Initial data from the global phase III SPOTLIGHT trial could herald the use of a new targeted agent for a subset of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. First-line treatment with zolbetuximab, which targets the transmembrane protein claudin 18.2 (CLDN18.2), plus chemotherapy led to a statistically significant improvement in progression-free survival and overall survival in patients whose tumors expressed CLDN18.2 and were HER2-negative. These findings were presented by Kohei Shitara, MD, and colleagues at the 2023 ASCO Gastrointestinal Cancers Symposium (Abstract LBA292).
Kohei Shitara, MD
The addition of zolbetuximab to leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) reduced the risks for both progression/death and death by 25%. Median progression-free survival, the primary endpoint, was 10.61 months with zolbetuximab plus chemotherapy vs 8.67 months with chemotherapy alone (P = .0066). Median overall survival was 18.23 months vs 15.54 months, respectively (P = .0053).
“This is the longest overall survival seen in patients with locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma in a global phase III trial,” Dr. Shitara, of the National Cancer Center Hospital East, Kashiwa City, Chiba, Japan, 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
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 usefulness of CLND18.2 as a biomarker in this malignancy, which had been suggested by phase II studies. “We’ve been waiting to see if this finding could be validated in a phase III trial with robust statistics, and I think it’s held up,” said Dr. Wainberg.
More About Zolbetuximab
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/GEJ adenocarcinoma. As gastric tumors develop, CLDN18.2 may become more exposed on the surface of the cancer cells, thus making it a promising target for drugs such as zolbetuximab. Zolbetuximab induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
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/GEJ adenocarcinoma. Expression of CLDN18.2 was indicated by moderate-to-strong membrane staining in ≥ 75% tumor cells by immunohistochemistry.
The study’s 565 patients were randomly assigned 1:1 to receive zolbetuximab intravenously at 800 mg/m2 on day 1 of cycle 1, followed by 600 mg/m2 on day 22 of cycle 1, and every 3 weeks in later cycles, plus mFOLFOX6, or to receive placebo every 3 weeks plus mFOLFOX6 every 2 weeks; both regimens were completed in 42-day cycles. Patients without progressive disease continued for at least four cycles with zolbetuximab or placebo plus leucovorin 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.
Improved Progression-Free and Overall Survival
Median progression-free survival was 10.61 with zolbetuximab/mFOLFOX6 vs 8.67 months with chemotherapy alone (hazard ratio [HR] = 0.751, P = .0066). Median overall survival was 18.23 months vs 15.54 months, respectively (HR = 0.750, P = .0053 [statistical boundary was < 0.0135]). For both endpoints, most patient subgroups derived significant benefit from zolbetuximab, though the benefit was largely confined to the three-quarters of patients with gastric tumors, the study found.
While response rates were similar between the treatment arms—60.7% with zolbetuximab plus chemotherapy and 62.1% with chemotherapy—responses to the experimental treatment appeared to be more durable. This was suggested, Dr. Shitara said, by the tails on both the progression-free and overall survival curves. At 36 months, 21% vs 9% of patients, respectively, were alive and 4% vs 15%, respectively, were progression-free.
The 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 rates of serious events were similar (44.8% vs 43.5%). The on-target effects of nausea and vomiting were largely limited to the first cycle, Dr. Shitara noted.
Much of the discussion of the abstract at the meeting focused on the need to find the right subgroup of patients who can benefit from this novel therapy should it be approved by regulatory agencies. The consensus was that its use will be limited to patients with CLDN18.2 expression, although this is currently difficult to accomplish, as there is not a companion diagnostic or readily available assay to test for this biomarker.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
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