Zolbetuximab (IMAB362), an investigational, first-in-class chimeric IgG1 antibody that targets and binds to CLDN18.2 (Claudin18.2), being developed by Astellas, in combination with CAPOX, a combination chemotherapy regimen that includes capecitabine (Xeloda™; Genentech/Roche) and oxaliplatin (Eloxatin®; Sanofi) extends survival in patients with 1L claudin-18.2-positive/HER2-negative locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma.

The detailed results from these study results were be presented by Manish A. Shah, M.D., Medical Oncologist and Director of the Gastrointestinal Oncology Program, Weill Cornell Medicine, New York. during the March 2023 session of the American Society of Clinical Oncology (ASCO) Plenary Series. [1]

Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide. [2] 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.[3] Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue and vomiting blood or having blood in the stool.[4]

Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastro-esophageal reflux disease (GERD).[3][5] 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.[3]

The five-year relative survival rate for patients at the metastatic stage is approximately six percent.[6] Gastroesophageal junction (GEJ) adenocarcinoma is a cancer that starts at the area where the esophagus joins the stomach.[7]

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Claudin18.2
CLDN18.2, a transmembrane protein, is an isoform of claudin18.2, a member of the tight junction protein family, is a highly selective biomarker with limited expression in normal tissues and often abnormal expression during the occurrence and development of various primary malignant tumors, such as gastric cancer/gastro-esophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small-cell lung cancer.[8]

CLDN18.2 is involved in the proliferation, differentiation and migration of tumor cells.[8]

Zolbetuximab binds to CLDN18.2 on cancer cells, causing cancer cell death. CLDN18.2 status is not routinely evaluated in patients with locally advanced resectable or metastatic gastric/GEJ adenocarcinoma, and there is currently no approved therapy for these patients.

GLOW study
In the GLOW study, 507 patients were randomized 1:1 to receive zolbetuximab along with a chemotherapy regimen of capecitabine plus oxaliplatin (CAPOX) or placebo with CAPOX.

In the study, zolbetuximab plus CAPOX demonstrated a statistically significant improvement in progression-free survival (PFS) compared to placebo plus CAPOX.

After eight cycles, patients continued with zolbetuximab or placebo, plus capecitabine, until disease progression or a discontinuation criterium was met. Progression-free survival (PFS) was a median of 8.2 months (95% CI: 7.46–8.84) in the zolbetuximab group compared to 6.8 months (95% CI: 6.14–8.08) in the placebo group. Overall survival (OS), a key secondary endpoint, reduced the risk of death by 22.9% (HR=0.771; 95% CI: 0.615-0.965; p=0.0118). Median OS was 14.39 months (95% CI: 12.29-16.49) and 12.16 months (95% CI: 10.28-13.67) for the treatment arm and placebo arm, respectively.

The results of the study demonstrated that zolbetuximab plus CAPOX reduced the risk of progression or death by 31.3% (n=507; hazard ratio [HR]=0.687; [95% confidence interval [CI]: (0.544-0.866)]; p=0.0007) compared to placebo plus CAPOX, meeting GLOW’s primary endpoint. The study also showed that zolbetuximab plus CAPOX significantly prolonged overall survival (OS),

The incidence of serious treatment-emergent adverse events (TEAEs) was similar between both treatment arms (47.2% versus 49.8% in the zolbetuximab versus placebo arms, respectively) and consistent with previous studies.[9] 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.

“The progression-free and overall survival data from GLOW demonstrate the potential of zolbetuximab in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric and gastroesophageal junction cancer,” noted Rui-Hua Xu, M.D., Ph.D., Professor in the Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China, and the primary investigator of GLOW.

“While the treatment landscape is continuing to evolve, patients at this stage of the disease are in need of options and the GLOW data are encouraging for this patient population,” Xu added.

SPOTLIGHT trial
The authors recently presented findings from the SPOTLIGHT trial at the 2023 ASCO Gastrointestinal Cancers Symposium. That study found that patients with CLDN18.2-positive/HER2-negative locally advanced or metastatic gastric/GEJ adenocarcinoma treated with zolbetuximab and folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) had better PFS and OS compared to those treated with placebo and mFOLFOX6.

Clinical practice
According to the authors, platinum/fluoropyrimidine chemotherapy is one of the standard first-line therapies for patients with HER2-negative, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma, but there is no consensus among the available guidelines on the specific regimen that should be used in clinical practice. To account for this, the authors selected standard approved chemotherapy regimens used globally in combination with zolbetuximab—mFOLFOX6 in the SPOTLIGHT trial and CAPOX in the GLOW trial.

“The results of GLOW and SPOTLIGHT suggest that zolbetuximab plus chemotherapy has the potential to be an innovative therapeutic option and a potential new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma,” explained lead GLOW study author Rui-hua Xu, MD, PhD from Sun Yat-sen University Cancer Center in Guangzhou, China.

The GLOW and SPOTLIGHT studies are a 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.

In both trials, approximately 38% of these patients had CLDN18.2-positive tumors (≥75% of tumor cells with strong-to-moderate membranous CLDN18.2 staining intensity), as determined by a validated immunohistochemistry assay.[10]

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

Highlights of prescribing information
Capecitabine (Xeloda™; Genentech/Roche)[Prescribing Information]
Oxaliplatin (Eloxatin®; Sanofi)[Prescribing Information]

Reference
[1] Xu RH. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW. Abstract 405736. Wednesday, March 22, 2023, ASCO Plenary Series Program.[Abstract]
[2] 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.
[3] American Cancer Society. Signs and symptoms of stomach cancer. Online. Last accessed on March 21, 2023.
[4] National Cancer Institute. Gastric cancer treatment (PDQ®): patient version. Online. Last accessed on March 21, 2023.
[5] American Cancer Society. Esophageal cancer risk factors. Online. Last accessed on March 21, 2023.
[6] National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. Online. Last accessed on March 21, 2023.
[7] American Cancer Society. About esophagus cancer Online. Last accessed on March 21, 2023.
[8] Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, Yu J. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. 2022 May 31;10(1):38. doi: 10.1186/s40364-022-00385-1. PMID: 35642043; PMCID: PMC9153115.
[9] Shitara K, Lordick F, Bang YJ, et al: Zolbetuximab + mFOLFOX6 as first-line treatment for patients with claudin-18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. 2023 ASCO GI Cancers Symposium. Abstract LBA292. Presented January 19, 2023.
[10] American Cancer Society (ACS). Signs and symptoms of stomach cancer. Online. Last accesses March 20,  2023.

Featured image:Stomach cancer shown by EGD. Its histology was poorly differentiated with signet ring cells. Photo courtesy: © 2011 – 2023 Med Chaos Mas. licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

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