STAR-221 Trial: Domvanalimab Plus Zimberelimab Shows Promise in Gastric Cancer Treatment
Table of Contents
- STAR-221 Trial: Domvanalimab Plus Zimberelimab Shows Promise in Gastric Cancer Treatment
- Understanding the STAR-221 Trial Design
- TIGIT Inhibitors: A Novel Approach to Cancer Immunotherapy
- Fc-Silent vs. Fc-Activated TIGIT Antibodies
- Phase 2 Data Supporting STAR-221
- PD-L1 Status and Treatment Outcomes
- Implications of Positive STAR-221 Results
- Current landscape of Gastric Cancer Treatment
- STAR-221: Key Comparison
- Evergreen insights: Background, context, Past Trends
- Frequently Asked Questions About Domvanalimab and Gastric Cancer Treatment
The STAR-221 trial (NCT05568095), evaluating the combination of domvanalimab plus zimberelimab and chemotherapy, could redefine first-line treatment strategies for gastric cancers, especially in patients with PD-L1-positive tumors.This phase 3 study is the first to investigate an Fc-silent, anti-TIGIT agent in solid tumors, potentially clarifying the therapeutic role of this novel combination.
Understanding the STAR-221 Trial Design
STAR-221 is a phase 3 clinical trial assessing the efficacy and safety of domvanalimab,a TIGIT monoclonal antibody,combined with zimberelimab,a PD-1 inhibitor,and FOLFOX chemotherapy.The trial aims to determine if this combination improves outcomes for patients with gastric cancers compared to the standard chemotherapy plus nivolumab regimen.
Did You Know? TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor found on immune cells, and blocking it can enhance anti-tumor immune responses.
TIGIT Inhibitors: A Novel Approach to Cancer Immunotherapy
TIGIT inhibitors represent a promising class of cancer immunotherapeutic agents. These inhibitors target the TIGIT receptor on immune cells, preventing it from suppressing the immune response against cancer cells. by blocking TIGIT, these agents aim to enhance the activity of immune cells, such as T cells and natural killer cells, to better recognise and destroy cancer cells. This approach is ofen combined with other immunotherapies, such as PD-1 or PD-L1 inhibitors, to achieve a synergistic effect.
The rationale behind targeting TIGIT stems from its role in suppressing immune responses within the tumor microenvironment. TIGIT is often upregulated on exhausted T cells and regulatory T cells (Tregs),contributing to immune evasion by cancer cells. By blocking TIGIT, researchers hope to reinvigorate these immune cells and promote a more robust anti-tumor response.
Fc-Silent vs. Fc-Activated TIGIT Antibodies
TIGIT antibodies can be classified into two main types based on their fc region: Fc-silent and Fc-activated. Fc-silent antibodies are engineered to lack Fc receptor engagement, which means they do not deplete TIGIT-expressing immune cells. Rather, they primarily enhance the expansion of effector cells. In contrast, Fc-activated antibodies retain Fc receptor binding capabilities, leading to antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, which can deplete TIGIT-expressing immune cells, including Tregs.
The choice between Fc-silent and Fc-activated TIGIT antibodies depends on the desired mechanism of action and potential toxicity profile. Fc-maintained antibodies may deplete Tregs,which could be beneficial for antitumor response but may also increase autoimmune toxicity. fc-silent antibodies, like domvanalimab, are designed to avoid Treg depletion, potentially leading to a more manageable safety profile.
Phase 2 Data Supporting STAR-221
The development of the domvanalimab/zimberelimab combination is supported by data from the EDGE-Gastric trial, a first-line gastric cancer study. Initial results presented at the 2024 ASCO Annual Meeting showed an objective response rate (ORR) of 59% in the entire population, with a median progression-free survival (PFS) of 12.9 months. While the small sample size is a limitation, these findings suggest an increased ORR and longer median PFS compared to previous pivotal trials like CheckMate 649 and KEYNOTE-859.
Subgroup analysis also indicated that the combination works better in patients with high PD-L1 expression, such as a combined positive score (CPS) of 5% or higher. This aligns with expectations, as TIGIT is often co-expressed with other checkpoints like PD-1 on T effector cells. The safety profile also appears manageable, with no increased autoimmune reactions due to the lack of Treg depletion.
PD-L1 Status and Treatment Outcomes
PD-L1 expression levels play a crucial role in determining the effectiveness of certain cancer treatments. In the context of the STAR-221 trial, PD-L1 status is a key stratification factor. Subgroup analyses are planned to assess the treatment’s effectiveness based on PD-L1 expression levels, with a focus on patients with a CPS of 5% or higher. This is particularly relevant because TIGIT is often co-expressed with other checkpoints like PD-1 on T effector cells,suggesting that patients with high PD-L1 expression may derive greater benefit from the domvanalimab/zimberelimab combination.
Pro Tip: Monitoring PD-L1 expression levels can definitely help clinicians tailor treatment strategies and identify patients who are most likely to respond to specific therapies.
Implications of Positive STAR-221 Results
If the domvanalimab/zimberelimab/chemotherapy combination demonstrates an overall survival (OS) benefit compared to chemotherapy plus nivolumab, it could become a new standard of care, particularly in PD-L1-high populations. Even if the benefit is limited to the PD-L1-high population, it would still represent a significant advancement for these patients. Moreover, if the combination shows an OS benefit irrespective of PD-L1 status, it could be attractive for patients with low PD-L1 status who typically achieve limited benefit with chemotherapy plus a PD-[L]1 inhibitor.
Positive results from STAR-221 could also lead to the inquiry of this agent in other types of tumors where previous anti-TIGIT therapies have failed to show a survival benefit. This could potentially expand the use of domvanalimab/zimberelimab to a broader range of cancer patients.
Current landscape of Gastric Cancer Treatment
Currently, chemotherapy plus nivolumab is a standard treatment for patients with a PD-L1 CPS of 1 or higher. However,this combination has not shown benefit in patients with a CPS less than 1. The STAR-221 trial was initiated before the FDA’s Oncologic Drugs Advisory Committee meeting, which restricted frontline PD-1 inhibitors to patients with HER2-negative, microsatellite-stable gastric/GEJ adenocarcinoma with a PD-L1 CPS greater than 1. Thus, the trial population is expected to be representative of the general gastric cancer population regarding CPS frequency.
The main objective of the STAR-221 study is to assess the treatment effect, especially in patients with a CPS or TAP score of 5% or higher.CPS levels are being monitored during the trial, and the results will be reported after the analysis.
STAR-221: Key Comparison
| Treatment Arm | Agents | Patient Population | Primary Endpoint |
|---|---|---|---|
| Experimental | Domvanalimab + Zimberelimab + Chemotherapy (FOLFOX/CAPOX) | Gastric Cancer Patients | Overall Survival (OS) |
| control | Chemotherapy + Nivolumab | Gastric Cancer Patients | Overall Survival (OS) |
What are your thoughts on the potential of Fc-silent antibodies in cancer treatment? How might the results of STAR-221 influence future clinical trials?
Evergreen insights: Background, context, Past Trends
gastric cancer remains a significant global health challenge, ranking as the fifth most common cancer worldwide and the fourth leading cause of cancer-related deaths. In 2020, there were over 1 million new cases and an estimated 769,000 deaths globally, highlighting the urgent need for more effective treatment strategies. The incidence rates vary significantly across different regions, with higher rates observed in Eastern Asia, particularly in countries like China, Japan, and South Korea. These variations are frequently enough attributed to dietary habits, genetic factors, and the prevalence of Helicobacter pylori infection, a major risk factor for gastric cancer.
The treatment landscape for gastric cancer has evolved considerably over the past few decades.Surgery remains the primary curative option for early-stage disease, but many patients are diagnosed at advanced stages when surgery is no longer feasible. In these cases, systemic therapies, including chemotherapy, targeted agents, and immunotherapy, play a crucial role in improving survival outcomes. The introduction of combination chemotherapy regimens,such as FOLFOX and CAPOX,has led to significant improvements in response rates and progression-free survival. However, the overall survival benefits have been modest, underscoring the need for novel therapeutic approaches.
Immunotherapy has emerged as a promising strategy for treating gastric cancer, particularly with the advent of immune checkpoint inhibitors.Agents targeting PD-1 and PD-L1 have demonstrated clinical activity in a subset of patients, leading to their approval as first-line and subsequent-line treatments. Though,not all patients respond to these therapies,and predictive biomarkers,such as PD-L1 expression,are used to identify those most likely to benefit. the development of TIGIT inhibitors, such as domvanalimab, represents the next wave of immunotherapeutic innovation, aiming to overcome resistance mechanisms and enhance anti-tumor immune responses. The STAR-221 trial is a pivotal study that could potentially reshape the treatment paradigm for gastric cancer,offering new hope for patients with this challenging disease.
Frequently Asked Questions About Domvanalimab and Gastric Cancer Treatment
What are the common symptoms of gastric cancer?
Common symptoms of gastric cancer include persistent indigestion, stomach pain, nausea, vomiting, loss of appetite, and unexplained weight loss. However, early-stage gastric cancer may not cause any noticeable symptoms.
How is gastric cancer typically diagnosed?
Gastric cancer is typically diagnosed through a combination of physical examination, medical history review, and diagnostic tests such as endoscopy, biopsy, and imaging studies (e.g., CT scan, PET scan).
What are the risk factors for developing gastric cancer?
Risk factors for gastric cancer include Helicobacter pylori infection, chronic gastritis, smoking, excessive alcohol consumption, a diet high in salt and processed foods, and a family history of gastric cancer.
What are the different stages of gastric cancer?
Gastric cancer is staged using the TNM (Tumor, Node, Metastasis) staging system, which classifies the extent of the tumor, the involvement of regional lymph nodes, and the presence of distant metastasis. The stages range from stage 0 (vrey early-stage cancer) to stage IV (advanced-stage cancer).
What are the treatment options for advanced gastric cancer?
Treatment options for advanced gastric cancer may include chemotherapy,targeted therapy,immunotherapy,radiation therapy,and palliative care. The choice of treatment depends on the stage of the cancer, the patient’s overall health, and other factors.
have you or a loved one been affected by gastric cancer? Share your experiences and thoughts on these emerging therapies in the comments below.
Disclaimer: This article provides information about a clinical trial and potential treatment options for gastric cancer. It is not intended to provide medical advice. Always consult with a qualified healthcare professional for diagnosis and treatment recommendations.
