On May 23, 2017, Merck & Co. announced the FDA approval of Keytruda (pembrolizumab), a programmed cell death ligand-1 (PD-1) inhibitor, for the treatment of advanced Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) cancer. Keytruda is not only the first-in-class PD-1 inhibitor to enter the CRC treatment paradigm, but also represents the first oncology treatment to be approved by the FDA based on a specific biomarker rather than on primary tumor location. Thanks to the recent green light obtained for urothelial carcinoma, non-small cell lung cancer (NSCLC), and this broad approval, Merck & Co.’s PD-1 candidate is now the leading agent within its drug class for a number of approved indications.

The discovery that tumors characterized by high mutational burden and, consequently, by a higher number of neoantigens, such as melanoma or NSCLC, are more likely to benefit from immunotherapies has prompted developers to investigate these agents in specific cancer types. However, it has recently been proven that small subsets of almost any solid tumor may have high mutational loads due to defects in DNA mismatch repair (MMR) mechanisms. Microsatellite Instability (MSI) is a hypermutable cancer phenotype caused by MMR that allows the creation of multiple tumor-specific neoantigens, typically 10–50 times that of MSS tumors, thereby making them more likely to respond to immunotherapies. Microsatellites are short tracts of repetitive DNA consisting of 1–6 nucleotides that, because of their repetitive nature, are more prone to replication errors. Loss of MMR can result in changes in the length of microsatellites, and tumors are defined as MSI-H if they present instability in two or more loci. MSI-H tumors are more commonly found in endometrial (15 percent) and gastrointestinal cancers. Given the high incidence of the disease among gastrointestinal cancers, CRC has been the subject of several investigations; these led to the discovery that MSI-H advanced CRC accounts for approximately 5 percent of the general metastatic CRC population.

The clinical efficacy of Keytruda in patients with MSI-H tumors, including CRC, had been initially evaluated in a Phase II study (SKCCC, NCT01876511). The trial enrolled, among others, 28 MMR-deficient CRC patients and 25 MMR-proficient mCRC subjects who received Keytruda. Results from the CRC cohort of this study, which supported the initiation of the five trials that led to the FDA approval, were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. The PD-1 blockade with Keytruda was confirmed to be highly active in MMR deficient metastatic CRC, with an overall response rate (ORR) of 57 percent and a disease control rate (DCR) of 89 percent. Median progression free survival (mPFS) and median overall survival (mOS) were not reached after 36 weeks. In contrast, single agent Keytruda was not effective in MMR proficient CRC.

The latest FDA approval of Keytruda was based on five single-arm studies that assessed the safety and efficacy of the drug in 149 patients with dMMR or MSI-H solid tumors. CRC, endometrial cancer, and gastrointestinal cancer patients made up the majority of the patients enrolled. Patients received an intravenous infusion of Keytruda (200mg) every three weeks for 24 months or until disease progression. ORR and durability of response were the main criteria backing the approval of the drug. Across all the different tumor types, 39.6 percent of the patients achieved a partial or complete response, and these responses lasted for more than six months in 76 percent of the cases.

This approval marks a substantial turning point for the oncology area by offering a novel approach to a biomarker-driven design for clinical trial. Recently, there has been a debate over some of the biomarkers used to evaluate the response to immunotherapies. For example, the use of programmed death-ligand 1 (PD-L1) expression, one of the most common predictive biomarkers for anti-PD-1 directed therapy, has been questioned since PD-L1 levels can vary both spatially and temporally throughout the course of disease, and can also depend on the treatment or test received. Given the persistent nature of the MSI status, in that a patient with MSI-H will retain their MSI-H status despite receiving treatment, microsatellite instability represents a better biomarker than PD-L1 expression. As payers and government health agencies are trying to restrict the patient population eligible to receive expensive PD-1 checkpoint modulator therapy in an effort to control oncology-related healthcare expenditure, the availability of a biomarker that is predictive of response to treatment will become increasingly important, and the design of biomarker-driven over location-driven clinical trials might become one of the key strategies among developers.

Despite the fact that the patient share available in each single tumor type is limited by the low number of MSI-H tumors, Keytruda could exploit cross-indication efficacy and the anticipated long duration of treatment to garner relevant sales among MSI-H patients. GlobalData forecasts sales for $690 million in 2019 coming from second- and third-line CRC only, which is expected to grow to $1.3 billion after the anticipated first line approval in 2020 in the seven major markets (US, France, Germany, Italy, Spain, UK, and Japan).

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