VYLOY^® (zolbetuximab-clzb): A Novel Treatment That Targets Claudin 18.2-positive (CLDN18.2+), HER2-negative Locally Advanced Unresectable, or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Descriptions of the VYLOY mechanism of action are based on preclinical data.

VYLOY is a first-in-class monoclonal antibody indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are claudin 18.2 positive as determined by an FDA-approved test.

Preclinical studies have shown that VYLOY is a claudin 18.2 directed cytolytic antibody that selectively binds to cells that express claudin 18.2, where cytotoxic immune responses are activated.

Claudin 18.2 Overview

Claudin 18.2 is present in gastric and gastroesophageal junction adenocarcinoma.

According to estimates from two global Phase 3 studies, 38% of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma are claudin 18.2-positive, which was defined as 75% or more of tumor cells demonstrating moderate to strong membranous claudin 18.2 staining by immunohistochemistry.

Claudin 18.2 may become more exposed and accessible to antibodies as gastric tumors develop.

To understand the relevance of this protein to these types of cancers, let’s take a closer look at the role of claudin 18.2 within healthy gastric mucosal tissue.

Claudin 18 in Healthy Gastric Tissue

Claudin 18 is a member of the Claudin family of transmembrane tight junction proteins.

Claudin 18.2 is the dominant claudin 18 isoform found in normal healthy gastric tissue and is typically buried within tight junctions.

As a component of tight junctions, claudins are involved in the regulation of permeability, barrier function, and polarity of epithelial layers.

Claudin 18.2 Overview

Now that we’ve explored the role of claudin 18.2 in normal tissue, let’s examine what happens in gastric adenocarcinomas.

Claudin 18.2 is often retained during malignant transformation, when cell polarity disruptions and structure loss occur.

As a result, claudin 18.2 may become more exposed and accessible to antibodies as gastric tumors develop.

Claudin 18.2 may also be expressed in lymph node metastases of gastric adenocarcinoma as well as other distant metastatic sites.

The Mechanism of Action for VYLOY

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.

VYLOY is a claudin 18.2-directed cytolytic antibody that selectively binds to cells that express claudin 18.2.

When this binding occurs, cytotoxic immune responses are activated.

This is achieved through the induction of antibody-dependent cell-mediated cytotoxicity, or ADCC, and complement-dependent cytotoxicity, or CDC, leading to the destruction of cancer cells.

Let’s take a look at how VYLOY-mediated activation of ADCC and CDC may result in cancer cell depletion.

During ADCC, effector cells, such as natural killer cells, recognize antibody-targeted tumor cells and release cytotoxic molecules that cause tumor cell lysis.

At the same time, the induction of CDC gathers complement proteins at the tumor site or sites where they converge and assemble a membrane attack complex which forms pores on the tumor cell surface causing lysis of the tumor cell.

Through VYLOY-induced ADCC and CDC, claudin 18.2-positive gastric tumor cells are depleted.

Combining VYLOY and Chemotherapy

In addition to the action of VYLOY binding to claudin 18.2-positive gastric adenocarcinoma cells, it’s important to consider what happens when this cytolytic antibody is combined with chemotherapy.

In the presence of the combination of chemotherapy and VYLOY, the antitumor effect has been shown to be increased compared to chemotherapy or VYLOY alone (in claudin 18.2-expressing mouse models).

VYLOY represents a novel approach to treating cancer, and is the first-in-class monoclonal antibody to target the novel claudin 18.2 biomarker, mediating the immune system mechanisms, ADCC and CDC, in locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.

IMPORTANT SAFETY INFORMATION

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.