What Is Tumor Agnostic Treatment for Cancer?

Tumor agnostic therapy refers to cancer treatments that work across cancer types. In other words, instead of working for only one type of cancer, such as breast cancer, these treatments may work for a number of different cancers, for example, melanoma, breast cancer, and sarcomas. In addition, they may work for both adults and children.

Instead of treatments based on where a tumor originated, this therapy treats a cancer that originates anywhere based on the particular molecular characteristics that drive the growth of the tumor. Despite arising in different tissues, it's not uncommon for very different types of cancer to use the same pathway to grow.

An increased understanding of cancer biology, the ability to do genomic testing to determine what is driving the growth of a particular cancer, and the availability of medications that target these pathways has given researchers the ability to treat a wide range of cancers at a molecular level.

There are currently only a few drugs approved specifically for tumor agnostic treatment but this is expected to expand rapidly in the very near future. We will take a look at the definition and importance of tumor agnostic treatments, examples that are currently being used, and the benefits and limitations of this treatment approach.

Importance

Cancer treatments have advanced such that with specific types of cancer (eg. lung cancer) treatments are already often chosen based on the molecular characteristics of the tumor.

For example, with non-small cell lung cancer, rather than choosing treatments primarily based on what is seen under the microscope, genomic testing (such as next generation sequencing) allows physicians to determine if the cancer has a specific gene mutation (or other alteration) for which targeted therapies are now available.

While a particular chemotherapy drug may be given for more than one type of cancer, the principle behind treatment is different. Chemotherapy essentially treats any cells that are dividing rapidly.

In contrast, targeted therapies (and in a different way, immunotherapy drugs) target a very specific pathway in growth. Two cancers that are of the same type and stage and that would respond similarly to chemotherapy, may respond very differently to treatment with a targeted drug.

If the tumor harbors a mutation, such as an EGFR mutation, using a drug that targets the mutation (such as an EGFR inhibitor) is very likely to result in control of the growth of the cancer. In contrast, if the tumor that does not have this mutation it would be unlikely to respond at all to the EGFR inhibitor.

Treatments that target these specific genomic alterations (which is sometimes referred to as the "molecular signature" of the tumor) have greatly changed both the treatment of many cancers, as well as the focus on drug development.

Biology and Terminology

In order to discuss tumor agnostic treatments, it's helpful to talk about some of the confusing biology. Fortunately, people are becoming more empowered and learning about their cancers, but it's not unlike learning a challenging foreign language.

In order for a cancer to continue to grow, the cells need to be different enough from normal cells that they don't listen to the body's normal signals to stop growing or eliminate themselves. There are complex pathways involved in the growth of cells, and abnormalities at a number of these points can lead to uncontrolled growth.

Gene mutations (and other alterations) are the basis of cancer, and it is a series of these mutations that leads to a cell becoming a cancer cell. Genes are the blueprint for proteins, and proteins, in turn, are the agents that either stimulate or inhibit different points on these pathways.

There are now a number of medications (and many more in development and clinical trials) that inhibit some of these proteins, and hence, stop the signaling that leads to the continued growth of a cancer. A few terms sound very confusing but are fairly straightforward when defined.

The term driver mutation refers to a mutation in a gene that codes for a protein that controls the growth of a cancer. Cancers that have this mutation (or other alteration) are "dependent" on the abnormal protein produced to continue growing. Oncologists often use the term oncogene addiction to describe this behavior.

The particular mutation would then be called the molecular signature of the cancer.

Criteria for Tumor Agnostic Treatments

In order for a treatment to be effective across cancer types, there are few criteria that use be met.

• The particular mutation (or other alteration) must be found. In other words, testing has to be available to detect the alteration and be performed fairly often.
• Tumors that have the particular mutation must respond to treatments that target the treatment.
• The mutation must be found across many different types of cancer.

Uses and Examples

There are currently a few drugs that have been approved for tumor agnostic use and others that are used off-label in this way. We will look at some of these medications.

Keytruda

Keytruda (pembrolizumab) was the first drug approved for tumor agnostic treatment in 2017. Ketruda is a PD-a monoclonal antibody classified as a checkpoint inhitibor (a type of immunotherapy drug). It works by essentially "taking the brakes off" the body's own immune system's response to a cancer.

Keytruda is approved for solid tumors in adults or children that are found to high microsatelite instability (MSI-H) or are deficient in mismatch repair (dMMR). Either MSI-H or dMMR can be found with tests that are done on the tumor (PCR or immunohistochemistry).

In 2020, Keytruda received a second tumor agnostic approval for people with solid tumors that have a high mutation burden. Mutation burden is a measure of the number of mutations present in a cancerous tumor, and is associated (but not always) with a positive response to immunotherapy drugs.

Vitrakvi

Vitrakvi (larotrectinib) is the second medication that received approval for tumor agnostic treatment in 2018. It is approved for adults or children with tumors with NTRK fusion proteins. The neurotrophic receptor kinase (NTRK) gene fusion is found in only around 1% of many solid tumors, such as lung cancer, but may be present in up to 60% of some types of sarcomas.

Some of the types of cancer for which a response has been demonstrated include lung cancer, melanoma, GIST tumors, colon cancer, soft tissue sarcomas, salivary gland tumors, infantile fibrosarcoma, breast cancer, and pancreatic cancer.

In adults with tumors harboring the NTRK gene fusion, the response rate to Vitrakvi was 75% to 80%. In a separate trial in children, the overall response rate was 90%.

These responses were seen even when the people had received previous treatments. What this does is confirm how dependent on this pathway these tumors are for growth. Not only were responses high, but using Vitrakvi was able to, win some cases, allow surgeons to perform less disfiguring surgeries on children.

Rozlytrek

In 2019, the FDA approved the use of Rozlytrek (entrectinib) for people with tumors harboring the NTRK gene fusion as well as for non-small cell lung cancer with a ROS1 alteration.

The drug was approved for adults or children who have metastatic cancer or for who surgery could result in significant disfigurement. During evaluation, the overall response rare was 78%.

The most common cancers in the study were sarcoma, non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and mammary analogue secretory cancer.

BRAF Mutations

Researchers have found that people with different cancer types harboring BRAF mutations often respond to treatment with BRAF inhibitors (usually in combination with a MEK inhibitor). BRAF and MEK inhibitors are medications that target the pathways cancer cells use to grow in tumors that harbor BRAF mutations.

In 2022, the FDA approved the combination of the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib) for tumor agnostic treatment. The use is approved for people 6 years and older with tumors harboring BRAF mutations.

BRAF mutations were initially noted (and treated) in people with metastatic melanoma, but have now been demonstrated in non-small cell lung cancer (around 3%), colon cancer, hairy cell leukemia, thyroid cancer, serous ovarian cancer, and others.

Other Examples

As next-generation testing is performed more often, researchers are starting to see gene alterations that had been thought to be isolated to one type of cancer in other types.

For example, the alteration seen with HER2 positive breast cancer is present in some people with lung cancer. Other examples include the use of the drug Lynparza (olaparib) not only for breast cancer, but ovarian cancer, prostate cancer, and pancreatic cancer harboring a BRCA mutation.

Testing and Trials

There are a number of drugs in development as well as those in clinical trials at this time. The types of clinical trials that sometimes evaluate drugs across different classes of cancer include basket trials and umbrella trials. Evaluation is being facilitated by a precision match protocol called NCI-MATCH.

Benefits and Limitations

There are clear benefits when it comes to being able to use one treatment for several different types of cancer, but there are limitations as well.

Benefits

It goes without saying that tumor agnostic drugs have benefits when it comes to the research and development of drugs. Drug development is very costly. Where this approach really stands out, however, is in the treatment of rare cancers.

With cancers that affect only a small percentage of the population (for example, infantile fibrosarcoma), it doesn't necessarily "pay" for a company to study and develop a medication. This is not to say it isn't important, but corporations tend to invest money in ways that they will see a return.

With tumor agnostic treatments, however, drug companies may receive reimbursement when there are a number of people with more common cancers that benefit from a medication. An example is Vitrakvi.

Another strong benefit is that the research is advancing the science surrounding cancer. But studying the molecular pathways of growth in hope of finding a treatment, new pathways are being discovered with hope for yet more treatments.

Limitations/Risks

While tumor agnostic therapies may sound like the treatment goal of the future, there are a number of limitations to their use.

Not All Cancers Respond the Same

Even when two different types of cancer have the same mutation that drives the growth of the cancer, the response to a drug that targets that mutation may be very different.

An example is with BRAF V600E mutations. Melanomas or hairy cell leukemia cells that harbor the mutation tend to be very responsive to medications that inhibit BRAF. In contrast, colon cancers that have the same mutation do not tend to respond to BRAF inhibitors.

Another limitation is that genomic testing has not yet become routine for all people even with cancers in which this would be strongly recommended (for example, with non-small cell lung cancer). With some type of cancers, especially those that are seen infrequently, there may be little data as to common molecular characteristics present.

Most often, the use of newer medications, especially tumor agnostic treatments is available only through a clinical trial. Not only is clinical trial participation far too low in the United States, but there are significant disparities in participation that make evaluating treatments across age, race, sex, and more challenging

Development also takes time. According to one study, the average time from drug discovery to testing and approval in the United States is 15 years. And even when these treatments reach advanced levels in clinical trials, they may still only help a minority of people.

Finally, most new treatments for cancer are now priced in a range that isn't sustainable.

A Word From Verywell

Treating cancers based on molecular characteristics isn't new, but using these treatments across many cancer types can almost be thought of as precision medicine on steroids.

While the origin of a cancer (histology) will remain important, beginning to focus treatment on molecular characteristics (genomics and immunologic abnormalities etc.) promises to advance the field of oncology in ways that may surprise us as much as recent advances in targeted therapy and immunotherapy.

At the same time, it is exciting to think that tumor agnostic therapy may lead to treatments for rare cancers (especially those in children) that would otherwise not have been possible.