SAN FRANCISCO ― 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 to 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, 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 here at the Gastrointestinal Cancers Symposium (GICS) 2023, organized by the American Society of Clinical Oncology.
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% 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 advance gastric cancer since trastuzumab."
But one question, he noted, is, why did the control arm do 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, 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.
As previously reported by Medscape Medical News, 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 Shitera. "Some patients may benefit from targeted therapies, but clearly, better therapies are needed."
Significantly Improved Survival
In the current phase 3 trial, dubbed SPOTLIGHT, Shitera and colleagues randomly assigned 565 patients to receive either zolbetuximab IV 800 mg/m2 (cycle 1, day 1) followed by 600 mg/m2 (cycle 1 day 22, and every 3 weeks in later cycles) plus mFOLFOX6 IV for four 42-day cycles or placebo plus mFOLFOX6.
All patients were treatment naive with CLDN18.2/HER2− locally advanced unresectable or metastatic mG/GEJ adenocarcinoma. Treatment continued until disease progression or discontinuation criteria were met.
The primary endpoint of progression-free survival was statistically significantly improved among patients who received combination therapy with zolbetuximab as compared with patients who received placebo (median 10.61 vs 8.67 months; hazard ratio [HR], 0.751; P = .0066).
"This was highly significant, and study met its primary endpoint," said Shitera. "The subgroup analysis shows that there was also consistent benefit in the prespecified subgroups."
In similar fashion, overall survival was also significantly improved (median, 18.23 vs 15.54 months; HR, 0.750; P = .0053).
However, the overall response rate was similar between groups (60.7% vs 62.1%).
Toxicity was higher in the zolbetuximab group. The most common treatment-related adverse events were nausea (82.4% vs 60.8% in zolbetuximab vs placebo arms), vomiting (67.4% vs 35.6%), and decreased appetite (47.0% vs 33.5%), although the incidence of serious events was similar between the groups (44.8% vs 43.5%).
Most events occurred at first or second cycle and could be resolved, Shitera noted, and treatment-related events were consistent with those of previous studies.
The study was funded by Astellas Pharma Inc. Shitara has relationships with numerous pharmaceutical companies, as listed in the abstract.
Gastrointestinal Cancers Symposium (GICS) 2023: Abstract LBA292. Presented January 19, 2023.
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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Cite this: Longest Overall Survival Ever Seen in Advanced Gastric Cancer - Medscape - Jan 20, 2023.
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