Metastatic gastric cancer, also known as stage IV gastric cancer, is a serious and advanced form of the disease in which the cancer has spread beyond the stomach to other parts of the body. The current standard of care for patients with metastatic gastric cancer includes chemotherapy, Her2 targeted therapy and immunotherapy. However, there remains an unmet need for more effective treatments.
Recently, two clinical trials presented at GI ASCO 2023, the SPOTLIGHT study and the CheckMate 649 study, have shown promising results in the treatment of metastatic gastric cancer. The SPOTLIGHT study evaluated the combination of a drug called zolbetuximab, which targets a protein called CLDN18.2, with a standard chemotherapy regimen known as mFOLFOX6, versus a placebo with mFOLFOX6. CLDN18.2 was considered positive with 75% expression present in tumor cells and screened positive in 35-40% of patients. The study found that the combination of zolbetuximab and mFOLFOX6 led to a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) compared to placebo and mFOLFOX6. Adverse effects were manageable.
The CheckMate 649 study evaluated the combination of a drug called nivolumab, which blocks the PD-1 immune checkpoint, with chemotherapy (XELOX or FOLFOX) versus chemotherapy alone. The study found that the combination of nivolumab and chemotherapy continued to demonstrate OS and PFS benefit compared to chemotherapy alone. The objective response rate (ORR) per BICR was higher with nivolumab + chemotherapy compared to chemotherapy alone and responses were more durable with nivolumab + chemotherapy especially for those with PLD1 expression above 5%. Most patients were MSS with 2 year OS of 20-30% however MSI patients although were limited in the study had 2 year OS of 50% and responses tended to be more durable.
These recent studies demonstrate exciting new options for patients with metastatic gastric cancer. Targeting CLDN18.2 with zolbetuximab in combination with mFOLFOX6 and blocking the PD-1 immune checkpoint with nivolumab in combination with chemotherapy are both showing promising results and may be new standards of care for patients with Her2 negative metastatic gastric adenocarcinoma that are CLDN18+ or PDL1+. Future clinical trials will have to address other combinational therapies if concurrent positivity with CLDN18 and PDL1 and or in addition to Her2+ positivity? We know for patients with both PDL1 and Her2 positivity, chemotherapy with PD1 and Her2 inhibitors has demonstrated high response rates and is already an approved treatment option in the metastatic setting. It is important for patients to discuss these options with their oncologist to see if they may be suitable for their particular case. Enrollment into clinical trials always preferred and highly encouraged.
About the author
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. Currently practicing at the renowned Orlando Health Cancer Institute, he brings a wealth of expertise to the complex and challenging world of oncology.
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