On January 26, 2021, the European Medicines Agency approved pembrolizumab as first-line treatment in adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.

Microsatellites, also called Short Tandem Repeats (STRs), are short tandem repeat sequences of 1-6 nucleotides, distributed throughout the genome. Due to their repeated structure, microsatellites are particularly prone to replication errors that are normally repaired by the MisMatch Repair (MMR) system.

Microsatellite instability (MSI) consists of length variation of microsatellites sequences that occurs in some cells, like the tumour ones, through the loss or the insertion of one or more repeating units.

The cause of microsatellite instability was determined to be a defect in the ability to correct errors made during the process of DNA replication, referred as mismatch repair deficient (dMMR).

MSI is recognised as one of the major carcinogenetic pathways of colorectal cancer, where it is found in about 15% of patients: 12% sporadic cases and 3% hereditary cases. It represents a molecular hallmark of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), usually linked to germ-line mutations in one of MMR genes; moreover, it is detected in sporadic colorectal cancers, more often due to an epigenetic inactivation of MLH1.

Due to the accumulation of mutations that are not repaired by a defective MMR, colorectal tumours with instable microsatellites are highly immunogenic, because they can produce heterologous antigens that are easily recognised by T cells. For this reason, some studies have shown the effectiveness of immunotherapy with anti-PD-1 inhibitors on MSI-H solid tumours to be higher than solid tumours with stable microsatellites (MSS) or low instable microsatellites (MSI-L).

Two months ago, the European Commission approved the anti-PD-1 immunotherapy pembrolizumab as first-line treatment of adult patients with metastatic colorectal cancer who have tumours that are MSI-H/dMMR.

This approval marks the first gastrointestinal indication for pembrolizumab in Europe, thus becoming the first anti-PD-1/L1 therapy approved in Europe for these patients.

The EC approval is based on results from the Phase III KEYNOTE-177 trial.

In this study, pembrolizumab monotherapy significantly reduced the risk of disease progression or death by 40% (HR 0.60) compared to chemotherapy.

Treatment with pembrolizumab also more than doubled median progression-free survival (PFS) compared to chemotherapy: 16.5 months versus 8.2 months.

For patients treated with pembrolizumab, the overall response rate (ORR) was 44% with a complete response rate of 11% and a partial response rate of 33%. Meanwhile, in the chemotherapy arm, patients demonstrated an ORR of 33%, a complete response rate of 4% and a partial response rate of 29%.

Lastly, a lower incidence of treatment-related adverse events of grade ? 3 has been reported with pembrolizumab compared to chemotherapy (22% versus 66%) and no new toxicities have been observed with the anti-PD-1 inhibitor.

In general, the microsatellite instability is detected indirectly by analysis of MMR proteins expression by immunohistochemistry (IHC), or directly by amplification of specific microsatellite repeats and subsequent fragment length analysis by capillary electrophoresis. The two methods show high concordance. However, molecular test, unlike the IHC, is not compromised by pre-analytic artifacts and  can detect MSI also in case of mutated MMR proteins with impaired function but unaltered expression.

Recently, alternative methodologies have been successfully implemented: Next Generation Sequencing (NGS) and Real Time PCR. The last one is the technology underlying the innovative solution offered by Diatech Pharmacogenetics for the analysis of microsatellite instability.

More information at www.diatechpharmacogenetics.com



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  4. Press Release January 26, 2021. European Commission Approves KEYTRUDA® (pembrolizumab) as First-Line Treatment in Adult Patients With Metastatic Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer.