New Combination Therapy for HER2-Positive Stomach Cancer: A Study of Rilvegostomig in Combination with Immunotherapy and Chemotherapy as First-Line Treatment Compared to Standard Treatment

Stomach cancer is one of the more common types of cancer of the digestive system and usually develops from glandular cells in the stomach lining. The development of stomach cancer is a complex process influenced by the interaction of various risk factors. One of the most significant causes is a chronic infection with the bacterium Helicobacter pylori, which can damage the stomach lining over many years and lead to persistent inflammation. Other risk factors include smoking, excessive alcohol consumption, and certain pre-existing conditions such as stomach ulcers. In some cases, there is also a family or genetic predisposition. Stomach cancer typically develops gradually over many years, starting with initially benign changes in the mucosa. Particularly aggressive forms, such as HER2-positive tumors, require targeted treatment. HER2 is a receptor on the surface of tumor cells that plays an important role in cell growth and division. Overexpression of HER2—that is, an increased number of the receptor on cancer cells—leads to faster tumor growth. The current standard of care for advanced HER2-positive gastric cancer combines chemotherapy with trastuzumab (an HER2 antibody) and, frequently, with the immune checkpoint inhibitor pembrolizumab if the PD-L1 protein is also present on the cancer cells. However, the prognosis remains poor, as many patients do not respond to the therapy long-term or may develop resistance. The experimental combination in the ARTEMIDE-Gastric01 study aims to establish a more effective treatment by combining several modern targeted and immunotherapeutic treatment principles. Rilvegostomig is a novel, so-called bispecific antibody used to treat cancer. It works by blocking two different checkpoint proteins (TIGIT and PD-1) that cancer cells use to hide from the immune system. Blocking these proteins enhances the body’s own immune response against the cancer cells and controls tumor growth. Trastuzumab Deruxtecan is an antibody-drug conjugate, meaning it is a medication that combines both an antibody (trastuzumab) and a chemotherapy agent (deruxtecan) to specifically target and fight cancer cells. When the antibody recognizes the cancer cells via their HER2 surface receptor, the attached chemotherapy agent is taken up by the cancer cells and destroys them from the inside. In addition, fluoropyrimidines (capecitabine or 5-FU) are used. These are a group of anticancer drugs used to treat various types of cancer. The primary mechanism of action of fluoropyrimidines is the inhibition of the enzyme thymidylate synthase (TYMS). This disrupts the formation of genetic material (DNA) and proteins (RNA), thereby inhibiting the growth of cancer cells. In addition, fluoropyrimidines may also act through other mechanisms, such as the incorporation of building blocks into the genetic material of cancer cells, leading to their destruction. This combination could be particularly effective, as it both activates the immune system and targets HER2 while also delivering chemotherapy to the tumor.

The goal of the ARTEMIDE-Gastric01 study is to investigate the efficacy and safety of the new combination of rilvegostomig, trastuzumab, and chemotherapy with fluoropyrimidines (capecitabine or 5-FU). To this end, patients will be randomly assigned to three groups: Arm A receives rilvegostomig + trastuzumab deruxtecan + chemotherapy; Arm B receives the standard treatment with pembrolizumab + trastuzumab + chemotherapy; and Arm C receives rilvegostomig + trastuzumab + chemotherapy. The chemotherapy for Arms B and C consists of either 5-FU (fluorouracil) plus cisplatin or CAPOX (capecitabine plus oxaliplatin). The study aims to determine whether the new combination can more effectively slow the progression of HER2-positive stomach cancer and prolong patient survival compared to the current standard of care. The primary endpoint of the study is progression-free survival (PFS), defined as the time from the start of the study until the first occurrence of disease progression, recurrence, or death from any cause.

Eligible participants include adult women and men with microscopically confirmed HER2-positive and PD-L1-positive gastric cancer or adenocarcinoma of the gastroesophageal junction (GEJ). The tumor must be at an advanced stage or have already formed metastases and be inoperable. Participants must not have received any prior treatment.