Immunotherapy for Gastrointestinal Cancers

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Which diagnostic tests are helpful in predicting the utility of immunotherapy for the treatment of a particular cancer type?

Following is a list of some diagnostic tests that are usually performed to estimate the efficacy of immunotherapy for different cancer types:

Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing: MMR proteins are helpful in repairing the faults in the DNA. A mutation or modifications in the MMR genes (changes in the length of predetermined repetitive DNA elements, or microsatellite) may lead to MMR protein deficiency (dMMR) or MSI.

Depending on the extent of instability in the markers tested, tumors with the presence of MSI are classified as either MSI-H or MSI-low (MSI-L). Tumors without MSI are classified as microsatellite-stable (MSS). Patients with MSI-H status are almost always determined to have defective MMR (dMMR). MSI or MMR testing can be done using a validated next-generation sequencing (NGS) panel or immunohistochemical analysis.

MMR or MSI testing is recommended to be performed in patients who are candidates for the treatment with PD-1/L1 inhibitors. The MSI/MMR testing is also helpful in the diagnosis of Lynch syndrome, a common hereditary syndrome that is considered an important risk factor for the development of many cancer types.

Programmed Death-Ligand 1 (PD-L1) Testing: PD-L1 is a protein (ligand) commonly found on the surface of healthy human cells. PD-L1 (and other similar ligands) binds with the programmed cell death protein 1 (PD-1) receptor present on activated T- cells to prevent the attack of T-cells on the healthy tissue. Cancer cells take advantage of this mechanism and express PD-L1 on their surface to evade immune attack. PD-L1 testing can be done using a qualitative immunohistochemical analysis.

PD-L1 specific stains are used to detect the PD-L1 positive cells. For accurate PD-L1 evaluation, at least 100 tumor cells must be present in the PD-L1–stained tumor specimen. Then, the total number of viable tumor cells and PD-L1 staining cells (tumor cells, lymphocytes, macrophages) is computed to determine the Combined Positive Score (CPS). The CPS is defined as the number of PD-L1 staining cells divided by the total number of viable tumor cells, multiplied by 100. A tumor specimen is designated as PD-L1 expression positive if the CPS >/=1. PD-L1 testing is recommended in patients who are candidates for the treatment with PD-1/L1 inhibitors.

Tumor Mutational Burden: As per available pieces of evidence, tumor mutation burden has been proposed to be a predictive biomarker for the efficacy of immunotherapy, especially immune checkpoint inhibitors. It has been reported that patients with diverse tumor types and high tumors mutation burden (>/=16 mutations per megabase) are most likely to derive benefit from the immunotherapy.

What are different Immuno-therapeutic agents approved for the treatment of different gastrointestinal cancers?

Following is the list of various immunotherapeutic regimen that have been approved for different gastrointestinal cancer types.

Esophagus, Esophago-gastric junction (EGJ), and Gastric Cancer: Only one immunotherapeutic agent, pembrolizumab, has been approved for the treatment of advanced stage esophagus/EGJ/gastric cancer. Pembrolizumab had been granted US FDA approval to be used as the second-line or subsequent line therapy for MSI-H or dMMR positive unresectable/metastatic esophagus/EGJ/gastric tumors that have progressed on prior treatment and for which no satisfactory alternative treatment option is available. It has also been approved for third-line or subsequent line therapy of PD-L1 positive esophagus/EGJ/gastric tumors that have progressed on >/=2 prior lines of therapy.

Liver/Hepatic and Gallbladder Cancer: Specific immunotherapeutic agents, nivolumab and pembrolizumab, have been approved for the treatment of advanced stage hepatic cancer (hepatocellular carcinoma) and gallbladder (or biliary tract) cancer, respectively. Nivolumab has been approved by US FDA for the treatment of hepatic tumors that have progressed on or after targeted therapy with sorafenib, and adequate liver function (Child-Pugh Class A or B7 only). Pembrolizumab had been granted US FDA approval for the treatment of MSI-H or dMMR positive unresectable/metastatic gallbladder/biliary tract tumors that have progressed on prior treatment and for which no satisfactory alternative treatment option is available.

Pancreatic Cancer: Pembrolizumab had been granted US FDA approval for the treatment of MSI-H or dMMR positive unresectable/metastatic pancreatic cancers that have progressed on prior treatment and for which no satisfactory alternative treatment option is available.

Colorectal Cancer: Pembrolizumab and nivolumab have been approved as the second- or third-line therapy for patients with unresectable or advanced/metastatic, dMMR/MSI-H positive colorectal cancers that have progressed on prior treatment (except a checkpoint inhibitor).

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