Hyper

Hyper-progression (or hyperprogression) is a term that is used to describe the accelerated (more rapid than expected) growth or progression of a cancer after treatment is initiated. While witnessed rarely in the past with other therapies, hyperprogression has become more common with the addition of immunotherapy drugs to treat some advanced cancers.

Medications such as Opdivo (nivolumab) and Keytruda (pembrolizumab) can sometimes lead to a durable response (long-term control) of even very advanced cancers, but may also result in hyperprogression in an estimated 3% to 29% of people depending on the type of cancer—progression that may be associated with lower survival.

We will look at what we currently know about hyperprogression, how it differs from pseudoprogression, and who may be more at risk of developing this rapid progression of cancer on immunotherapy drugs.

Verywell / Hugo Lin

Immunotherapy drugs have been a game-changer in cancer treatment for many people. Some people respond exceedingly well to these drugs ("superresponders"), attaining a durable response (lasting effect of treatment) with either partial or complete remission of tumors that would otherwise be rapidly fatal.

At the same time, however, a small number of people may experience a paradoxical effect (hyperprogression of their cancer) leading to a lower than otherwise expected survival rate. Hyperprogression was first reported as a "disease flare" that occurred with Opdivo (nivolumab) in 2016.

There is no universally accepted definition of hyperprogression at this time. For this reason, it's also difficult to determine the exact incidence of the phenomenon since this can vary with the definition used. Definitions that have been used in studies include:

A change in the growth rate of a tumor is perhaps most accurate (tumor growth kinetics), but requires looking at the growth rate before immunotherapy is started and comparing this with the growth rate (progression pace) after treatment has begun. When other treatments are used prior to immunotherapy (when immunotherapy is used as a second-line treatment or later), scans may be available to make these calculations, but when immunotherapy drugs are used first line, a comparison may not be possible.

Hyperprogression may also be suspected based on symptoms when a seemingly drastic and rapid progression of a cancer is seen after immunotherapy drugs are started.

When an increase in tumor growth is seen after immunotherapy is started, it's important to try to distinguish this from another phenomenon sometimes seen with these drugs: pseudoprogression. Pseudoprogression is defined as an initial increase in the apparent size of a tumor (or number of metastases) after immunotherapy is started, before a decrease in size is seen. Pseudoprogression has been reported in 0.6% to 5.8% of people depending on the study and tumor type.

Hyperprogression is most commonly seen among people treated with checkpoint inhibitors. This includes drugs targeting PD-1 (programmed cell death), PD-L1 (programmed cell death ligand) and CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitors. Examples of drugs in this category include:

Cancers in which hyperprogression on these drugs has been noted include:

This incidence of hyperprogression on checkpoint inhibitors varies by both cancer type and the measurement (which definition is used). Overall, estimates of the frequency have ranged from 2.5% to 29.4%.

A 2018 study published in JAMA looked at the incidence of hyperprogression in people with advanced non-small cell lung cancer. In this study it was found that 13.8% of people treated with immunotherapy experienced hyperprogression vs. 5.1% treated with chemotherapy alone. Pseudoprogression was seen in 4.6%. As far as the impact of hyperprogression, the phenomenon was associated with poorer survival; the life expectancy was only 3.8 months in those who experienced hyperprogression compared to 6.2 months in those who did not.

Further information regarding the incidence of hyperprogression in non-small cell lung cancer was presented at the 2019 World Conference on Lung Cancer in Barcelona. In the study, researchers looked at people treated with immune checkpoint inhibitors in an Italian medical center between 2013 and 2019. They divided those people who received at least one course of immunotherapy into one of four categories:

They then looked for characteristics that might predict which people would experience hyperprogression. The results were mostly inconsistent (they were unable to make predictions based on extent and locations of disease, etc.) but it did appear that people who had a poorer performance status (an ECOG-PS score of greater than 1) were more likely to experience hyperprogression.

Several theories have been proposed to explain the phenomenon of hyperprogression, but at the current time it's not well understood. Some researchers have postulated that an immune mechanism may underlie the response, with checkpoint inhibitors paradoxically triggering immune suppression rather than an immune response.

It's been suggested that the Fc receptor (a protein on the surface of immune cells called macrophages that binds antibodies) may play a role. Tumor samples of people who experienced hyperprogression were found to have a greater number of tumor-associated macrophages (macrophages are cells that are part of the immune system that are present in the area surrounding tumors or "tumor microenvironment"). The theory is that checkpoint inhibitors may bind to this Fc receptor on macrophages somehow causing them to behave in a way to promotes the growth of a tumor.

That said, the precise mechanism remains unknown, and research is in progress that will hopefully allow researchers to examine ways to both predict when hyperprogression may occur and find ways to prevent the phenomenon.

Unfortunately, there are currently no simple tests (biomarkers) to predict which patients may experience hyperprogression, though a few potential risk factors have been noted. Some studies have found hyperprogression to be more common in people who have a higher tumor burden (larger tumors or a greater number of metastases) but others have not. Some have found it to be more common in people with poor performance status but others have not. With head and neck cancers, it appears to be more common in the elderly (but this is not seen in other studies), as well as people who have a recurrence in areas previously treated with radiation.

Tests to predict who is more likely to respond to checkpoint inhibitors (such as PD-L1 levels) don't seem to have any association (at the current time) with hyperprogression.

People who have tumors that carry specific genetic changes (alterations such as mutations and rearrangements) appear to be at greater risk of experiencing hyperprogression.

People who have tumors carrying EGFR mutations may be more likely to experience hyperprogression with the incidence being 20% in one study. The risk was significantly higher in people who had MDM2 amplifications (50%) and MDM4 amplifications (67%). Tumors with DNMT3A alterations also appear to increase risk.

Testing for genomic alterations such as EGFR inhibitors is currently recommended for everyone with non-small cell lung cancer, especially lung adenocarcinoma, but is not routinely done for everyone who has tumors that are treated with immunotherapy and, therefore, there is much to be learned. More widespread use of tests such as next-generation sequencing (tests that screen for a large number of possible genetic changes in tumors) may help define these as well as other genetic risk factors in the future.

The diagnosis of hyperprogression can be challenging. Since checkpoint inhibitors can sometimes lead to a durable response, it's important not to jump to the diagnosis and discontinue treatment too quickly. At the same time, since hyperprogression is linked to lower survival, it's important to catch it as quickly as possible. Hyperprogression may be suspected either when a tumor appears to increase on imaging studies or if a person experiences significant worsening of symptoms.

Hyperprogression may occur rapidly and has been documented in as little as two days after a dose of immunotherapy was given. A 2019 case report noted a patient with lung cancer who had a lung tumor increase in size from 40 milimeters to 57 milimeters two days after receiving Keytruda.

A biopsy of a tumor that appears to be hyperprogressing may help distinguish pseudoprogression from hyperprogression, but is invasive. Therefore, clinical judgment is most commonly used in making the diagnosis.

The option of using liquid biopsy samples (blood tests to look for cell-free circulating tumor DNA) has been raised, though this is still not well understood. While it's been predicted that cell-free DNA should decrease if it is pseudoprogression and increase if it is hyperprogression, clinical trials are needed to answer this question.

An evaluation of a person's general health and symptoms is critical in making the diagnosis of hyperprogression.

If an increase in tumor size (and/or increase in metastases) is noted on imaging tests, this needs to be correlated with clinical symptoms. If symptoms are worsening (for example, increased pain, a decline in general health, etc.), the immunotherapy drug may need to be discontinued immediately. If, however, if people appear to be stable or are improving with respect to symptoms, immunotherapy may often be cautiously continued with frequent visits to monitor symptoms and scans.

If symptoms are worsening, imaging tests will need to be done right away. An increase in the size of a tumor may indicate hyperprogression. Even if a scan is normal, evaluation for other causes of worsening (such as side effects of immunotherapy drugs) will need to be considered.

Certainly, every person is different, and any decisions about either continuing or stopping immunotherapy will require looking at an individual's specific situation.

Both pseudoprogression and interstitial lung disease (a potential complication of immunotherapy) may appear similar to hyperprogression early on, and need to be considered in the differential diagnosis.

If hyperprogression is strongly suspected, immunotherapy should be stopped immediately. The next steps, however, are not well defined as the phemonenon is relatively new. In addition, following the occurrence of hyperprogression, many people are very ill and may not tolerate additional therapies well. In general, it's thought that promptly using chemotherapy drugs—such as Taxol (paclitaxel)—that affect the cell cycle may be a next step in those who are able to tolerate further treatment.

As noted earlier, hyperprogression involves not only the more rapid growth of a tumor but a lower survival rate than otherwise would be expected—at least in one study.

At the current time, it's hard to predict who will develop hyperprogression on immunotherapy drugs, and therefore, when to question the use of these drugs. It's also unknown whether there are other ways of lowering the risk. There has been some concern about the increased rate of hyperprogression in people who have EGFR mutations, but most researchers don't believe this is a reason to avoid the drugs altogether. In contrast, the possibility that using these medications could result in a durable response (and increase life expectancy) still needs to be considered.

Hyperprogression is a challenging occurrence that is becoming of greater concern with the widespread adoption of immunotherapy drugs for cancer. On the one hand, promptly stopping checkpoint inhibitors if hyperprogression occurs in critical as the condition can reduce survival, but it's important not to throw the proverbial baby out with the bathwater; if it is pseudoprogression instead of hyperprogression, stopping the drug could result in discontinuing a potentially life-saving therapy.

Since there is not a simple diagnostic test that can discriminate hyperprogression from pseudoprogression or other side effects of immunotherapy drugs at this time, careful and individual clinical judgment is needed.

This same clinical judgment is needed when deciding whether or not to use immunotherapy drugs in those who may be at greater risk; such as those who have tumors with EGFR mutations or MDM2/MDM4 alterations. A better understanding of the incidence of hyperprogression vs. the incidence of durable responses in people harboring these changes may make this clearer going forward.

In the near future we will likely know much more. Evaluation of liquid biopsies as well as tumor biopsies taken during hyperprogression will help researchers better understand the underlying mechanism. Further research will hopefully also help physicians better predict who may or may not develop this serious complication of cancer treatment. There is also thought that drugs to counteract hyperprogression (such as MDM2 inhibitors) may be an option in the future.