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Pabrolizumab (pembrolizumab) is an immunotherapeutic agent that belongs to the family of PD-L1 inhibitors.PD-L1, known as programmed death-1 ligand, when expressed on the surface of cancer cells, binds to PD-1 on the surface of T lymphocytes, which are responsible for monitoring and destroying tumors. When PD-L1 is expressed on the surface of cancer cells, it can bind to PD-1 on the surface of T-lymphocytes, which are responsible for monitoring and destroying tumors, thereby inducing T-lymphocyte death and inhibiting their functions. It is by preventing PD-L1 from binding to PD-1 that pabrolizumab restores the ability of T lymphocytes to attack tumors.
Pabrolizumab is available in the U.S. Which gastric cancers are available? Test first!
Pabrolizumab was approved for marketing in the United States back in 2014, and in May 2017, the FDA approved pabrolizumab for the treatment of all solid tumors with high microsatellite instability (MSI-H) or defective mismatch repair (dMMR), which is the case in some cases of gastric cancer. This is the first time that the FDA has approved a cancer treatment not for a tumor type but only for a tumor marker. This means that regardless of the type of solid tumor, pabrolizumab may be considered if MSI-H or dMMR is detected if progression occurs after prior therapy.
Subsequently, in July 2017, the FDA approved an indication specifically for gastric cancer, where pabrolizumab can be used in recurrent locally advanced or metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction, and these patients can be selected for pabrolizumab in second-line later treatment if their tumor is tested and found to express PD-L1.
The National Comprehensive Cancer Network (NCCN) guidelines make clear recommendations for the use of pabrolizumab in gastric cancer, and pabrolizumab may be considered in second-line and beyond for tumors with MSI-H/dMMR, and in third-line and beyond for PD-L1-positive adenocarcinoma.
Therefore, gastric cancer patients usually need to be tested for MSI-H/dMMR mutations and PD-L1 expression before choosing pabrolizumab treatment, and physicians will consider pabrolizumab only if these tests are positive. Analysis of data from several studies showed that the proportion of MSI-H in gastric cancer patients was 11.68% to 33.82%. The detection of PD-L1 expression, on the other hand, has resulted in different settings of PD-L1 expression levels due to the different antibodies and technologies used for the assay, with positive rates ranging from 14% to 69%.
Pabrolizumab for gastric cancer, how does it work?
Pabrolizumab was approved by the FDA for gastric cancer treatment based on its excellent performance in a series of studies.
In the KEYNOTE-016 study, published in 2015, in dMMR metastatic non-colorectal cancer, including gastric cancer, 71% of patients had tumors in remission with pabrolizumab, and nearly 70% of patients had tumors that did not progress at 20 weeks of treatment, which translates to a progression-free survival (PFS) rate of 67%.
The FDA’s approval of an indication specifically for gastric cancer was based on the following study: 22% of patients in the KEYNOTE-012 study of PD-L1-positive recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma responded to pabrolizumab, and 2 of 4 patients who also had MSI-H achieved partial remission (i.e., 50% of patients responded to treatment). . Moderate-to-severe adverse effects on treatment were mainly fatigue, aspergillosis, hypothyroidism, and peripheral sensory neuropathy. In the subsequent KEYNOTE-059 study, 11.6% of patients who had progressed on two or more prior regimens responded to pablizumab, with 15.5% of PD-L1-positive patients and 2% of patients achieving complete remission.
In these studies, pabrolizumab showed efficacy and a good safety profile in advanced gastric cancer. However, it is important to note that in the newly published KEYNOTE-061 study, pablizumab did not improve overall survival (OS) and progression-free survival (PFS) compared with paclitaxel as second-line therapy in patients with PD-L1-positive advanced gastric cancer. Therefore, further studies are needed to determine which gastric cancers are more likely to benefit from pablizumab treatment. Investigators are currently exploring the role of pabrolizumab, as well as combination chemotherapy and targeted therapy, in the first-line treatment of advanced gastric cancer.
Summary
Pabrolizumab has been approved in the United States for the treatment of some advanced gastric cancers and its use has been recommended by US guidelines, and the drug will be approved for marketing in China in the near future, bringing additional expectations for the treatment of advanced gastric cancer.