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ABSTRACT: T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) is a receptor found on a multitude of immune cells and is commonly overexpressed in patients with cancer. Due to its selective expression in immune cells and its preliminary efficacy in preclinical models, TIM-3 is a promising target as a treatment for cancer. Both monotherapy and combination regimens are being developed and are currently under investigation. This clinical review seeks to summarize and compile past, present, and future TIM-3 inhibitors in clinical trials.

B7-H3 is a transmembrane receptor highly prevalent on malignant cells and plays an important role in adaptive immunity that is not fully elucidated. Targeted B7-H3 inhibitors, including antibody-drug conjugates, radioimmunotherapy, and monoclonal antibodies, are a new class of antineoplastic agents showing promising preliminary clinical efficacy, observed with several of these agents against multiple tumor types. Particularly promising treatments are enoblituzumab for prostate cancer, 131I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. There are clinical trials on the horizon that have not yet enrolled patients examining chimeric antigen receptor T-cell therapies, bi- and tri-specific killer engagers, and dual-affinity retargeting proteins. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials.

Protein arginine methyltransferase 5 (PRMT5) inhibitors are a new class of antineoplastic agents showing promising preliminary clinical efficacy. Targeting an enzyme involved in a wide array of cellular and transcriptional pro-oncogenic processes, this class offers multifaceted tumor-suppressive effects. Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811. Both alone and in combination with existing chemotherapies and immunotherapies, this class shows promising preliminary data, particularly in cancers with splicing mutations and DNA damage repair deficiencies. Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials.

The bromodomain and extraterminal (BET) domain protein family is involved in the process of transcription of genetic information. The BET protein family includes BRD2, BRD3, BRD4, and bromodomain testis-specific protein. BET protein alterations are associated with some solid tumor cancers, including nuclear protein in testis midline carcinoma. BET protein has a role in carcinogenesis and in the regulation of the cell cycle. A number of BET inhibitors have entered clinical trials. This review discusses the results of BET inhibitor clinical trials in solid tumor cancers.

The mitogen-activated protein kinase (MAPK) pathway consists of the series of protein kinases RAS-RAF-MEK- Extracellular signal-regulated kinase (ERK), and its function is important to cell proliferation, differentiation, motility, and survival. Certain mutations in the pathway, such as KRAS or BRAF V600 mutations are associated with cancer. Inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic, but a variety of selective ERK inhibitors are still being tested in clinical studies. To date, common adverse events associated with ERK inhibitors include diarrhea, nausea, fatigue, and rash. ERK inhibitors have demonstrated preliminary antitumor activity and may be most effective against cancers with RAS, RAF, or MAPK pathway alterations. This review discusses the MAPK pathway, the biological rationale for ERK inhibitors, and clinical trials involving ERK inhibitors.