Tumor-Agnostic Cancer Drugs

An exciting new avenue in cancer research is the development of tumor-agnostic drugs. A couple have been approved and are on the market with others in pipeline.

Some have heralded these “site agnostic” medicines and their use as a “paradigm shift” in cancer treatment. Although that phrase may be overused, this new technology is a different way of approaching medical treatment of neoplasms and may actually have heralded a new definition of disease.

Drug development, especially development of “precision medicine” drugs, focuses on attacking disease while leaving healthy tissue unaffected. Genetic mutations in tumor cells are one way to distinguish them from non-cancerous cells. These mutations have been employed in both drug development (to identify targets) and in diagnosis techniques that allow the doctor to choose an appropriate targeted therapy. However, in the past, drugs were still approved for cancers that originated in specific organs or parts of the body. The clinical trials were set up so that only subjects with one type of cancer were admitted. The regulatory agencies approved the cancer with labels specifying use for one or a few types of cancer.

But in the past few years the FDA has approved three tissue-agnostic, or histology-agnostic cancer medicines – pembrolizumab, larotrectinib, and entrectinib.

Pembrolizumab is labeled for any solid tumor with microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR).  But the tumor can be anywhere in the body. Larotrectinib and entrectinib are likewise approved for solid tumors with neurotrophic receptor tyrosine kinase (NTRK) gene fusion.  Traditionally cancer is classified by where the tumor stars in the body. A FDA official, Steven Lemery, was quoted as saying “the tissue-agnostic approval of pembrolizumab has, in essence, defined a new disease entity,” The new entity is histology-agnostic and biomarker-defined. And not only does this new paradigm change how disease might be defined, it influences the approval process for new medicines. While in recent years, new medicines have been approved partly on new measures of success including length of time until metastasis and minimal residual disease rate.  The tumor-agnostic drugs may drive the more to approval by molecular information rather than clinical endpoints.

iv bagAn article on the American Association for the Cancer Research website listed other tissue-agnostic drugs in development for cancer include Loxo-195 (Loxo Oncology), Loxo-292 (Loxo Oncology), Entrectinib (Genentech), BLU-667 (Blueprint Medicines), and AB5470 (Abcam). The FDA has designate some of these compounds fast-track in the approval and review process.

The practice of testing patients for the genetic mutations these drugs target will probably expand as the drugs become more widely used.  The promise of this sort of medicine is pushing innovation in the clinical trial process as developers and regulators work out new forms of evidence to show a drug works well enough to enter general use.  The FDA in 2018 published a guidance document to help developers formulate clinical trials that yield enough evidence.