Full Prescribing Information

ZELVARA is indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative, claudin 18.2 (CLDN18.2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. CLDN18.2 positivity should be determined by an FDA-approved test [see Clinical Studies (14)].

2.1 Patient Selection Select patients for treatment based on the presence of CLDN18.2-positive tumor status, as determined by an FDA-approved test. CLDN18.2 positivity is defined as ≥75% of tumor cells showing moderate-to-strong membranous staining (IHC 2+/3+). 2.2 Recommended Dosage The recommended dosage of ZELVARA is: • Loading dose: 800 mg/m² administered as an intravenous infusion over approximately 3.5 hours on Day 1 of Cycle 1. • Maintenance dose: 600 mg/m² administered as an intravenous infusion over approximately 2.5 hours on Day 1 of each subsequent 21-day cycle. Administer ZELVARA prior to chemotherapy when given on the same day. Continue treatment until disease progression or unacceptable toxicity. 2.3 Premedication Administer the following premedication approximately 30 minutes prior to each ZELVARA infusion: • Dexamethasone 12 mg intravenously • Ondansetron 8 mg intravenously • Diphenhydramine 25-50 mg intravenously or orally (optional for Cycle 2 onward if no prior infusion reaction) 2.4 Dose Modifications Nausea/Vomiting: • Grade 3: Withhold until ≤ Grade 1, then resume at 75% dose. For recurrence, reduce to 50% dose or discontinue. • Grade 4: Permanently discontinue. Infusion-Related Reactions: • Grade 1-2: Interrupt infusion, administer medications, resume at 50% rate if resolved. • Grade 3-4: Permanently discontinue. Hematologic Toxicity: • Neutrophils < 1.0 × 10⁹/L or Platelets < 75 × 10⁹/L: Withhold until recovery, then resume at same dose. For recurrence, reduce by 25%. 2.5 Preparation and Administration • Dilute in 250 mL 0.9% Sodium Chloride Injection, USP. • Do not mix with or administer as an infusion with other medicinal products. • Use within 24 hours if stored at 2°C to 8°C (36°F to 46°F); 8 hours at room temperature. • Administer using an infusion set with a 0.2-micron in-line filter.

Injection: 500 mg/20 mL (25 mg/mL) as a clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.

ZELVARA is contraindicated in patients with known severe hypersensitivity to celdatuzumab-mkrz or any component of the formulation.

5.1 Nausea and Vomiting ZELVARA can cause severe nausea and vomiting. In the BEACON-1 trial, nausea of any grade occurred in 70.2% and Grade ≥3 nausea in 14.8% of patients treated with ZELVARA plus chemotherapy, compared with 52.1% and 6.4% in the placebo plus chemotherapy arm. Vomiting of any grade occurred in 64.8% and Grade ≥3 vomiting in 12.1%, compared with 32.4% and 3.8%. The median time to onset of first nausea event was 2 days (range: 1-42 days). Nausea led to dose reduction in 8.2% and discontinuation in 2.8% of patients. Administer antiemetic prophylaxis prior to and during ZELVARA treatment. Withhold, dose reduce, or permanently discontinue ZELVARA based on severity [see Dosage and Administration (2.4)]. 5.2 Infusion-Related Reactions Infusion-related reactions were reported in 8.4% of patients treated with ZELVARA plus chemotherapy. Grade 3 infusion-related reactions occurred in 1.2% of patients. No Grade 4 or fatal infusion-related reactions were reported. Monitor patients during and for at least 30 minutes after each infusion. Interrupt or slow the rate of infusion for mild to moderate reactions. Permanently discontinue ZELVARA for severe or life-threatening reactions. 5.3 Embryo-Fetal Toxicity Based on its mechanism of action targeting CLDN18.2, which is expressed in fetal gastric tissue, and findings from animal reproduction studies, ZELVARA can cause fetal harm when administered to a pregnant woman. In animal studies, administration of an anti-CLDN18.2 antibody to pregnant animals resulted in increased embryo-fetal loss and structural abnormalities at exposures below the human exposure at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELVARA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

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 safety of ZELVARA was evaluated in 538 patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma who received ZELVARA plus chemotherapy in the BEACON-1 (n=282) and BEACON-2 (n=256) trials. Most Common Adverse Reactions (≥10% in ZELVARA + chemotherapy arm): • Nausea: 70.2% (all grades), 14.8% (Grade ≥3) vs 52.1% / 6.4% (placebo + chemo) • Vomiting: 64.8% / 12.1% vs 32.4% / 3.8% • Decreased appetite: 42.1% / 5.2% vs 28.4% / 2.8% • Fatigue: 38.4% / 4.1% vs 32.6% / 3.2% • Diarrhea: 28.7% / 3.4% vs 22.1% / 2.1% • Peripheral neuropathy: 22.5% / 2.8% vs 19.8% / 2.1% • Neutropenia: 18.2% / 12.4% vs 16.8% / 10.2% • Anemia: 15.6% / 4.8% vs 14.2% / 4.1% • Thrombocytopenia: 12.8% / 3.2% vs 10.4% / 2.4% • Weight loss: 18.4% / 1.2% vs 12.1% / 0.8% • Infusion-related reactions: 8.4% / 1.2% vs 2.1% / 0.2% • Dehydration: 14.2% / 4.8% vs 8.4% / 2.1% • AST/ALT elevation: 10.2% / 2.1% vs 8.8% / 1.8% Serious Adverse Reactions: Serious adverse reactions occurred in 42% of patients treated with ZELVARA plus chemotherapy versus 34% in the control arm. The most common serious adverse reactions (≥2%) were vomiting (8.2%), nausea (4.1%), dehydration (3.8%), and decreased appetite (2.4%). Fatal Adverse Reactions: Fatal adverse reactions occurred in 2.1% of patients treated with ZELVARA plus chemotherapy, including sepsis (0.7%), pneumonia (0.4%), cardiac arrest (0.4%), and hepatic failure (0.4%). Discontinuation: Permanent discontinuation of ZELVARA due to adverse reactions occurred in 12.4% of patients. The most common adverse reactions leading to discontinuation (≥1%) were nausea (2.8%), vomiting (2.4%), and infusion-related reactions (1.2%).

No formal drug interaction studies have been conducted with ZELVARA. Based on the known elimination pathways of celdatuzumab (catabolism via proteolytic degradation), no clinically significant pharmacokinetic drug interactions are expected.

8.1 Pregnancy Risk Summary: Based on its mechanism of action and animal data, ZELVARA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3)]. There are no available data on ZELVARA use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, administration of an anti-CLDN18.2 antibody to pregnant animals during organogenesis resulted in embryo-fetal toxicity at exposures below the human exposure at the recommended dose. Advise pregnant women of the potential risk to a fetus. 8.2 Lactation Risk Summary: There are no data on the presence of celdatuzumab in human milk, its effects on the breastfed child, or its effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ZELVARA and for 3 months after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ZELVARA. Contraception — Females: Advise females of reproductive potential to use effective contraception during treatment with ZELVARA and for 3 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of ZELVARA have not been established in pediatric patients. 8.5 Geriatric Use Of the 538 patients who received ZELVARA plus chemotherapy in BEACON-1 and BEACON-2, 42% were 65 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 Hepatic Impairment No dose adjustment of ZELVARA is recommended in patients with mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN with any AST). ZELVARA has not been studied in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × ULN) hepatic impairment. 8.7 Renal Impairment No dose adjustment of ZELVARA is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min). ZELVARA has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease.

12.1 Mechanism of Action Celdatuzumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against claudin 18.2 (CLDN18.2). CLDN18.2 is a tight junction protein expressed on the surface of gastric epithelial cells. In gastric and GEJ adenocarcinomas, disrupted cell polarity leads to exposure of CLDN18.2 on the tumor cell surface. Celdatuzumab binds to the first extracellular loop of CLDN18.2 with high affinity (KD = 0.48 nM). Upon binding, the Fc region of celdatuzumab mediates tumor cell killing through: • Antibody-dependent cellular cytotoxicity (ADCC) via engagement of FcγRIIIa on natural killer cells • Complement-dependent cytotoxicity (CDC) via activation of the classical complement cascade through C1q binding 12.3 Pharmacokinetics Following intravenous administration at the recommended dosage, the geometric mean Cmax was 682 µg/mL after the loading dose and 524 µg/mL at steady state. Steady-state exposure was achieved by Cycle 3. The terminal half-life is approximately 12.8 days. Clearance is approximately 0.21 L/day with an estimated volume of distribution of 4.8 L.

14.1 BEACON-1 BEACON-1 (NCT04XXXXXX) was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated ZELVARA in combination with mFOLFOX6 compared to placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma who had not received prior systemic therapy for advanced disease. A total of 565 patients were randomized 1:1 to receive ZELVARA plus mFOLFOX6 (N=282) or placebo plus mFOLFOX6 (N=283). Randomization was stratified by geographic region (Asia vs. non-Asia), ECOG performance status (0 vs. 1), and number of metastatic sites (≤2 vs. >2). Efficacy Results: • Progression-Free Survival: Median PFS was 10.8 months in the ZELVARA arm vs 8.4 months in the placebo arm (HR 0.73; 95% CI: 0.61, 0.87; p=0.0049). • Overall Survival: Median OS was 18.6 months in the ZELVARA arm vs 15.2 months in the placebo arm (HR 0.74; 95% CI: 0.62, 0.88; p=0.0041). • Overall Response Rate: ORR was 48.6% (95% CI: 42.7%, 54.5%) in the ZELVARA arm vs 39.2% (95% CI: 33.5%, 45.1%) in the placebo arm. 14.2 BEACON-2 BEACON-2 (NCT04YYYYYY) was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated ZELVARA in combination with CAPOX compared to placebo plus CAPOX in patients with CLDN18.2-positive, HER2-negative gastric or GEJ adenocarcinoma. A total of 510 patients were randomized 1:1 to receive ZELVARA plus CAPOX (N=256) or placebo plus CAPOX (N=254). Randomization was stratified by ECOG performance status and prior gastrectomy status. Efficacy Results: • Progression-Free Survival: Median PFS was 8.4 months in the ZELVARA arm vs 6.6 months in the placebo arm (HR 0.69; 95% CI: 0.57, 0.83; p=0.0008). • Overall Survival: Median OS was 14.7 months in the ZELVARA arm vs 12.0 months in the placebo arm (HR 0.77; 95% CI: 0.64, 0.93; p=0.0105). • Overall Response Rate: ORR was 45.1% (95% CI: 38.9%, 51.4%) in the ZELVARA arm vs 37.8% (95% CI: 31.8%, 44.1%) in the placebo arm.

16.1 How Supplied ZELVARA (celdatuzumab-mkrz) injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied as: • 500 mg/20 mL (25 mg/mL) in a single-dose vial — NDC XXXXX-XXX-01 16.2 Storage and Handling Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Discard any unused portion remaining in the vial.

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Nausea and Vomiting: Inform patients that ZELVARA may cause severe nausea and vomiting. Advise patients to contact their healthcare provider if they experience persistent nausea or vomiting. Advise patients to take antiemetics as prescribed. Infusion-Related Reactions: Advise patients to immediately report signs and symptoms of infusion-related reactions (fever, chills, rash, flushing, dyspnea, hypotension). Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose. Advise women not to breastfeed during treatment and for 3 months after the last dose. Manufactured by: Meridian Oncology, Inc., Cambridge, MA 02142 U.S. License No. XXXX ZELVARA is a registered trademark of Meridian Oncology, Inc. © 2025 Meridian Oncology, Inc. All rights reserved. ZEL-PI-001 Revised: 01/2025