“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 treatment of advanced gastric cancer,” said David Wang, MD, PhD, of UT Southwestern Medical Center and VA North Texas Health Care System, the study’s invited discussant.
David Wang, MD, PhD
Dr. Wang reminded listeners that TOGA showed the benefit of trastuzumab added to chemotherapy in HER2-positive gastric and gastroesophageal junction cancer. Significant improvements were demonstrated in both median overall survival (P = .0046) and median progression-free survival (P = .0002). Unfortunately, later trials of drugs targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), and the vascular endothelial growth factor receptor 2 (VEGFR2) failed to show an overall survival benefit, although a progression-free survival benefit was achieved with bevacizumab in AVAGAST3 and ramucirumab in RAINFALL.4
Zolbetuximab is a chimeric monoclonal antibody that specifically targets claudin18.2 (CLDN18.2), which is a splice variant of a tight junction protein that is expressed in gastric, lung, and gallbladder epithelium and that can be detected by immunohistochemistry (Ventana 43-14A antibody). In gastric cancer, CLDN18.2 is expressed by all molecular subtypes and has not been shown to be an adverse prognostic factor. Although a clear threshold for CLDN18.2 positivity has not been established, tumors in the SPOTLIGHT trial were considered positive if they had moderate-to-strong staining in at least 75% of tumor cells. In the overall screened population, 38% of patients met this eligibility criteria, Dr. Wang noted.
In the previous phase II FAST trial,5 zolbetuximab in combination with chemotherapy (epirubicin, oxaliplatin, and capecitabine [EOX]) led to significant improvements in progression-free survival (hazard ratio [HR] = 0.38; P < .0005) and overall survival (HR = 0.50; P < .0005) in patients with CLDN18.2 expression in at least 70% of cells. In the ongoing GLOW trial, zolbetuximab is being administered in combination with capecitabine and oxaliplatin (CAPOX), and those results are being awaited, he said.
Closer Look at SPOTLIGHT Findings
In the SPOTLIGHT trial, zolbetuximab’s benefits in progression-free and overall survival were seen across prespecified subgroups. “I will point out that the patients who had the most benefit were those from Asia, those with limited disease, those who had undergone gastrectomy, those with primaries in the stomach, and those with an intestinal phenotype where you’d expect higher expression of a tight junction protein,” explained Dr. Wang.
Pointing out that the control arm performed better than would be expected—with chemotherapy achieving a median overall survival of 15 months, rather than 11 to 12 months as other studies have shown—Dr. Wang commented: “We know that all patients who were eligible for the trial were CLDN18.2-positive, and interestingly, diffuse-type gastric cancer was reported in 42% of the control arm and just 29% of the experimental arm. This raises the question of whether CLDN18.2 positivity characterizes a better prognostic subset of diffuse-type gastric cancer that usually does more poorly.”
Dr. Wang also questioned whether the good-performing control arm might reflect the population’s limited disease or earlier disease stage at enrollment. “Three-quarters of the patients had limited metastases (zero to two sites), and one-third had undergone prior gastrectomy, which means they may have had less tumor burden or could have been in an active surveillance program where they were diagnosed with earlier disease. There could also have been some effect of subsequent therapy,” he further suggested.
Choosing Between Zolbetuximab and Nivolumab
For clinicians, the practical question will be choosing between zolbetuximab and nivolumab, both with chemotherapy, in the first-line setting of advanced gastric cancer, he said. In the study population, 13% of patients would have been eligible for either drug as they had PD-L1 combined positive score ≥ 5 (the criterion for nivolumab treatment, per CheckMate 649).
“I would suggest that for patients with high PD-L1 expression, you would favor nivolumab. Howver, having an appropriate CLDN18.2 expression level would be a reason to use zolbetuximab,” he maintained. “Obviously, the combination of these two agents could be investigated in future trials. Other considerations [in drug choice] could include microsatellite instability–high status, volume of disease, and presence of poor risk factors.”
“I believe the SPOTLIGHT trial validates CLDN18.2 as a new predictive biomarker for advanced gastric cancer. For widespread implementation of this agent, however, an assay for claudin expression needs to be more widely available, and there also needs to be standardization for interpretation of positivity,” he said.
DISCLOSURE: Dr. Wang reported no conflicts of interest.
REFERENCES
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.
2. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.
3. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29:3968-3976, 2011.
4. Fuchs CS, Shitara K, Di Bartolomeo M, et al: Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 20:420-435, 2019.
5. Sahin U, Türeci Ö, Manikhas G, 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 32:609-619, 2021.
