%0 Journal Article
%T FDA approvals for mismatch repair deficiency in metastatic colorectal cancer and non-metastatic colorectal cancer: a next-generation oncology treatment based on biomarker expression
%A Luis Mendoza
%J Open Access Journal of Hematology impact factor| International Journal of Blood Disorders
%D 2019
%X Colorectal, gastric and hepatocellular cancers have been traditionally considered to be poorly immunogenic; however, increasing evidence now suggests that these tumors are recognized by the immune system. Immune checkpoint blockade is showing promising clinical activity in multiple tumors including colorectal and non-colorectal. In fact, one of the most significant achievements witnessed in the field of immunotherapy has been the success of immune checkpoint inhibitors (CPIs) in microsatellite instability-high colorectal and non-colorectal tumors. For this reason, the US FDA has granted accelerated approval to Pembrolizumab and Nivolumab as monotherapies and Nivolumab plus Ipilimumab as combined therapy. These new findings open the door to a next-generation oncology treatment based on biomarker expression. The average tumor displays dozens of mutations; however, tumors with DNA deficient mismatch repair (dMMR) may harbor thousands of them, especially in the regions of repetitive DNA known as microsatellites [1]. Tumors that are found to harbor mutations in select microsatellite sequences called microsatellite instability (MSI) regions are referred to as ¡°microsatellite instability-high (MSI-H).¡± It is now understood that two distinct immunologic subtypes of cancer tumors exist according to the dMMR status, namely, MSI and microsatellite stable (MSS) subtypes, which are mutually exclusive [2, 3]. Recently, on May 23, 2017, the US Food and Drug Administration (FDA) granted accelerated approval to Pembrolizumab (Keytruda£¿, Merck & Co) for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-high or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-high or dMMR metastatic CRC (mCRC) following progression on a fluoropyridine, oxaliplatin and irinotecan regimen [4]. The approval was based on the data from 149 patients with MSI-H or dMMR cancers enrolled across five uncontrolled multi-cohort, multi-center, single-arm clinical trials (KEYNOTE-16, -164, -012, -028, and -158). Ninety patients had mCRC and the remaining 59 patients suffered from one of 14 other cancer types. The objective response rate (ORR) was 39.6 % (95% CI: 31.7, 47.9) including 11 (7.4 %) complete responses (CRs) and 48 (32.2 %) partial responses (PRs). On July 31, 2017, the FDA granted accelerated approval to another CPI, Nivolumab (Opdivo£¿, Bristol-Myers Squibb Company), for the treatment of patients aged 12 years and older with dMMR and MSI-H mCRC and on
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