VYLOY™ (zolbetuximab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours are Claudin (CLDN) 18.2 positive
Hypersensitivity reactions in patients treated with VYLOY in combination with fluoropyrimidine and platinum-containing chemotherapy during clinical studies were characterized by anaphylactic reaction or drug hypersensitivity. Monitor patients during and after infusion with VYLOY (at least 2 hours, or longer if clinically indicated) for hypersensitivity reactions with symptoms and signs that are highly suggestive of anaphylaxis (e.g., urticaria, repetitive cough, wheeze and throat tightness/change in voice). If an anaphylactic reaction occurs, administration of VYLOY should be immediately and permanently discontinued and appropriate medical therapy administered.
For any Grade 3 or 4 hypersensitivity reaction or hypersensitivity reaction with features of anaphylaxis, administration of VYLOY should be immediately and permanently discontinued and appropriate medical therapy instituted based on the type of reaction.
For any Grade 2 hypersensitivity reaction, interrupt the VYLOY infusion until Grade ≤1, then resume the infusion at a reduced infusion rate for the remaining infusion. Pre-medicate the patient with antihistamines for the next infusion, administer per the infusion rates in the Singapore Approved Package Insert, and closely monitor the patient for symptoms and signs of a hypersensitivity reaction. The infusion rate may be gradually increased as tolerated.
Infusion-related reaction (IRR) has occurred during clinical studies with VYLOY in combination with fluoropyrimidine and platinum-containing chemotherapy. Monitor patients for signs and symptoms of infusion-related reaction including nausea, vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough and hypertension. These signs and symptoms are usually reversible with the interruption of the infusion. For Grade 3 or 4 IRRs, administration of VYLOY should be immediately and permanently discontinued and appropriate medical therapy instituted.
For Grade 2 IRRs, interrupt the VYLOY infusion until Grade ≤1, then resume the infusion at a reduced infusion rate for the remaining infusion. Pre-medicate the patient with antihistamines for the next infusion, administer per the infusion rates in the Singapore Approved Package Insert, and closely monitor the patient for symptoms and signs of an IRR. The infusion rate may be gradually increased as tolerated.
During clinical studies, nausea and vomiting were the most frequently observed gastrointestinal (GI) adverse reactions with VYLOY in combination with fluoropyrimidine and platinum-containing chemotherapy treatment.
Nausea and vomiting occurred more often during the first cycle of treatment but decreased in incidence with subsequent cycles of treatment. To prevent nausea and vomiting, pretreatment with a combination of antiemetics is recommended prior to each infusion of VYLOY. During and after infusion, patients should be monitored and managed using standard of care, including antiemetics or fluid replacement, as clinically indicated.
For Grade 4 vomiting, permanently discontinue treatment with VYLOY.
For Grade 2 or 3 nausea or vomiting, interrupt the VYLOY infusion until Grade ≤1, then resume at a reduced infusion rate for the remaining infusion. For the next infusion, administer per the infusion rates in the Singapore Approved Package Insert, and closely monitor the patient for symptoms and signs of nausea or vomiting. The infusion rate may be gradually increased as tolerated.
Serious upper gastrointestinal (GI) haemorrhage has been observed in patients receiving VYLOY in combination with fluoropyrimidine and platinum-containing chemotherapy. In the clinical studies, serious upper GI haemorrhage occurred more frequently in patients receiving zolbetuximab in combination with fluoropyrimidine and platinum-containing chemotherapy [1.0% (6/631)) in comparison with patients receiving placebo in combination with fluoropyrimidine and platinum-containing chemotherapy [0.2% (1/611)]. Monitor patients for signs and symptoms of upper GI haemorrhage during treatment. Promptly evaluate and treat any suspected upper GI haemorrhage.
One event of PRES has been reported in a patient. This is a rare reversible, neurological disorder that can present with rapidly evolving symptoms including seizure, headache, confusion, visual and neurological disturbances, with or without associated hypertension and altered mental status. If PRES is suspected, it should be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of zolbetuximab treatment in patients who develop PRES is recommended.
Chemotherapy‡ increases CLDN18.2 cell surface expression.4
*Descriptions of VYLOY mechanism of action are based on pre-clinical studies.4,7
†The frequency of tumour-infiltrating NK cells tended to be higher with VYLOY vs control.7
‡Chemotherapy=gemcitabine.4
§P<0.05.7
||Chemotherapy=5-fluorouracil (5-FU) and oxaliplatin.
ADCC=antibody-dependent cell-mediated cytotoxicity; CDC=complement-dependent cytotoxicity; CLDN18.2=Claudin 18.2.
Watch an in-depth animation of the VYLOY mechanism of action, from the initial exposure of CLDN18.2 to the destruction of tumour cells targeted by VYLOY.
Zolbetuximab: A Novel Treatment for Claudin 18.2-positive, HER2-negative Locally Advanced Unresectable or Metastatic Gastric or Gastro-oesophageal Junction Adenocarcinoma
Descriptions of the zolbetuximab mechanism of action are based on preclinical studies.
Zolbetuximab is the first monoclonal antibody approved for treatment of Claudin 18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma.
In these tumours, zolbetuximab binds specifically to Claudin 18.2 on tumour cell membranes activating cytotoxic immune mechanisms to destroy cancer cells.
Claudin 18.2 in Gastric Cancer
Claudin 18.2 is present in gastric and gastro-oesophageal junction adenocarcinoma.
According to two global Phase 3 studies, 38% of patients with locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma were Claudin 18.2 positive, which was defined as showing moderate to strong membranous Claudin 18 staining in 75% or more of tumour cells.
Claudin 18.2 may become more exposed and accessible to antibodies as gastric tumours 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 18.2 in Healthy Tissue
Claudin 18.2 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 in the supramolecular complex between gastric epithelial cells.
Normally, this protein contributes to epithelial cell-to-cell adhesion, which is critical to cell polarity as well as the regulation of the flow of molecules between cells.
Claudin 18.2 in Gastric Cancer
Now that we’ve explored the role of Claudin 18.2 in normal tissue, let’s examine what happens in gastric adenocarcinomas.
Malignant transformation leads to cell polarity disruptions and structural loss in the gastric epithelial cells.
As a result, Claudin 18.2 may become more exposed as gastric tumours develop.
Claudin 18.2 is retained in metastatic progression and may be detected in both the primary tumour and metastases.
The Mechanism of Action for Zolbetuximab
Zolbetuximab binds directly to Claudin 18.2 on the surface of tumour cells with high specificity and affinity.
When this binding occurs, the tumour is flagged for precise targeting, and the immune system is 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 zolbetuximab-mediated activation of ADCC and CDC may result in cancer cell destruction. When zolbetuximab induces ADCC, tumour-infiltrating natural killer cells are deployed to the tumour site or sites where the immune cells mount a lytic attack by releasing cytotoxic granules to the tumour cell.
At the same time, the induction of CDC means that complement proteins are deployed to the tumour site or sites where they converge and assemble a membrane attack complex which forms pores on the tumour cell surface causing lysis of the tumour cell.
With zolbetuximab as a guide, both ADCC and CDC processes are directed to destroy Claudin 18.2-positive gastric tumours through cell lysis.
Combining Zolbetuximab and Chemotherapy
In addition to the action of zolbetuximab binding to Claudin 18.2-positive gastric adenocarcinoma cells, it’s important to consider what happens when this monoclonal antibody is combined with chemotherapy.
Preclinical studies have shown that chemotherapy increased Claudin 18.2 cell surface expression and, when combined with zolbetuximab, improved the ability of zolbetuximab to induce ADCC and CDC.
In the presence of the combination of chemotherapy and zolbetuximab, tumour growth is significantly inhibited compared to zolbetuximab monotherapy or chemotherapy alone.
Zolbetuximab represents a novel approach to treating cancer, and is the first approved monoclonal antibody to target the highly prevalent Claudin 18.2 biomarker, activating the immune system through the induction of ADCC and CDC in locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma.
Find out how IHC testing for CLDN18.2 may help identify patients who may be candidates for VYLOY + chemotherapy.
IHC=immunohistochemistry.
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