Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease

Abstract

The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.

Keywords: Biomarker; DNA mismatch repair; Immunotherapy; Microsatellite instability; Pembrolizumab.

Fig. 1

Prevalence of somatic mutations across respective cancer types. Each dot represents an individual sample and red horizontal lines represent the median number of mutations across samples. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia. Adapted from 27

Fig. 2

In patients with dMMR or MSI-H – positive tumors, multiple mutations accumulate and increase the likelihood of immunologically relevant neoantigens (a). Neoantigens are presented in the context of the MHC molecules on the tumor cells (b). T-cells specific for presented neoantigens can become activated initiating a series of molecular events including production and secretion of IFN-gamma by the T-cell (c). Among other things, this will cause up regulation of PD-L1 on the tumor cell which binds to PD-1 on the T-cell and sends a signal to inhibit activation (c). However, interruption of that negative signal (e.g., by an anti-PD-1 antibody) can reinvigorate the T-cell and promote anti-tumor activity (d)