Tumor-Agnostic Cancer Drugs

An exciting avenue in cancer research is the development of tumor-agnostic drugs, also called tissue-agnostic chemotherapy. A few 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 approach to medical treatment of neoplasms and may actually herald a new definition of disease.   The success of these new compounds demonstrates that scientists can try new paths to find even more oncogene-targeted therapies that work across cancers.

Tumor-agnostic drugs are a form of personalized or precision medicine.  Drug development, especially development of precision medicine compounds, 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; these drugs are classified as TRK inhibitors. Traditionally cancer is classified by where the tumor stars in the body. NTRK gene fusions occur in several different types of cancer, and it is estimated that about 1 percent of human cancers have this characteristic and are thus amenable to this type of treatment.

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 regulators even further toward approvals based on 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), BLU-667 (Blueprint Medicines), and AB5470 (Abcam). The FDA has designated 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.

A Reason to Be Cautious

Although early indicators are promising, there are unknowns as to how these drugs work.   While some aberrations occur in multiple cancers, the importance of a given aberration in a particular cancer is not always understood.  And as with all new drug development, there have been attempts that have yielded no practical medicines.

If this all works, histology-agnostic medicines could redefine the very disease of cancer itself.  It could also lead to a new framework for regulatory approval of new medicines with faster approvals based on molecular information.

Hexokinase Inhibitor Drugs

Cancer cells consume glucose at a higher rate than normal cells, and for decades researchers have been trying to find ways to exploit that difference to target malignant cells. The success of kinase inhibiting drugs in treating cancer has spurred scientists to look to Hexokinase, an enzyme in the glycolytic metabolic pathway (the breakdown of glucose.) The scientists looked closer and found more than one isoform of Hexokinase. HK-1 is present in most cells, while malignant cells have HK-1 and HK-2. This presents an intriguing opportunity and some early lab tests show that chemicals that target hexokinases can slow multiplication of cancer cells.

The hope is that Hexokinase inhibitor drugs could be used as tumor-agnostic therapy

These drugs may also be effective in increasing the efficacy of HDAC inhibitors.