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 https://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.

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.

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

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, 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)].

6.1 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.

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.

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.

Other clinically relevant adverse reactions (<15%) in GLOW with a difference between arms of 5% compared to placebo included peripheral edema.

8.1 Pregnancy

Risk Summary

There are no data with VYLOY use in pregnant women to inform any drug-associated risks. Embryo-fetal toxicity was not observed in pregnant mice intravenously administered zolbetuximab-clzb [see Data]. VYLOY should only be given to a pregnant woman if the benefit outweighs the potential risk.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

In an embryo-fetal development toxicity study, zolbetuximab-clzb was intravenously administered to pregnant mice during the period of organogenesis and did not result in embryo-fetal toxicity at doses up to 300 mg/kg (approximately 1.9 times the recommended clinical dose based on AUC). Zolbetuximab-clzb crossed the placental barrier resulting in higher fetal serum concentrations on Day 18 of gestation than maternal serum concentrations on Day 16 of gestation.

8.2 Lactation

Risk Summary

There are no data on the presence of zolbetuximab-clzb in human milk, the effects on the breastfed child, or the effects on milk production. Because antibodies may be excreted in human milk and because of the potential for adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with VYLOY and for 8 months after the last dose.

8.3 Females and Males of Reproductive Potential

VYLOY is used in combination with fluoropyrimidine- or platinum-containing chemotherapy. Refer to the Full Prescribing Information of fluoropyrimidine- and platinum-containing chemotherapy products for pregnancy testing, contraception, and infertility information.

8.4 Pediatric Use

The safety and effectiveness of VYLOY in pediatric patients have not been established.

8.5 Geriatric Use

Of the 533 patients in clinical studies of VYLOY in combination with mFOLFOX6 or CAPOX, 34% (n=179) were over 65 years, and 5% were over 75 years (n=28) [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients.

12.1 Mechanism of Action

Zolbetuximab-clzb is a claudin 18.2 (CLDN18.2)-directed cytolytic antibody that depletes CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Zolbetuximab-clzb in combination with chemotherapy had increased antitumor activity in CLDN18.2-expressing mouse tumor models compared to zolbetuximab-clzb or chemotherapy alone.

12.2 Pharmacodynamics

The exposure-response relationships for efficacy and safety at the recommended dosages of zolbetuximab-clzb in patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are CLDN18.2 positive have not been fully characterized.

12.3 Pharmacokinetics

Following a 2-hour intravenous infusion, zolbetuximab-clzb exhibited dose-proportional pharmacokinetics at doses ranging from 33 mg/m2 to 1000 mg/m2 (0.04 times to 1.25 times the recommended first dose). When administered at a first dose of 800 mg/m2 followed by subsequent doses of 600 mg/m2 every 3 weeks, steady state was achieved by 18 weeks with a geometric mean (coefficient of variation [CV]%) Cmax of 415 (22%) mcg/mL and AUCtau of 3149 (37%) day•mcg/mL.

Distribution

The estimated geometric mean (CV%) of the steady state volume of distribution of zolbetuximab-clzb was 14.0 (59%) L.

Metabolism

Zolbetuximab-clzb is expected to be catabolized into small peptides and amino acids.

Elimination

The estimated geometric mean (CV%) of the clearance (CL) and t1/2 of zolbetuximab-clzb was 0.013 (44%) L/h and 41 (62%) days, respectively.

Specific Populations

The following factors had no clinically important effect on the clearance of zolbetuximab-clzb: age (range: 22 to 83 years), sex, race including White (50%), Asian (42%), Black (0.8%), mild to moderate (CLcr ≥30 to <90 mL/min) renal impairment and mild hepatic impairment (total bilirubin (TB) ≤upper limit of normal (ULN) and AST >ULN, or TB >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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies in animals have been performed with zolbetuximab-clzb to evaluate carcinogenicity, mutagenicity, or impairment of fertility.