New gastric & gastro-oesophageal junction cancer treatment VYLOY™ ▼ (zolbetuximab): the first claudin 18.2 biomarker targeted therapy licensed in Great Britain

• Claudin18.2 is an innovative drug-target which is not currently used for any other authorised treatment.
• There is a large unmet need in gastric and gastro-esophageal junction (GEJ) cancers. In the UK, only 20 out of 100 people (around 20%) with stage 4 stomach cancer will survive their cancer for 1 year or more after diagnosis.¹

Addlestone, UK, August 15 – Astellas Pharma Ltd. today announced the Medicines and Healthcare products Regulatory Agency (MHRA) has licensed VYLOY^™ (zolbetuximab), an anti-claudin 18.2 (CLDN18.2) monoclonal antibody, 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 gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours are Claudin (CLDN) 18.2 positive.²

Zolbetuximab is the only licensed treatment to target the CLDN18.2 protein, a member of the claudin family of proteins, that is expressed in gastric, oesophageal, lung and ovarian tissues.^{3, 4} Claudins are a major component of epithelial and endothelial tight junctions, which are involved in holding cells together and controlling the flow of molecules between cells.^{4, 5, 6, 7} In healthy tissue CLDN18.2 proteins are largely inaccessible, but studies have shown that CLDN18.2 becomes more exposed and accessible as gastric or GEJ tumors develop, presenting a target for antibody treatment.^{3, 8, 9} In two large international trials approximately 42% of gastric and GEJ adenocarcinoma patients were shown to be CLDN18.2 positive (defined as: 2+/3+ IHC staining in ≥75% of tumour cells) and HER2 negative.^{11, 12}  

The license is based on the results from the Phase 3 SPOTLIGHT and GLOW trials, which, between the two multi-center, double-blind, randomized studies, recruited 1072 patients to clinical trial sites in the U.S., Canada, United Kingdom, Europe, Australia, South America, and Asia, including Japan.^{10, 11}

Dr Timir Patel, Astellas Medical Director:

“Zolbetuximab marks a new era in the targeted treatment of gastric cancer, where more treatment options are desperately needed. This treatment holds the potential to provide patients with more valuable time to spend with their loved ones.”

About VYLOY^™

VYLOY™ (zolbetuximab) is an anti-claudin 18.2 (CLDN18.2) monoclonal antibody that is licensed by the MHRA in combination with 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 gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours are Claudin (CLDN) 18.2 positive.¹ VYLOY is the first and only CLDN18.2-targeted therapy licensed in Great Britain.¹ CLDN18.2 positivity should be confirmed by pathologist or laboratory with a using a validated assay.¹ Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tight junction molecule CLDN18.2. Zolbetuximab depletes CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Cytotoxic drugs were shown to increase CLDN18.2 expression on human cancer cells and to improve zolbetuximab-induced ADCC and CDC activities.

For more information, please see the Great Britain full Summary of Product Characteristics for VYLOY.

About Unresectable, Advanced or Recurrent Gastric and GEJ Cancer

Gastric cancer, also known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide.¹² Gastric cancer killed 4,216 people in the UK in 2019. Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhea or constipation, bloating of the stomach after meals, loss of appetite, and sensation of food getting stuck in the throat while eating. Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue, and vomiting blood or having blood in the stool.¹³ Risk factors associated with gastric and GEJ cancer can include older age, male gender, family history, H. pylori infection, and smoking.^{14, 15} GEJ adenocarcinoma is a cancer that starts at the area where the oesophagus joins the stomach.¹⁶ Because early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor’s origin to other body tissues or organs.¹⁷

INVESTIGATIONAL STUDIES

About SPOTLIGHT Phase 3 Clinical Trial

SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus mFOLFOX6 (a combination chemotherapy regimen that includes oxaliplatin, folinic acid, and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 565 patients (283 patients in the zolbetuximab group and 282 patients in the placebo group) at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America, and Asia, including Japan.¹¹

The primary endpoint is progression-free survival (PFS) of participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability, and quality-of-life parameters.^{2, 11}

As of the date of cut-off (September 2022), treatment with zolbetuximab in combination with mFOLFOX6 showed a statistically significant 25% reduction in the risk of a patient experiencing a PFS event (as assessed by IRC) compared with placebo in combination with mFOLFOX6 treatment (HR = 0.75, 95% CI: 0.598, 0.942, 2-sided p-value=0.00132). The median PFS was approximately 2 months longer for zolbetuximab in combination with mFOLFOX6 (10.6 months, 95% CI: 9.7, 12.5) versus placebo in combination with mFOLFOX6 (8.7 months, 95% CI: 8.2, 10.4). The PFS rate at 12 months was 49% (95% CI: 41.9, 55.4) for zolbetuximab in combination with mFOLFOX6 and 35.0% (95% CI: 28.5, 41.7) for placebo in combination with mFOLFOX6. ^{2, 11}  

OS as a key secondary endpoint was statistically significantly prolonged in patients receiving zolbetuximab in combination with mFOLFOX6 (as assessed by IRC) compared to placebo in combination with mFOLFOX6 treatment (HR = 0.75, 95% CI 0.601, 0.936, 2-sided p-value 0.0107). The median OS was 18.2 months (95% CI: 16.4, 22.9) for zolbetuximab in combination with mFOLFOX6 compared to 15.5 months (95% CI: 13.5, 16.5) for placebo in combination with mFOLFOX6. Overall survival at 12 months was 67.7% (CI 95%: 61.5, 73.1) for zolbetuximab in combination with mFOLFOX6 and 60% (CI 95%: 53.6, 65.7) for placebo in combination with mFOLFOX6. ^{2, 11}  

The incidence of serious treatment-emergent adverse events (TEAEs) was similar between both arms (45% versus 44% in the zolbetuximab versus placebo arms) and consistent with previous studies. The most frequent TEAEs in the SPOTLIGHT study were nausea (82% versus 61%), vomiting (67% versus 36%) and decreased appetite (49%

versus 35%).^{2, 11} 

Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19, 2023, and were subsequently published in The Lancet on April 14, 2023.^{2, 11} The final analysis from the SPOTLIGHT trial were presented in June 2024 at ASCO as a Poster and Oral Abstract #4036 and a manuscript is expected to be published later this year.¹⁸

For more information, please visit clinicaltrials.gov under Identifier NCT03504397.

About GLOW Phase 3 Clinical Trial

GLOW is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 507 patients (254 in the zolbetuximab group and 253 assigned to the placebo group) at 166 study locations in the U.S., Canada, United Kingdom, Europe, South America, and Asia, including Japan. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability, and quality-of-life parameters.¹²

As of the data cut-off date (October 2022), treatment with zolbetuximab in combination with CAPOX showed a statistically significant benefit with a 31% reduction in the risk of a patient experiencing a PFS event (as assessed by IRC) compared with placebo in combination with CAPOX treatment (HR = 0.687, 95% CI: 0.544, 0.866; 2-sided P = 0.0014). The median PFS was approximately 1.4 months longer for zolbetuximab in combination with CAPOX (8.2 months, 95% CI: 7.5, 8.8) versus placebo in combination with CAPOX (6.8 months, 95% CI: 6.1, 8.1).^{2, 10}

OS as a key secondary endpoint was statistically significantly prolonged in patients receiving zolbetuximab in combination with CAPOX (as assessed by IRC) compared to placebo in combination with CAPOX treatment (HR = 0.771, 95% CI 0.615, 0.965, 2-sided p-value 0.0236). The median OS was 14.4 months (95% CI: 12.3, 16.5) for zolbetuximab in combination with CAPOX compared to 12.2 months for placebo (95% CI: 10.3, 13.7) in combination with CAPOX. Overall survival at 12 months was 57.5% (CI 95%: 50.7, 63.8) for zolbetuximab in combination with CAPOX and 50.8% (CI 95%: 44.1, 57.1) for placebo in combination with mFOLFOX6. ^{2, 10} 

The incidence of serious treatment-emergent adverse events (TEAEs) was similar between both arms (47.2% versus 49.8% in the zolbetuximab versus placebo arms, respectively) and consistent with previous studies.¹ The most frequent TEAEs in the GLOW study were nausea (68.5% versus 50.2%), vomiting (66.1% versus 30.9%) and decreased appetite (41.3% versus 33.7%) in the zolbetuximab versus placebo arms.¹⁰  

Data from the GLOW study were initially presented at the March 2023 ASCO Plenary Series with an updated oral presentation at the 2023 ASCO Annual Meeting on June 3, 2023, and were subsequently published in Nature Medicine on July 31, 2023. A manuscript detailing the results from the final analysis is expected to be published later this year.

For more information, please visit clinicaltrials.gov under Identifier NCT03653507.or refer to the Summary of Product Characteristics and Patient Information leaflets (https://products.mhra.gov.uk/) which will be published on the MHRA Products website within 7 days of approval.

About Astellas

Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational prescription medicine focus to create Rx+^® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at https://www.astellas.com/en.