Conference Coverage

Longest overall survival ever seen in advanced gastric cancer


 

AT GI CANCERS SYMPOSIUM 2023

An experimental monoclonal antibody combined with chemotherapy could offer a new standard of care for patients with claudin-18.2+ (CLDN18.2+) / HER2− advanced gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma, say researchers in reporting a phase 3 trial.

Used in the frontline setting, zolbetuximab (under development by Ganymed Pharmaceuticals AG) combined with chemotherapy led to significantly longer progression-free survival and overall survival, compared with what was seen with chemotherapy alone.

The chemotherapy used was the mFOLFOX6 regimen, comprising folinic acid (leucovorin), fluorouracil (5-FU), and oxaliplatin (OX).

“Zolbetuximab plus mFOLFOX6 is a new potential standard treatment for these patients,” said lead study author Kohei Shitara, MD, department of gastrointestinal oncology, National Cancer Center Hospital East Kashiwa City, Chiba, Japan.

This is one of the longest median overall survival outcomes for patients with locally advanced mG/GEJ adenocarcinoma in phase 3 trials, Dr. Shitera emphasized. “Survival benefits were observed across most subgroups,” he said. “Zolbetuximab plus mFOLFOX6 demonstrated a tolerable and manageable safety profile, and it was consistent with prior studies of the combination.”

The findings were presented at the 2023 Gastrointestinal Cancers Symposium.

Zolbetuximab is a monoclonal antibody that targets the cell surface molecule CLDN18.2, which is expressed in normal gastric mucosa cells and is retained in mG/GEJ tumor cells. It represents a unique target in that it is restricted to differentiated stomach cells only, and LDN18.2 is absent from all other healthy tissues.

However, it is upregulated in various cancers, including about 80% of gastrointestinal adenocarcinomas, 60% of pancreatic tumors, and biliary, ovarian, and lung cancers.

In a discussion of the paper, David H. Wang, MD, PhD, an associate professor in the department of internal medicine at University of Texas Southwestern Medical Center, Dallas, pointed out that “zolbetuximab is the first molecularly targeted therapy, exclusive of immune checkpoint inhibitors, to demonstrate a statistically significant survival benefit in first-line treatment of advanced gastric cancer since trastuzumab.”

But he asked why the control arm did so well.

One reason may be that claudin 18 positivity may be associated with a better prognosis for patients with diffuse gastric cancer, he explained. “It may also be due to more limited or earlier disease – the majority had limited metastases, and one-third had a prior gastrectomy.”

Overall, Dr. Wang believes that these results validate claudin 18 as a new predictive biomarker for advanced gastric cancer, although he noted that widespread implementation for this indication may be limited, as the assay to determine claudin 18 levels is not widely available. “Standardization is also needed for interpretation,” he added.

Study details

First-line therapy for HER2− mG/GEJ adenocarcinoma generally consists of chemotherapy and immunotherapy, but among patients with advanced disease, the prognosis continues to be poor, and therapeutic options are limited.

Zolbetuximab improved survival in the phase 2 FAST trial, which was conducted in a similar patient cohort. Median overall survival was significantly longer for patients who received zolbetuximab in comparison with those who did not (13.2 vs. 8.4 months). For patients with the highest levels of CLDN18.2, median overall survival was even longer (16.7 vs. 9.0 months).

“There is a need for better therapies, as chemotherapy is still the primary treatment,” said Dr. Shitera. “Some patients may benefit from targeted therapies, but clearly, better therapies are needed.”

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