Subset of Patients With Advanced Gastric Cancer May Benefit From Claudin18.2-Targeted Agent Zolbetuximab

Get Permission

Initial data from the global phase III SPOTLIGHT trial may herald the use of a new targeted agent for a subset of patients with advanced gastric or gastroesophageal junction adenocarcinoma.1 The addition ofzolbetuximab, which targets the transmembrane protein claudin18.2 (CLDN18.2), to chemotherapy in the first-line setting led to a statistically significant improvement in progression-free survival and overall survival in patients whose tumors expressed CLDN18.2 and were HER2-negative. This benefit was observed despite a control arm outperforming the study’s a priori estimated survival, according to Kohei Shitara, MD, of the National Cancer Center Hospital East, Kashiwa City, Chiba, Japan, who presented the findings at the 2023 ASCO GI Cancers Symposium.

Kohei Shitara, MD

Kohei Shitara, MD

Patients treated with the combination of zolbetuximab and modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) had a 25% reduction in the risk of disease progression or death as well as a 25% reduction in mortality. Median -progression-free survival, the primary endpoint, was 10.6 months with zolbetuximab plus chemotherapy vs 8.7 months with chemotherapy alone (P = .0066), and median overall survival was 18.2 vs 15.5 months, respectively (P = .0053), reported Dr. Shitara.

“This is the longest overall survival seen in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma in a global phase III trial,” Dr. -Shitara noted. “Zolbetuximab plus mFOLFOX6 is a new potential standard-of-care treatment for a biomarker-based subgroup of patients with CLDN18.2, HER2-negative disease.”

Zev Wainberg, MD, Professor of Medicine at the University of California Los Angeles (UCLA) and Co-Director of the UCLA GI Oncology Program, told The ASCO Post that SPOTLIGHT validates the utility of CLDN18.2 as a biomarker in this malignancy, which had been suggested by phase II studies. “We’ve been waiting to see whether this finding could be validated in a phase III trial with robust statistics, and I think it’s held up.”

Zev Wainberg, MD

Zev Wainberg, MD

Ian Chau, MD

Ian Chau, MD

Also speaking to The ASCO Post, Ian Chau, MD, a consultant medical oncologist in the Gastrointestinal and Lymphoma Units at the Royal Marsden NHS Foundation Trust and Professor at the Institute of Cancer Research, London, said the findings are potentially practice-changing. “Obviously, we need to see the full data, but from what Dr. Shitara reported, there are likely to be a lot of CLDN18.2-positive patients who also have PD-L1 CPS [combined positive score] < 5, and we generally feel this group may get less benefit from nivolumab plus chemotherapy…. The patients with a CPS < 5 who are positive for CLDN18.2 may be a group who could really benefit from zolbetuximab.”

About the Drug

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a tight junction protein normally expressed in gastric mucosa cells and retained in gastric or gastroesophageal junction adenocarcinoma. As gastric tumors develop, CLDN18.2 may become more exposed on the surface of the cancer cells, thus making it a potential target for drugs such as zolbetuximab. Zolbetuximab induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

About the SPOTLIGHT Trial

The global double-blind phase III SPOTLIGHT trial compared zolbetuximab plus mFOLFOX6 vs placebo plus mFOLFOX6 as first-line treatment for patients with previously untreated CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Expression of CLDN18.2 was indicated by moderate-to-strong membrane immunohistochemical staining in at least 75% of tumor cells.

The study’s 565 patients were randomly assigned 1:1 to receive zolbetuximab intravenously at 800/600 mg/m2 every 3 weeks plus mFOLFOX6 every 2 weeks or placebo every 3 weeks plus mFOLFOX6 every 2 weeks, in 42-day cycles. Patients without progressive disease continued for at least four cycles with zolbetuximab or placebo plus folinic acid and fluorouracil at the investigator’s discretion.

The primary endpoint was progression-free survival by independent review. Overall survival, a secondary endpoint, was tested because the progression-free survival endpoint was significant.

Improvement in Progression-Free
and Overall Survival

Median progression-free survival was 10.6 months with zolbetuximab plus mFOLFOX6 vs 8.7 months with chemotherapy alone (hazard ratio [HR] = 0.751, P = .0066). “The Kaplan-Meier curve shows strong separation, and this separation was maintained to the tail of the curve,” Dr. Shitara noted. Progression-free survival rates were 49% vs 35%, respectively, at 1 year and 24% vs 15%, respectively at 2 years, “suggesting a long-term benefit from zolbetuximab.”

Median overall survival was 18.2 months vs 15.5 months, respectively (HR = 0.750; P = .0053 [statistical boundary was < .0135]. At 36 months, 21% and 9% of patients, respectively, were alive. For both progression-free and overall survival, most subgroups derived significant benefit from zolbetuximab; by tumor type, benefit was limited to patients with primary stomach cancers, Dr. Shitara reported.

Although response rates were similar between the treatment arms—60.7% with zolbetuximab plus chemotherapy and 62.1% with chemotherapy alone—responses to the experimental treatment appeared to be more durable, he said.

Most common treatment-emergent adverse events with zolbetuximab plus mFOLFOX6, vs mFOLFOX6 alone, were nausea (82.4% vs 60.8%), vomiting (67.4% vs 35.6%), and decreased appetite (47.0% vs 33.5%), but the rate of serious events was similar (44.8% vs 43.5%). The on-target effects of nausea and vomiting were largely limited to the first cycle, Dr. Shitara noted.

Interest is now focused on identifying which patients might benefit from this novel therapy, should it become approved. It is generally accepted that zolbetuximab’s utility will be in patients with CLDN18.2-expressing tumors—though this is currently difficult to accomplish, as there is not a companion diagnostic or readily available assay. 

DISCLOSURE: Dr. Shitara reported financial relationships with Bristol Myers Squibb, Janssen, Takeda, AbbVie, Amgen, Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical. Dr. Wainberg has served on the advisory board or received honoraria from Eli Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck Serono, Ipsen, Amgen, Arcus, AstraZeneca, Incyte, Astellas, and Daiichi Sankyo. Dr. Chau has served on the advisory board or has received honoraria or research funding from Eli Lilly, Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas, GlaxoSmithKline, Sotio, Eisai, Daiichi Sankyo, Taiho, Servier, Seagen, Turning Point Therapeutics, and Janssen-Cilag.


1. 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.

Related Articles

Expert Point of View: David Wang, MD, PhD

“We can say with confidence that based on the results of the SPOTLIGHT trial,1 zolbetuximab is the first molecularly targeted therapy since [trastuzumab in] the TOGA trial,2 exclusive of immune checkpoint inhibitors, to demonstrate a statistically significant survival benefit in the first-line...