review committee (IRC) or a subsequent anticancer treatment was initiated. Tumor assessments were performed every 9 weeks up to and including Week 54, then every 12 weeks thereafter. The major efficacy outcome measure was progression free survival (PFS) as assessed per RECIST v1.1 by IRC. Additional efficacy outcome measures were overall survival (OS), objective response rate (ORR) and duration of response (DOR) as assessed per RECIST v1.1 by IRC. The study population characteristics were median age of 61 (range: 20-86); 62% were male; 48% were White, 34% Asian, 3.0% American Indian or Alaska, 1.2% Black or African American, 4.1% other racial groups, and race in 9% was unknown or missing; 78% non-Hispanic or Latino, 13% Hispanic or Latino, and ethnicity in 10% was missing; 98% had ECOG performance status (PS) of 0 or 1; 76% had gastric cancer, 24% had GEJ cancer; 84% were metastatic, 16% were locally advanced; and 29% had undergone prior gastrectomy. Subsequent anticancer therapy was received by 135 (48%) patients in the VYLOY in combination with mFOLFOX6 arm and 148 (53%) patients in the placebo in combination with mFOLFOX6 arm. VYLOY in combination with mFOLFOX6 demonstrated a statistically significant improvement in PFS and OS compared with placebo in combination with mFOLFOX6. Table 7, Figures 1 and 2 summarize the efficacy results for the SPOTLIGHT study. Table 7. Efficacy Results in SPOTLIGHT VYLOY Placebo with mFOLFOX6 with mFOLFOX6 Endpoint n=283 n=282 Progression Free Survival Number (%) of patients with events 146 (51.6) 167 (59.2) Median in months (95% CI)1 10.6 (8.9, 12.5) 8.7 (8.2, 10.3) Hazard ratio (95% CI)2,3 0.751 (0.598, 0.942) 1-sided p-value2,4 0.0066 Overall survival Number (%) of patients with events 149 (52.7) 177 (62.8) Reference ID: 5464272  VYLOY Placebo with mFOLFOX6 with mFOLFOX6 Endpoint n=283 n=282 Median in months (95% CI)1 18.2 (16.4, 22.9) 15.5 (13.5, 16.5) Hazard ratio (95% CI)2,3 0.750 (0.601, 0.936) 1-sided p-value2,4 0.0053 Objective Response Rate (CR + PR)5 ORR (%) (95% CI)6 40.3 (34.5, 46.3) 39.7 (34.0, 45.7) Complete response rate (%) 14 (4.9) 8 (2.8) Partial response rate (%) 100 (35.3) 104 (36.9) Duration of Response N=114 N=112 Median in months (95% CI) 10.3 (8.3, 10.9) 10.5 (7.7, 13.3) 1. Based on Kaplan-Meier estimate. 2. Stratification factors were region, number of metastatic sites and prior gastrectomy from IRT. 3. Based on a stratified Cox proportional hazards model. 4. Based on a 1-sided stratified log-rank test. 5. Based on confirmed response. 6. Based on binomial distribution (Clopper-Pearson). Figure 1. Kaplan Meier Plot of Progression Free Survival, SPOTLIGHT Study Reference ID: 5464272  Figure 2. Kaplan Meier Plot of Overall Survival, SPOTLIGHT Study GLOW The efficacy of VYLOY in combination with CAPOX was evaluated in GLOW (NCT03653507), a double-blind, randomized, multicenter study that enrolled 507 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. CLDN18.2 positivity (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining) was determined by immunohistochemistry on gastric or GEJ tumor tissue specimens from all patients with the VENTANA CLDN18 (43-14A) RxDx Assay performed in a central laboratory. Patients were excluded from the study if they had a complete or partial gastric outlet syndrome, or history of central nervous system metastases. Patients were randomized 1:1 to receive VYLOY in combination with CAPOX (n=254) or placebo in combination with CAPOX (n=253). VYLOY was administered intravenously at an initial dose of 800 mg/m2 (Day 1 of cycle 1) followed by a subsequent dose of 600 mg/m2 every 3 weeks in combination with up to 8 treatments (8 cycles) 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. After 8 treatments of oxaliplatin, patients were allowed to continue treatment of VYLOY and capecitabine at the discretion of the investigator, until progression of disease or unacceptable toxicity. Treatment with VYLOY continued until RECIST v1.1-defined progression of disease as determined by IRC or subsequent anticancer treatment was initiated. Tumor assessments were performed every 9 weeks up to and including Week 54, then every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed per RECIST v1.1 by IRC. Additional efficacy outcome measures were OS, ORR, and DOR as assessed per RECIST v1.1 by IRC. The study population characteristics were median age of 60 years (range: 21-83); 62% were male; 62% were Asian, 36% were White and race in 1.4% was missing; 95% non-Hispanic or Latino, 3.4% were Hispanic or Latino and ethnicity in 1.4% was missing; 99% had ECOG performance status (PS) of 0 or 1; 84% had primary gastric cancer, 16% had primary Reference ID: 5464272  gastroesophageal adenocarcinoma; 88% were metastatic, 12% were locally advanced; and 27% had undergone prior gastrectomy. VYLOY in combination with CAPOX demonstrated a statistically significant improvement in PFS and OS compared with placebo in combination with CAPOX. Table 8, Figures 3 and 4 summarize the efficacy results for the GLOW study. Table 8. Efficacy Results in GLOW VYLOY Placebo Endpoint with CAPOX with CAPOX n=254 n=253 Progression Free Survival Number (%) of patients with events 137 (53.9) 172 (68.0) 1 Median in months (95% CI) 8.2 (7.5, 8.8) 6.8 (6.1, 8.1) Hazard ratio (95% CI)2,3 0.687 (0.544, 0.866) 1-sided p-value2,4 0.0007 Overall survival Number (%) of patients with events 144 (56.7) 174 (68.8) Median in months (95% CI)1 14.4 (12.3, 16.5) 12.2 (10.3, 13.7) Hazard ratio (95% CI)2,3 0.771 (0.615, 0.965) 1-sided p-value2,4 0.0118 Objective Response Rate (CR + PR)5 ORR (%) (95% CI)6 32.3 (26.6, 38.4) 31.2 (25.6, 37.3) Complete response rate (%) 6 (2.4) 2 (0.8) Partial response rate (%) 76 (29.9) 77 (30.4) Duration of Response N=82 N=79 Median in months (95% CI) 8.3 (6.3, 11.4) 6.2 (6.0, 7.6) 1. Based on Kaplan-Meier estimate. 2. Stratification factors were region, number of metastatic sites and prior gastrectomy from IRT. 3. Based on a stratified Cox proportional hazards model. 4. Based on a 1-sided stratified log-rank test. 5. Based on confirmed response. 6. Based on binomial distribution (Clopper-Pearson). Reference ID: 5464272  Figure 3. Kaplan Meier Plot of Progression Free Survival, GLOW Study Figure 4. Kaplan Meier Plot of Overall Survival, GLOW Study 16 HOW SUPPLIED/STORAGE AND HANDLING VYLOY (zolbetuximab-clzb) for injection is supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials. Each vial contains 100 mg of Vyloy and is available in the following package: Reference ID: 5464272  Carton of one 100 mg single-dose vial (NDC 0469-3425-10) Store VYLOY vials refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypersensitivity reactions, including anaphylaxis and infusion-related reactions Advise patients of the risk of hypersensitivity reactions including anaphylaxis and infusion-related reactions and to contact their healthcare provider right away if they experience symptoms of a hypersensitivity or infusion-related reaction during or after the administration of VYLOY. [see Warnings and Precautions (5.1)]. Severe nausea and vomiting Advise patients of the risk of severe nausea and vomiting and to immediately contact their healthcare provider if they experience persistent or worsening nausea or vomiting [see Warnings and Precautions (5.2)]. Lactation Advise women not to breastfeed during treatment with VYLOY and for 8 months after the last dose of VYLOY [see Use in Specific Populations (8.2)]. Manufactured by: Astellas Pharma US, Inc. Northbrook, Illinois 60062 U.S. License 2124 All trademarks are the property of their respective owners. ©2024 Astellas Pharma US, Inc. Reference ID: 5464272  PATIENT INFORMATION VYLOY® (vye-LOY) (zolbetuximab-clzb) for injection What is VYLOY? VYLOY is a prescription medicine used to treat adults with cancer of the stomach (gastric cancer) or cancer located where the esophagus joins the stomach (gastroesophageal junction cancer). VYLOY is used in combination with chemotherapy that contains fluoropyrimidine and platinum as the first treatment when your gastric or gastroesophageal junction cancer: cannot be removed with surgery or has spread to other parts of the body, is HER2-negative, and your tumor tests positive for “claudin (CLDN)18.2.” It is not known if VYLOY is safe and effective in children. Before receiving VYLOY, tell your healthcare provider about all of your medical conditions, including if you: have nausea or vomiting. are pregnant or plan to become pregnant. It is not known if VYLOY will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if VYLOY passes into your breast milk. Do not breastfeed during treatment with VYLOY and for 8 months after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive VYLOY? VYLOY will be given to you by intravenous (IV) infusion into your vein. Your healthcare provider will decide how much VYLOY you will receive. You will usually receive VYLOY every 2 or 3 weeks based on the chemotherapy chosen by your healthcare provider. Your healthcare provider will decide how many treatments you need. What are the possible side effects of VYLOY? VYLOY may cause serious side effects, including: Allergic reactions, including anaphylaxis and infusion related reactions. Allergic reactions are common during treatment with VYLOY and can sometimes be serious. Serious allergic reactions can happen during or after your VYLOY infusion, including life-threatening allergic reactions and serious infusion-related reactions that may lead to death. Your healthcare provider will monitor you during your infusion and for 2 hours after or longer if needed. Tell your healthcare provider or get emergency medical help right away if you get any of the following symptoms of a serious allergic reaction during or after your infusion of VYLOY: o itchy, raised bumps on the skin (hives) o breathing problems such as wheezing o coughing that does not go away o throat tightness or change in voice o nausea or vomiting o fever o stomach (abdominal) pain o chest discomfort o increased saliva o chills or shaking o back pain Severe nausea and vomiting. Nausea and vomiting are common during treatment with VYLOY and can sometimes be severe. Nausea and vomiting happened more often during the first treatment cycle. Before you receive each VYLOY infusion, your healthcare provider will give you medicines to help prevent nausea and vomiting. Tell your healthcare provider right away if nausea or vomiting does not go away or gets worse. The most common side effects of VYLOY include: tiredness fever decreased appetite decreased white blood cells, red blood cells and diarrhea platelets tingling or numbness of the arms or legs decreased protein (albumin) in the blood stomach (abdominal) pain changes in kidney function tests constipation changes in blood sugar (glucose) decreased weight changes in liver function tests changes in body salts (electrolytes) in your blood Reference ID: 5464272  Your healthcare provider may slow the rate of your infusion, temporarily stop, or completely stop treatment with VYLOY if you have certain side effects. These are not all of the possible side effects of VYLOY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of VYLOY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about VYLOY that is written for health professionals. What are the ingredients in VYLOY? Active ingredient: zolbetuximab-clzb Inactive ingredients: arginine, polysorbate 80, sucrose, and phosphoric acid to adjust pH. Manufactured by: Astellas Pharma US, Inc. Northbrook, Illinois 60062 U.S. License 2124 ©2024 Astellas Pharma US, Inc. For more information, go to www.VYLOY.com or call 1-888-727-7003. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 10/2024 Reference ID: 5464272