title: Pembrolizumab (Keytruda).
abstract: The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.
authors.affiliation: a Department of Medicine , Queen Mary Hospital , Hong Kong.
authors.forename: Gerry
authors.initials: G
authors.lastname: Kwok
authors.affiliation: a Department of Medicine , Queen Mary Hospital , Hong Kong.
authors.forename: Thomas C C
authors.initials: TC
authors.lastname: Yau
authors.affiliation: a Department of Medicine , Queen Mary Hospital , Hong Kong.
authors.forename: Joanne W
authors.initials: JW
authors.lastname: Chiu
authors.affiliation: a Department of Medicine , Queen Mary Hospital , Hong Kong.
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.affiliation: a Department of Medicine , Queen Mary Hospital , Hong Kong.
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C582435:pembrolizumab
keywords: PD1; PDL1; PDL2; lymphoma; melanoma; non-small cell lung cancer; pembrolizumab; solid tumors