Tumour-Agnostic Treatments

Tumour-agnostics treatments are a new class of cancer therapies (cancer drugs) that target tumours not according to their location in the body, but by targeting a certain property of the tumour cells, called a biomarker. They are called “agnostic” because unlike typical cancer therapies, they can, in principle, fight tumours no matter where they originate. In practice, it is not necessarily the case that tumours of any origin with the same biomarker will respond equally well to a tumour-agnostic treatment targeting that biomarker. Nonetheless, tumour-agnostic treatments represent a paradigm shift in the way cancer is treated.

Examples of tumour-agnostic treatments approved to date in Canada include pembrolizumab, which targets MSI-H tumours, and larotrectinib, which targets NTRK gene fusions. Read more about examples of biomarkers and therapies targeting them.

A biomarker is an abnormality in the genes of the cancer cells that both identifies them as cancerous and governs (at least in part) their malignant behaviour. In order to find out whether your cancer has a certain biomarker, you must get a test for it. Unlike the location of the cancer, whether your cancer has a certain biomarker does not reveal itself unless it’s specifically tested for. Read more about biomarkers.

Tumour-agnostic treatments go by a handful of different names: they are also called histology-agnostic, histology-independent, tissue-agnostic, or cancer type (or tumour type) agnostic treatments. The word “therapies” may also be used interchangeably with ‘”treatments.” (In this context both mean “drugs.”)

Tumour-agnostic treatments are a kind of targeted therapy. This is a class of cancer treatments that target cancer cells based on biomarkers. On the other hand, not all targeted therapies are tumour-agnostic, because some are designed to fight cancer at a particular location in the body. Read more about the relationship between tumour-agnostic treatments and targeted therapies. Targeted therapies are often called personalized medicine, which is a broader term for medicine that is targeted specifically against your disease, rather than against a broader class of diseases.

One important difference between tumour-agnostic treatments and other cancer treatments is that they require a novel kind of clinical trial. These clinical trials are called basket trials. They involve people with several different types of cancer, grouped by cancer type into “baskets.” Read more about basket trials.

It is well known that cancer is not a single disease, but a family of diseases. The discovery of genomic mutations that drive cancer development, however, has revealed a greater diversity within that family than previously thought. Tumour-agnostic treatments suggest that location may not be the most important property of a tumour, and that genomic mutations may be equally or more important.

Our idea of how cancers are classified has changed before. Early in cancer research researchers thought it was important whether a tumour was solid or liquid (e.g. in the blood), but this turned out not to be significant in terms of how cancers should be treated. Location-based treatment, although it has seen many successes, has also shown its limitations over the years. The science of cancer treatment is poised to change a great deal as tumour-agnostic treatments become more widely used and better understood (Raez & Santos, 2018, p. 541).


A biomarker is a molecular aberration that indicates that a cell is cancerous because of a specific aberration in its genes. Once a biomarker is identified, it may then be possible to develop a drug that targets it. Targeting a biomarker means not only using it to identify the cells to act on, but also blocking the ability of that biomarker to drive cancer development. In other words, tumour-agnostic treatments do not kill cancer cells (unlike chemotherapy); rather, they attack the molecular aberrations that make the cell cancerous, thereby slowing or even stopping tumour growth.

For this reason, tumour-agnostic treatments are sometimes called a more “rational” kind of cancer therapy than traditional therapies, because they try to attack the root biological mechanisms of cancers. This is not quite as magical as it sounds: many cancers are driven by multiple mutations, and they can mutate further to outwit drugs, even tumour-agnostic treatments. However, tumour-agnostic treatments have so far been shown to be remarkably effective.

The advent of tumour-agnostic treatments reflects advances in our understanding of how cancer works. To be precise, it is a practical response to the now widely accepted thesis that cancer is driven by genetic mutations. That is, the reason that cells become cancerous is because of aberrations in their genes. Tumour-agnostic treatments represent a completely different approach to cancer treatment, focussed not on the organ in which the tumour develops, but on the genetic abnormalities that make it cancerous (Rosas & Raez, 2020, p. 60).

Genes that have mutated and drive cancer development are called oncogenes. These genes are supposed to support and regulate normal cell growth and division, but a mutation causes them to promote cell division in an uncontrolled way. There are a great variety of different types of genetic mutations that can cause cells to become cancerous; most have yet to be discovered. Those that have been discovered may happen in one of a few different ways: chromosome swapping, chromosome fusion, and chromosome overexpression.

Biomarkers currently targeted by tumour-agnostic treatments

As of this writing (September 2020), there are two biomarkers that are targeted by approved tumour-agnostic treatments: MSI-H or dMMR, and NTRK fusion genes.

Microsatellite instability-high (MSI-H). Also called mismatch-repair deficiency (dMMR), this is an abnormality in a cell’s genes that can give rise to cancer. It happens if the mechanism that the cell uses to correct errors in DNA replication has been seriously hindered. MSI-H tumours are found in 15% of colorectal cancers; they are also found, less commonly, in endometrial, pancreatic, biliary, gastric and oesophageal cancers (Pestana et al., 2020, p. 556).

Pembrolizumab (Keytruda®) is a tumour-agnostic treatment targeting MSI-H/dMMR tumours. It was approved by the U.S. FDA in May 2017, and by Health Canada in April 2019 (that was when it was approved specifically for MSI-H/dMMR tumours; it was already approved for a variety of other indications). This was the first tumour-agnostic treatment to be approved by health regulators.

NTRK fusion genes. Sometimes a genetic abnormality occurs called a fusion gene, in which part of one chromosome fuses with part of another chromosome. These produce fusion proteins that may give rise to cancer. The NTRK (neurotropic tyrosine receptor kinase) family of genes is susceptible to gene fusions that have been suspected to drive tumour activity. NTRK gene fusions are very rare in the most common types of cancer (less than 1%), but appear very frequently in certain very rare cancer types. For example, they have been reported to occur extremely frequently – up to 90% – in infantile fibrosarcoma, secretory breast cancer, and mammary analogue secretory carcinoma. They are also very common in colorectal cancer patients with dMMR status (Lassen, 2019).

Larotrectinib (Vitravki®) and entrectinib (Rozlytrek®) are drugs of a type called TRK inhibitors (where TRK refers to the proteins produced by the NTRK genes). These drugs target these gene fusions proteins and inhibits them, slowing cancer growth in cases where they exist. Both have been found to be effective and to produce a durable response in clinical trials, as well as having few and mild side effects.

In trials for larotrectinib, 80% of patients had their tumour reduced or destroyed, and one year after treatment cancer had not progressed further for 55% of patients. Larotrectinib was approved by the U.S. FDA in November 2018 and by Health Canada in July 2019. Trials for entrectinib likewise showed good results. Overall, 57% of patients’ tumours were reduced or destroyed; responses lasted typically for 10 months (Pestana et al., 2020, p. 557). Entrectinib was approved by the U.S. FDA in August 2019, and was approved by Health Canada in April 2020.

Biomarkers that could by targeted by tumour-agnostic treatments in the future

BRAF mutation. Drugs targeting the BRAF mutation in melanomas have potential to be approved for other cancer types too. Certain melanomas exhibit mutations in the BRAF gene that helps send signals that govern cell growth. Mutated BRAF proteins are targeted by vemurafenib (Zelboraf®), approved in Canada since 2012. This drug inhibits the action of the mutated BRAF protein, slowing cancer growth.

In the U.S., the FDA approved vemurafenib for use with Erdheim-Chester disease after a large basket trial, VE-BASKET, showed strong evidence of its efficacy for that disease, as well as for other cancers including non-small-cell lung cancer and pleomorphic xanthroastrocytoma (Offin et al., 2018, p. 184). Vemurafenib is therefore moving towards being a tumour-agnostic treatment, although its regulatory approval is still connected to specifc cancer types. In Canada, vemurafenib is only approved for treating melanoma (with the BRAF mutation).

Relation of tumour-agnostic treatments to targeted therapies

Tumour-agnostic treatments are a kind of targeted therapy. This is a class of cancer treatments that target cancer cells based on biomarkers. Not all targeted therapies are tumour-agnostic: some are designed to fight cancer at a particular location in the body. These are said to target a molecular subtype of a cancer type. Targeted therapies have been around since the early 2000s; tumour-agnostic treatments are a more recent development.

For instance, ALK inhibitors are a type of drug that targets a molecular subtype of non-small-cell lung cancer. This is considered a kind of targeted therapy, because it targets a specific genetic mutation, but is not considered tumour-agnostic, because it is only known to be effective for non-small cell lung cancer (Lacombe et al., 1058).

Another difference is that clinical trials for targeted therapies that are not tumour-agnostic don’t need to have a basket trial design. They may be able to use the more established clinical trial structure, because they are only concerned with one cancer type.

That said, a targeted therapy can become more like a tumour-agnostic treatment if it is later found to be effective against tumours from a different location with the same biomarker. Trastuzumab is a targeted therapy that targets cells that produce too much of the HER2 protein. It was originally developed to target the HER2-positive subtype of breast cancer, but years later was found to also be effective against stomach cancers with the same mutation (Lacome et al., 1058). It’s possible that other targeted therapies may be found to be effective against more cancer types, making them more tumour-agnostic.

Clinical trials for tumour-agnostic treatments

Like any cancer drug, tumour-agnostic treatments must demonstrate their efficacy and safety through clinical trials. The typical clinical trial structure assumes that each drug targets exactly one type of cancer: the drug is tested with group of patients who all have the same cancer type. This kind of trial can provide evidence that a drug works, but it cannot provide evidence that a drug is tumour-agnostic. 

To meet this need, a new kind of clinical trial called a basket trial has emerged for trialling tumour-agnostic treatments. In this kind of clinical trial, a drug is tested against people with various types of cancer who also each have the biomarker that the drug is supposed to target. People who have the same type of cancer are grouped into ‘baskets’ (Offin et al., 2018, p. 184). This allows researchers to compare the effectiveness of the treatment across multiple cancer types.

Let’s examine in more detail two reasons why basket trials are needed.

  1. First, just because a drug targets a certain biomarker does not mean we can assume it is truly tumour-agnostic. It may be more effective against some cancer types and less effective against others, or the side effects may differ. Therefore, a potential tumour-agnostic treatment must be trialled against multiple cancer types to see how it behaves with tumours of different origins. 
  2. Second, the biomarker that the drug targets may be very rare, making it difficult to find enough participants – doubly so if they must all have the same cancer type. For example, NTRK fusion genes, a biomarker that is targeted by some tumour-agnostic treatments, occurs in less than 1% of the most common cancer types.

Further to the second point, an advantage of basket trials is that they provide opportunities for drugs to be tested against, and approved for, very rare cancer types, such as secretory breast cancer. This is very difficult with traditional clinical trials because of the difficulty of finding enough people to participate. It is easier with basket trials, because only some of the participants need have a certain rare cancer type in order for the drug in question to be approved for that type of cancer (Schilsky, 2018). 

For example, NTRK fusion genes also turn out to be very common among people with some of the rarest types of cancer. Basket trials for tumour-agnostic treatments targeting this mutation therefore hold promise for people with these rare types of cancer, who otherwise don’t have as many treatment options.

The need for a novel type of clinical trial also distinguishes tumour-agnostic treatments from other targeted therapies. For example, therapies that target breast cancers with too much HER2 protein (called HER2-positive) could be trialled in the traditional way, against only breast cancer patients, because those therapies were not originally intended to work across multiple tumour locations. (As it happens, tertuzumab, a drug that targets the HER2 mutation, has also been shown to be effective against metastatic stomach cancer, and has been approved for that use too.)

Basket trials also differ from traditional clinical trials in the way their results are analyzed. Traditional clinical trials assume that you can average all the results from the individual participants and get a meaningful result. In basket trials, because multiple cancer types are involved, the results may be meaningfully different for different cancer types. Some basket trials ignore these potential differences between cancer types and present an aggregated result. Others analyze each cancer type within the trial separately. Which approach is used depends on how many participants there are, among other factors (Pestana et al., 2020, p. 562). 

Testing for biomarkers

Whether a tumour has a certain biomarker is always invisible: it cannot be determined except by testing for that biomarker. Therefore tumour-agnostic treatments depend completely on biomarker testing in order to be useful. The test that detects the biomarker that a treatment targets is called a companion diagnostic test. The treatment and the test go hand in hand: neither is useful without the other.

Companion diagnostic tests may also allow you to tell

  • how well the treatment is working
  • whether the cancer is developing resistance to the treatment
  • whether the patient would experience unusually severe side effects from the treatment

Next-generation sequencing (NGS)

‘Conventional’ methods of testing include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). These methods are well-established and known to be sensitive and accurate. However, these methods are being displaced by a family of testing technologies called next-generation sequencing (NGS). The advantage of NGS is that it allows you to test for many different biomarkers at once. These may even be different kinds of biomarkers – mutations, fusions, variations in the number of copies of a gene, etc. Contrast with IHC and FISH, where you can only test for one biomarker at once, and you must always specify it beforehand. This means that NGS saves money and time, and requires fewer tissue samples, compared to conventional tests (Malone et al., 2020).

Typically an NGS test takes the form of a ‘panel’ of a predetermined selection of genes that are likely to be of interest to clinicians. NGS can also be used to analyze the entire genome of a cell, or the part of the genome that governs the production of proteins (the exome). Using a panel is a more sensitive and accurate test, and less costly, but a whole-genome or whole-exome test can catch novel variations that a panel would miss.

NGS is considered a ‘revolutionary technology’ for supporting tumour-agnostic treatments. Its ability to test for many biomarkers at once, efficiently and quickly, is very valuable: it will allow tumour-agnostic treatments to be used in a truly tumour-agnostic fashion, rather than dependent on if the patient has a cancer type that is thought to be likely to have certain mutations. The cost of NGS has been decreasing and is expected to continue to do so. Less costly, widely funded, and more available NGS will be an essential step towards greater adoption of tumour-agnostic treatments.

Availability of biomarker testing in Canada

As it stands, biomarker testing in Canada is not very widespread. Testing for a given biomarker may or may not be available, depending on the province; oncologists have varying degrees of familiarity and training in what tests are appropriate and how to interpret the results; and few tests are publicly funded. NGS, in particular, is largely not funded in Canada. It is also more expensive than conventional tests and less available.

Even when biomarker testing does occur, it is still typically organized around specific cancer types. One reason for this is that certain cancer types are more likely to have certain biomarkers. Non-small-cell lung cancer (NSCLC), for instance, has been found to be an especially fruitful target for targeted therapies: ? of NSCLC patients with adenocarcinomas have a biomarker that is targeted by a specific drug. A few of these drugs – such as entrectinib, targeting NTRK fusion genes – are considered tumour-agnostic. Broader use of NGS beyond the most common cancer types will be necessary in order for tumour-agnostic treatments to be useful for as many people as need them.


Cancer-related organizations – from research institutes to patient support groups – are generally organized around cancer type in the sense of tumour location. However, there are some cases of patients starting to organize by biomarker.

Government campaigns, organization, and funding also remain organized around cancer types. Even once a tumour-agnostic treatment has been approved by government regulators, provincial governments may not be prepared to recommend it or to fund it—or to fund its companion diagnostic test.

Testing for biomarkers has yet to become as common as it should be for tumour-agnostic treatments to benefit everyone they can. More funding for next-generation sequencing, and more knowledge about it in health authorities, will be essential.


Lassen, U. (2019). How I treat NTRK gene fusion-positive cancers. ESMO Open, 4(Suppl 2). https://doi.org/10.1136/esmoopen-2019-000612

Malone, E. R., Oliva, M., Sabatini, P. J. B., Stockley, T. L., & Siu, L. L. (2020). Molecular profiling for precision cancer therapies. Genome Medicine, 12(1), 8. https://doi.org/10.1186/s13073-019-0703-1

Offin, M., Liu, D., & Drilon, A. (2018). Tumor-Agnostic Drug Development. American Society of Clinical Oncology Educational Book, 38, 184–187. https://doi.org/10.1200/EDBK_200831

Pestana, R. C., Sen, S., Hobbs, B. P., & Hong, D. S. (2020). Considering issues beyond the tissue.pdf. Nature Reviews Clinical Oncology, 17, 555–568. https://doi.org/10.1038/ s41571-020-0384-0

Raez, L. E., & Santos, E. S. (2018). Tumor Type-Agnostic Treatment and the Future of Cancer Therapy. Targeted Oncology, 13, 541–544. https://doi.org/10.1007/s11523-018-0593-y

Rosas, D., & Raez, L. E. (2020). Review of the Agnostic-Type Treatment Approach: Treating Cancer by Mutations, Not by Location. Oncology and Therapy, 8, 59–66. https://doi.org/10.1007/s40487-020-00114-4

Schilsky, R. L. (2018, December 20). Tumor-Agnostic Treatment for Cancer: An Expert Perspective. Cancer.Net Blog. https://www.cancer.net/blog/2018-12/tumor-agnostic-treatment-cancer-expert-perspective