Zolbetuximab plus mFOLFOX6—a chemotherapy combination commonly used in gastric cancer—significantly prolonged patients’ progression-free survival compared with mFOLFOX6 alone in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction ( GEJ) adenocarcinoma, according to primary phase 3 data from the SPOTLIGHT trial.
The results, presented during the 2023 Gastrointestinal Cancer Symposium, a conference organized by the American Society of Clinical Oncology, showed that median progression-free survival (time from treatment to worsening) was 10.61 months for patients who received zolbetuximab/ mFOLFOX6, compared to 8.67 months seen with placebo plus mFOLFOX6, leading to a 25% reduction in the risk of disease progression or death.
“Zolbetuximab plus mFOLFOX6 is a new potential standard of care for a biomarker-based subset of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma,” said Dr. Kohei Shitara, lead study author and medical oncologist. at the National Cancer Center Hospital East in Japan, in a presentation during the meeting.
The standard treatment for patients with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, but there is still an unmet need in terms of targeted therapies for this population. Currently, patients live an average of about a year after treatment — a statistic known as overall survival.
The zolbetuximab target, CLDN18.2, is a protein expressed in normal gastric mucosal cells and retained in advanced gastric/GEJ tumor cells. Because CLDN18.2 can become exposed on the surface of gastric/GEJ cells, Shitara noted that it represents a promising target.
Zolbetuximab also resulted in prolonged survival in patients with higher CLDN18.2 expression in the phase 2b FAST trial. Here, median progression-free survival was nine months with zolbetuximab and epirubicin, oxaliplatin, and capecitabine (EOX), compared with 5.7 months with EOX alone; average overall survival was 16.5 months and 8.9 months, respectively.
In addition, the international, double-blind, placebo-controlled SPOTLIGHT trial enrolled patients with previously untreated locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma and positive for CLDN18.2. To be eligible for enrollment, patients must have moderate to strong CLDN18 staining in at least 75% of tumor cells, have HER2-negative disease, and have an ECOG performance status of 0 or 1, meaning they have few, if any, complications performing their daily tasks .
Study participants were randomly assigned to receive a combination of zolbetuximab and mFOLFOX6 (283 patients) or placebo and mFOLFOX6 (282 patients).
Patients were divided by region (Asian vs. non-Asian), number of organs with metastases (zero to two vs. three or more), and previous gastrectomy (yes vs. no).
The main objective of this study was progression-free survival. Key secondary endpoints were overall survival, time to confirmed worsening of global health status/quality of life, physical functioning, and OG25-pain.
Additional outcome measures included objective response rate (percentage of patients whose disease decreases due to treatment), duration of response, safety, and patient-reported outcomes.
As part of the study design, overall survival was tested only if the progression-free survival benefit with zolbetuximab was significant. Shitara noted that an interim analysis of overall survival is planned in the primary analysis of progression-free survival, with a cut-off date of September 9, 2022 for both analyses. A significant benefit was observed in the interim analysis of overall survival.
Forty-eight percent of patients in the zolbetuximab group received subsequent cancer therapies, compared with 53% in the placebo group.
Additional data showed 12- and 24-month progression-free survival
the rates were 49% and 24% in the zolbetuximab group and 35% and 15% in the placebo group, respectively. A PFS benefit with zolbetuximab/mFOLFOX6 was observed in most prespecified subgroups, except for those whose primary site of disease was GEJ and mixed/other classification.
Median overall survival was 18.23 months with zolbetuximab/mFOLFOX6 and 15.54 months with placebo/mFOLFOX6.
At 12, 24, and 36 months, the overall survival rates in the zolbetuximab and placebo groups were 68% versus 60%; 39% to 28%; that is, 21% against 9%. Similar to the analysis of progression-free survival, overall survival benefit was observed in most subgroups of patients, except those with GEJ as the primary site of disease and others with mixed/other classification.
The objective response rate with zolbetuximab was 60.7% and 62.1%. The best overall response was a complete response in 5.7% and 3.3% of patients treated with zolbetuximab and placebo, respectively; partial response in 55.0% and 58.8% of patients, stable disease in 21.3% and 24.6% of patients, and progressive disease in 6.6% of patients on both arms. The median duration of response was 8.51 months in the zolbetuximab group and 8.11 months in the placebo group.
Shitara noted that a formal analysis is ongoing, but an initial descriptive analysis did not indicate differences between the treatment arms.
Regarding safety, the incidence of side effects was similar between groups, 99.6% in both treatment groups. Moderate or severe adverse events were reported in 86.7% and 77.7% of those in the zolbetuximab and placebo groups, respectively; serious side effects occurred in 44.8% and 43.5%.
Treatment-related adverse events leading to discontinuation of zolbetuximab or placebo occurred in 13.6% and 2.2% of patients, respectively. Moreover, 1.8% and 1.4% of adverse events led to death, respectively.
The most common adverse reactions associated with zolbetuximab/mFOLFOX6 were nausea (all grades, 81.0%; grade ≥3, 16.1%), vomiting (all grades, 64.5%; grade ≥3, 16.1%), and decreased appetite (all grade, 47.0%; grade ≥3, 5.7%). Shitara added that the first onset of nausea and vomiting occurred in the first or second cycle of treatment. It should be noted that grade 3 or higher is considered severe or worse.
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