LAUSR

The introduction of programmed death-1 (PD-1) and the programmed death-ligand 1 (PD-L1) inhibitors have significantly impacted cancer therapy over a relatively short period of time. Within the past 5 years, the PD-1/PD-L1 inhibitors have become standard of care for 16 different cancer and tumor-agnostic indications. Some of the largest clinical development programmers ever seen in oncology have supported this expansion. Not only has the number of clinical indications been expanded, but also the number of compounds. By the end of 2019, nine different PD-1/PD-L1 inhibitors have obtained regulatory approval in different countries worldwide; however, three of these compounds are currently available in China only (1). The first immune checkpoint inhibitors to be approved by the regulatory authorities were pembrolizumab (Keytruda, Merck Sharp & Dohme) and nivolumab (Opdivo, Bristol-Myers Squibb). In 2014, both compounds obtained approval for treatment of patients with advanced melanoma, which in 2015, was followed by an approval for second-line treatment of metastatic non-small cell lung cancer (NSCLC) (2). For pembrolizumab, the first NSCLC indication was based on data from the KEYNOTE-001 study, which was an expanded large-scale phase Ib study. Besides assessing the safety and efficacy of pembrolizumab, this study also aimed at clinical validating the immunohistochemical (IHC) 22C3 assay for the determination of PD-L1 tumor expression (3). The KEYNOTE-001 study showed that the response to pembrolizumab was positively related to the PD-L1 expression level and based on the outcome data from the study, a tumor proportion score (TPS) of 50% was selected as the assay cut-off value. In parallel to the approval of pembrolizumab for second-line treatment of metastatic NSCLC, the PD-L1 22C3 IHC pharmDx assay (Dako) was granted approval as the companion diagnostic (2). In the subsequent KEYNOTE-010 study, which was a phase II/III study in second-line metastatic NSCLC, the TPS cut-off value was lowered to 1% (4). However, when pembrolizumab in the KEYNOTE-024 study moved into the first-line setting, the 50% PD-L1 TPS was reintroduced as cut-off value using the PD-L1 22C3 IHC pharmDx assay.