A review of the Phase 3 SPOTLIGHT clinical trial, evaluating the efficacy and safety of zolbetuximab (previously known as IMAB362) in combination with mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil), showed positive topline results for this combination in the treatment of patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Zolbetuximab, which is being developed by Astellas Pharma, is an investigational first-in-class monoclonal antibody targeting Claudin 18.2 (CLDN18.2). The agent 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). [1]

CLDN18.2 is a type of transmembrane protein found in normal gastric cells and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells.[2]

Pre-clinical studies have also shown that CLDN18.2, which can also be present in gastric tumors, may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. [3][4][5] Based on this study, approximately 38% of screened patients have CLDN18.2-positive tumors, defined as CLDN18.2 expression in ≥75% of tumor cells with strong-to-moderate staining intensity based on a validated immunohistochemistry assay. [6]

Unresectable Metastatic Gastric
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide. [9]

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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. [10]

Signs of more advanced gastric cancer can include unexplained weight loss; weakness and fatigue; and vomiting blood or having blood in the stool. [7]

Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastroesophageal reflux disease (GERD). [7][11]

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. [7] 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. [12]

Study design
SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6 as a first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer.

The study enrolled 566 patients at 220 study locations in the U.S., 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 (OS), objective response rate (ORR), duration of response (DoR), safety and tolerability and quality-of-life parameters.

Adverse events
The study met a secondary endpoint, overall survival (OS), showing statistical significance for patients treated with zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6. The most frequent treatment-emergent adverse events (TEAEs) in patients treated with zolbetuximab plus mFOLFOX6 were nausea, vomiting, and decreased appetite. Detailed results will be presented at a future scientific congress and submitted for publication.

“I am excited by the potential for a new treatment option to help patients with advanced-stage gastric cancer or GEJ cancer,” noted Kohei Shitara, MD, Primary Investigator for the SPOTLIGHT trial and Chief, Department of Gastrointestinal Oncology, the National Cancer Center Hospital East in Kashiwa, Japan.

“Gastric and GEJ cancers still have very limited treatment options available for patients with an advanced diagnosis,” Shitara added.

“We’re delighted and excited about the positive topline results from the SPOTLIGHT trial of zolbetuximab in combination with mFOLFOX6, and we have increased confidence in advancing development of zolbetuximab for the first-line treatment of patients with locally advanced or metastatic gastric cancer,” said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas.

“These topline results further support the role of CLDN18.2 as an emerging biomarker in gastric and GEJ cancer. We look forward to presenting the full results at a scientific congress in the near future,” Arozullah said.

Registration studies
The Phase 3 SPOTLIGHT trial, which assesses the efficacy and safety of zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6 and the Phase 3 GLOW trial, which is evaluating the efficacy and safety of zolbetuximab plus capecitabine and oxaliplatin (CAPOX) compared to placebo plus CAPOX, are being conducted to provide foundational data for regulatory submissions in the U.S., Europe, Asia and other countries globally.

Clinical 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

[1] 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.
[2] Sahin U, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624-34.
[3] Niimi T, et al. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21(21):7380-90.
[4] Türeci O, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol. 2019;30(9):1487-95.
[5] Rohde C, et al. Comparison of Claudin 18.2 expression in primary tumors and lymph nodes metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol. 2019;49(9):870-6.
[6] Data on file. Northbrook, Ill. Astellas Pharma Inc.
[7] National Cancer Institute. Gastric cancer treatment (PDQ®): patient version (08-24-2021). Online. Last accessed on November 16, 2022.
[8] National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. Online. Last accessed on November 16, 2022.
[9] 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.
[10] American Cancer Society. Signs and symptoms of stomach cancer (01-22-2021). Online. Last accessed on November 16, 2022.
[11] American Cancer Society. Esophageal cancer risk factors (06-09-2020). Online. Last accessed on November 16, 2022.
[12 American Cancer Society. About esophagus cancer (03-20-2020). Online. Last accessed on November 16, 2022.

Featured image: Stomach cancer illustration. Photo courtesy: © 2016 – 2022. Fotolia/Adobe. Used with permission.

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