Now FDA approved for advanced gastric/GEJ cancer positive for CLDN18.2
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A first-in-class FDA-approved monoclonal antibody that targets a novel biomarker in advanced* G/GEJ cancer: CLDN18.21-3
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Astellas Pharma US, Inc. is pleased to announce the FDA approval of VYLOY® (zolbetuximab-clzb) indicated for use in combination with fluoropyrimidine- and platinum-containing chemotherapy 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.1 Two global Phase 3 studies estimated that 38% of patients with advanced* G/GEJ adenocarcinoma have tumors that are CLDN18.2+.
2,3†‡
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VYLOY was studied in combination with mFOLFOX6§ or CAPOX|| in SPOTLIGHT and GLOW, two international, multicenter, double-blind, randomized, placebo-controlled Phase 3 trials involving more than 1,000 adult patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma.1-3 In both trials, progression-free survival (PFS)¶ was the major efficacy outcome measure. Additional efficacy outcome measures included overall survival (OS) and objective response rate (ORR).1¶
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In the SPOTLIGHT and GLOW Phase 3 trials
Improved PFS and OS with VYLOY + chemotherapy1-3#
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SPOTLIGHT1
(N = 565)
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GLOW1
(N = 507)
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Median
PFS
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10.6 months with VYLOY +
mFOLFOX6 vs 8.7 months
with mFOLFOX6 alone
(HR = 0.75 [95% CI: 0.60-0.94]; P = 0.0066)
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8.2 months with VYLOY +
CAPOX vs 6.8 months with
CAPOX alone
(HR = 0.69 [95% CI: 0.54-0.87]; P = 0.0007)
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Median
OS
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18.2 months with VYLOY +
mFOLFOX6 vs 15.5 months
with mFOLFOX6 alone
(HR = 0.75 [95% CI: 0.60-0.94]; P = 0.0053)
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14.4 months with VYLOY +
CAPOX vs 12.2 months with
CAPOX alone
(HR = 0.77 [95% CI: 0.62-0.97]; P = 0.0118)
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ORR
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40.3% with VYLOY+ mFOLFOX6 vs 39.7% with mFOLFOX6 alone
(95% CI: 34.5, 46.3) and (95% CI: 34.0, 45.7) respectively
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32.3% with VYLOY + CAPOX vs 31.2% with CAPOX alone
(95% CI: 26.6, 38.4) and (95% CI: 25.6, 37.3) respectively
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*Locally advanced unresectable or metastatic.
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SELECT IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
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. Follow Grade 2 management for Grade 3 infusion-related nausea and vomiting. Premedicate the patient with antihistamines for the subsequent infusions, and closely monitor the patient for symptoms and signs of a hypersensitivity reaction. The infusion rate may be gradually increased as tolerated.
See below for additional Important Safety Information.
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CAPOX, capecitabine, oxaliplatin; CI, confidence interval; CLDN18.2, Claudin 18.2; FDA, United States Food and Drug
Administration; G/GEJ, gastric/gastroesophageal junction; HR, hazard ratio; IHC, immunohistochemistry; mFOLFOX6,
oxaliplatin, leucovorin, fluorouracil; RECIST, Response Evaluation Criteria in Solid Tumors.
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† |
CLDN18.2+ is defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining by IHC.2,3
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‡ |
Data from two global randomized Phase 3 studies: SPOTLIGHT, which included 2,403 assessable patients, of whom 922 were CLDN18.2+; and GLOW, which included 2,104 assessable patients, of whom 808 were CLDN18.2+.2,3
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§ |
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 2,400 mg/m
2 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.1
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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 1,000 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.1
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¶ |
PFS and ORR were assessed per RECIST v1.1 by independent review committee.1
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# |
Fluoropyrimidine- and platinum-containing chemotherapy.1
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IMPORTANT SAFETY INFORMATION (cont’d)
WARNINGS AND PRECAUTIONS
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. Manage patients during and after infusion with antiemetics or fluid replacement. Interrupt the infusion, or permanently discontinue VYLOY based on severity.
ADVERSE REACTIONS
Most common adverse reactions (≥15%): Nausea, vomiting, fatigue, decreased appetite, diarrhea, peripheral sensory neuropathy, abdominal pain, constipation, decreased weight, hypersensitivity reactions, and pyrexia.
Most common laboratory abnormalities (≥15%): 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 Study: 279 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive who received at least one dose of VYLOY in combination with mFOLFOX6
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.
GLOW Study: 254 patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive who received at least one dose of VYLOY in combination with CAPOX
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.
SPECIFIC POPULATIONS
Lactation Advise lactating women not to breastfeed during treatment with VYLOY and for 8 months after the last dose.
Please click here for full Prescribing Information.
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For additional information on VYLOY,
please contact your Astellas Account Manager.
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References: 1. VYLOY [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 2023;29(8):2133-2141. 3. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023;401(10389):1655-1668. Errata in: Lancet 2023;402(10398):290; Lancet 2024;403(10421):30.
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