Zolbetuximab (IMAB362), an investigational monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), a transmembrane protein, being developed by Astellas Pharma, has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or esophageal junction adenocarcinoma (GEJ).

This is outcome of the Phase 3 SPOTLIGHT trial evaluating first-line treatment with zolbetuximab published in The Lancet.[1]

The study evaluating first-line treatment with zolbetuximab, an investigational first-in-class Claudin 18.2 (CLDN18.2) targeted monoclonal antibody being developed by Astellas Pharma + mFOLFOX6, a combination regimen that includes oxaliplatin, leucovorin and fluorouracil, versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways — antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[2]

“Patients with HER2-negative, CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction cancers have limited first-line treatments available that are biomarker-based,” said Kohei Shitara, MD, Primary Investigator for the SPOTLIGHT trial and Head, Department of Gastrointestinal Oncology, the National Cancer Center Hospital East in Kashiwa, Japan.

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The Lancet‘s decision to publish the SPOTLIGHT study reinforces the value this data provides to the gastrointestinal cancer scientific community,” Shitara concluded.

“The publication of the SPOTLIGHT study is an important report of the first Phase 3 trial to demonstrate clinical benefit following CLDN18.2-targeted therapy in any tumor type, and we are honored that it has been published in The Lancet,” said Pranob Bhattacharya, DrPH, MS, MBA, Executive Director and Interim Head of Immuno-Oncology Development, Astellas.

“This manuscript, which provides further insight into the investigational use of zolbetuximab, reinforces Astellas’ commitment to patients with advanced-stage gastric/GEJ cancer,” Bhattacharya said.

Gastric cancer development program
The SPOTLIGHT and GLOW studies are part of Astellas’ gastric cancer development program to investigate targeted treatment options, such as zolbetuximab, and address patient needs in locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. These two statistically significant Phase 3 trials will serve as the basis for global regulatory submissions. In both trials, approximately 38% of these patients had CLDN18.2-positive tumors (≥75% of tumor cells with strong-to-moderate membranous CLDN18 staining intensity), as determined by a validated immunohistochemistry assay. [3] GLOW study data were presented at the March 2023 American Society of Clinical Oncology (ASCO) Plenary Series.

Locally Advanced Unresectable Metastatic GEJ
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide.[4] 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 and loss of appetite and sensation of food getting stuck in the throat while eating.[5]

Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue and vomiting blood or having blood in the stool.[6] Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastroesophageal reflux disease (GERD).[5][7]

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.[5]

The five-year relative survival rate for patients at the metastatic stage is approximately six percent.[8] Gastroesophageal junction (GEJ) adenocarcinoma is a cancer that starts at the area where the esophagus joins the stomach.[9]

Study design
SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus mFOLFOX6 (combination regimen of oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ cancer. The study enrolled 565 patients at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America and Asia. The primary endpoint is progression-free survival of participants treated with combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability and quality-of-life parameters.

Study outcome
The study data was first published online on April 14 in The Lancet.[1] Initial results from SPOTLIGHT, which met its primary endpoint of progression-free survival (PFS) and a key secondary endpoint of overall survival (OS), were presented at the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.

In the study, investigational treatment zolbetuximab plus mFOLFOX6 demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared to placebo plus mFOLFOX6.

Specifically, zolbetuximab plus mFOLFOX6 reduced the risk of progression or death by 24.9% (n=565; Hazard Ratio [HR]=0.751; [95% Confidence Interval [CI]: (0.598-0.942)]; P=0.0066) compared to placebo plus mFOLFOX6, meeting SPOTLIGHT’s primary endpoint. Median PFS was 10.61 months (95% CI: 8.90-12.48) in the treatment arm and 8.67 months (95% CI: 8.21-10.28) in the placebo arm.

The study also showed that zolbetuximab plus mFOLFOX6 significantly prolonged OS, reducing the risk of death by 25.0% (HR=0.750; 95% CI: 0.601-0.936; P=0.0053). Median OS was 18.23 months (95% CI: 16.43-22.90) and 15.54 months (95% CI: 13.47-16.53) for the treatment arm and placebo arm, respectively.

The incidence of serious treatment-emergent adverse events (TEAEs) was similar between both arms (44.8% versus 43.5% in the zolbetuximab versus placebo arms) and consistent with previous studies. The most frequent TEAEs in the SPOTLIGHT study were nausea (82.4% versus 60.8%), vomiting (67.4% versus 35.6%) and decreased appetite (47.0% versus 33.5%).

Clinica trials
A Phase 3 Efficacy, Safety and Tolerability Study of Zolbetuximab (Experimental Drug) Plus mFOLFOX6 Chemotherapy Compared to Placebo Plus mFOLFOX6 as Treatment for Gastric and Gastroesophageal Junction (GEJ) Cancer (Spotlight) – NCT03504397
A Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX as First-line Treatment of Subjects With Claudin (CLDN) 18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (GLOW) – NCT03653507
A Study of ASP2138 in Adults With Stomach Cancer or Pancreatic Cancer – NCT05365581
A Study to Assess the Efficacy and Safety of IMAB362 in Combination With Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects With Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma – NCT03816163

[1] Shitara K, et al. Zolbetuximab plus mFOLFOX6 in patients with claudin-18 isoform 2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. The Lancet. Published online April 14, 2023; S0140-6736(23)00620-7.
[2] Data on file. Northbrook, Ill. Astellas Pharma Inc.
[3] Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.
[4] American Cancer Society. Signs and symptoms of stomach cancer (01-22-2021). Online Available at . Last accessed on April 12, 2023.
[5] National Cancer Institute. Gastric cancer treatment (PDQ®): patient version (08-24-2021). Online. Last accessed on April 12, 2023.
[6] American Cancer Society. Esophageal cancer risk factors (06-09-2020). Online. Last accessed on April 12, 2023.
[7] National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. Online. Last accessed on April 12, 2023.
[8] American Cancer Society. About esophagus cancer (03-20-2020). Online. Last accessed on April 12, 2023.
[9] Sahin U, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-19.

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