Gastric cancer develops in the lining of the stomach and is one of the most common gastrointestinal malignancies, worldwide. Most patients are diagnosed at an advanced stage of the disease, which gives them limited treatment options and a dismal prognosis. Thus, the chances of survival can be improved to a certain extent by early detection of gastric cancer and cutting-edge treatment alternatives [1].
How do things stand for gastric cancer?
Despite the advances in diagnostics and therapeutics, the majority of patients are still diagnosed at an advanced stage, and the first-line treatments that are now available have limited efficacy at this stage. Chemotherapy and targeted therapies currently experience bottlenecks, and the median overall survival (OS) is challenging to break out in 2 years. Additionally, the 5-year OS for advanced gastric cancer is only 10-15% globally.
Even though the overall 5-year survival rate for advanced stomach cancer remains extremely low, surgery is still the only curative treatment. Additionally, chemoradiation, adjuvant chemotherapy, and perioperative chemotherapy can all enhance clinical outcomes in gastric cancer patients. In recent years, immunotherapy, notably monoclonal antibodies, has emerged as a viable therapeutic agent in gastric cancer. Nivolumab and pembrolizumab are currently recommended as standard third-line therapy in gastric cancer patients [2].
Rationale behind the use of avelumab
Avelumab is a human anti-PD-L1 monoclonal antibody that has received FDA approval for the treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma. Avelumab has shown a tolerable safety profile and long-lasting anticancer efficacy in phase I and II studies on a variety of advanced malignancies.
The use of avelumab to treat solid tumors including gastric cancer patients offers certain advantages that are enlisted below:
Avelumab blocks the PD-L1/PD-1 interaction and disabling T-cell inhibition and eliminating the suppression of T-cell activity.
Avelumab also prevents PD-L1 from interacting with B7.1, a second inhibitory receptor that may be expressed on T-cells and antigen-presenting cells. Avelumab may reactivate T-cells and the release of cytokines by preventing the interaction between B7.1 and PD1 on T-cells and with PD-L1 on antigen-presenting cells in the lymph nodes or tumor microenvironment.
Avelumab also maintains the ability to engage natural killer cells with the crystallizable fragment (Fc)-γ receptor to generate tumor-targeted antibody-dependent cell-mediated cytotoxicity in vitro. This is due to its native IgG1 Fc domain.
Avelumab is used in ongoing clinical trials because of its ability to boost innate immune interactions against tumor cells [1].
Clinical efficacy of avelumab in gastric cancer?
In light of the fact that avelumab has shown promise in treating gastric cancer in early-phase clinical studies, it is anticipated that it will be investigated in more broad clinical settings. Avelumab would appear to be a potential opportunity for the treatment of gastric cancer as well. Clinical trials are currently being conducted to investigate whether it can improve the extremely poor prognosis of gastric cancer [1].
Avelumab demonstrated persistent anti-tumor effectiveness in a cohort of the phase I JAVELIN Solid Tumor trial (ClinicalTrials.gov identifier: NCT01943461). Avelumab showed acceptable safety in patients with advanced gastric or gastroesophageal junction cancer when used as first-line maintenance or second-line therapy [3].
On the other hand, the randomized phase III JAVELIN Gastric 300 trial (ClinicalTrials.gov identifier: NCT02625623) showed no benefit in terms of improvement in overall survival, progression-free survival, or objective response rate in the avelumab versus chemotherapy arms in patients with advanced gastric or gastroesophageal junction cancer. However, compared to chemotherapy, avelumab had a more tolerable safety profile [4].
Another randomized, Phase III JAVELIN Gastric 100 trial (ClinicalTrials.gov identifier: NCT02625610) did not show that avelumab maintenance therapy compared to continued chemotherapy improved overall survival in patients with advanced gastric or gastroesophageal junction cancer in general or in a predetermined PD-L1-positive population [5].
The whole shebang of avelumab
To determine whether or not checkpoint inhibitors can enhance clinical outcomes for patients with advanced gastric cancer, the outcomes of ongoing clinical trials investigating avelumab and other immunotherapies are highly awaited. Furthermore, accurate predictive biomarkers will be required in the future to assist physicians in determining whether patients respond to checkpoint inhibitors or not. Future studies on the role of tumor burden as a biomarker for predicting immunotherapy effectiveness in gastric cancer may also be useful. More and more monoclonal antibodies are joining the army of advanced therapy for gastric cancer on account of the continual development and advancement of monoclonal antibody clinical research.
References
1. Roviello, G. et al. 'Avelumab in gastric cancer'. Immunotherapy. (2019) 11(9), 759–768. DOI: 10.2217/imt-2019-0011.
2. Chang, X. et al. 'The current management and biomarkers of immunotherapy in advanced gastric cancer'. Medicine (Baltimore). (2022) 101(21), e29304. DOI: 10.1097/MD.0000000000029304.
3. Doi, T. et al. 'Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial'. Gastric Cancer. (2019) 22(4), 817–827. DOI: 10.1007/s10120-018-0903-1.
4. Bang, Y.-J. et al. 'Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300'. Ann Oncol. (2018) 29(10), 2052–2060. DOI: 10.1093/annonc/mdy264.
5. Moehler, M. et al. 'Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100'. J Clin Oncol. (2021) 39(9), 966–977. DOI: 10.1200/JCO.20.00892.
