Introduction: A New Hope for Metastatic Gastric Cancer
Gastric cancer (GC) is one of the most common and deadly cancers globally, especially in countries like China, where it accounts for a significant percentage of cancer-related deaths. Approximately 20% of gastric cancer cases involve human epidermal growth factor receptor 2 (HER2) overexpression, a genetic abnormality that plays a crucial role in the development and progression of the disease. Traditionally, HER2-positive gastric cancer has been treated with trastuzumab, a monoclonal antibody, combined with chemotherapy. However, for patients whose tumors do not respond to this standard treatment, the prognosis remains poor, and new treatment strategies are urgently needed.
The PRaG3.0 Treatment Approach
In this case study, a novel treatment approach combining an anti-HER2 antibody called RC48 with PD-1 inhibitors, stereotactic body radiotherapy (SBRT), and granulocyte-macrophage colony-stimulating factor (GM-CSF) was tested in a patient with metastatic HER2-positive gastric cancer. The PRaG3.0 regimen, as it is referred to, aims to combine the strengths of immunotherapy, targeted therapy, and radiotherapy to combat cancer more effectively.
RC48 is an innovative anti-HER2 antibody drug conjugate, specifically designed to target HER2 overexpressing tumor cells while minimizing damage to surrounding healthy tissue. Previous studies have demonstrated its potential efficacy in patients with HER2-positive gastric cancer, but combining it with other therapies may yield better results, especially in chemotherapy-resistant cases.
The inclusion of PD-1 inhibitors and GM-CSF in the PRaG3.0 regimen enhances the immune system’s ability to target and destroy cancer cells. PD-1 inhibitors block the immune checkpoint protein PD-1, which normally prevents immune cells from attacking cancer cells. GM-CSF, on the other hand, helps to activate and recruit immune cells, such as dendritic cells and T-cells, to the tumor site, further boosting the immune response. SBRT, a highly precise form of radiation therapy, is included to kill tumor cells directly and stimulate an immune response in the irradiated and non-irradiated parts of the body, inducing what is known as the abscopal effect.
Patient’s Treatment Journey
The patient, a 58-year-old male with metastatic gastric cancer, initially underwent surgery and chemotherapy. Despite these treatments, his cancer rapidly progressed, with metastases detected in his liver, lungs, and other organs. As his tumor continued to grow, the medical team decided to employ the PRaG3.0 regimen, a combination of RC48, PD-1 inhibitor (camrelizumab), SBRT, and GM-CSF.
The patient received two cycles of the PRaG3.0 regimen, targeting different metastatic foci. Following this treatment, the patient experienced a significant reduction in tumor size, with the target lesions in the liver and lungs showing substantial regression. This result was remarkable, as the patient had previously shown resistance to standard treatments, including trastuzumab and chemotherapy.
After the second treatment cycle, a follow-up CT scan showed a 58% decrease in the sum of the diameters of the unirradiated metastases. The patient was assessed as having achieved partial remission (PR), and his carcinoembryonic antigen (CEA) levels—a marker often used to monitor gastric cancer progression—decreased significantly from 5677 ng/mL to 1780 ng/mL.
Significance of Combined Treatment and Optimizing Radiation
The success of this four-drug combination highlights the potential of immunotherapy and targeted therapy to treat chemotherapy-resistant and advanced metastatic gastric cancer. The combination of RC48 with PD-1 inhibitors (camrelizumab), radiotherapy, and GM-CSF offers a multi-faceted approach to combating cancer, addressing the tumor directly while enhancing the body’s immune system to fight the disease more effectively.
Radiotherapy, particularly SBRT, plays an essential role in optimizing tumor response. By delivering high doses of radiation to targeted areas, SBRT can kill tumor cells and increase the immune system’s ability to recognize and destroy cancerous cells. Furthermore, radiation therapy may help convert “cold” tumors, which are less responsive to immune checkpoint inhibitors, into “hot” tumors, which are more likely to respond to immunotherapy.
The inclusion of GM-CSF further strengthens this approach by boosting the immune system’s response, enabling it to mount a more robust attack on the tumor. In this case, the combination therapy led to significant tumor regression and prolonged the patient’s progression-free survival (PFS), giving hope to those suffering from similar conditions.
Challenges and Future Directions
While the results of the PRaG3.0 regimen are promising, it is important to note that the patient ultimately experienced disease progression again after 6.5 months of PFS. This highlights the need for further research to optimize these treatments, particularly in terms of radiation dose, duration, and sequencing. Additionally, the potential adverse effects of immunotherapy, including reactive cutaneous capillary endothelial proliferation (RCCEP), require careful management.
The combination of SBRT, RC48, PD-1 inhibitors, and GM-CSF offers a potential breakthrough in the treatment of metastatic gastric cancer, especially for patients with HER2-positive, PD-L1-negative tumors. However, as with all cancer therapies, it is crucial to assess the safety and efficacy of these treatments in larger, randomized trials to better understand their potential for widespread use.
Conclusion: A New Hope for Metastatic Gastric Cancer
This case demonstrates that combining multiple treatment modalities—RC48, PD-1 inhibitors, SBRT, and GM-CSF—can offer a powerful strategy for treating refractory metastatic gastric cancer. With further research and clinical trials, this four-drug combination may become a new standard for treating advanced HER2-positive gastric cancer, especially for patients who do not respond to conventional therapies.
