Hyper-progression (or hyper-progression) is the term used to describe the accelerated (faster than expected) growth or progression of cancer after treatment initiation. Although it has rarely been seen in the past with other therapies, hyperprogression has become more common with the addition of immunotherapeutic drugs to treat certain advanced cancers.
Drugs like Opdivo (nivolumab) and Keytruda (pembrolizumab) can sometimes lead to a sustained response (long-term control) of even very advanced cancers, but can also cause hyperprogression in approximately 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 likely to develop this rapid cancer progression on immunotherapy drugs.
Introduction
Immunotherapeutic drugs have changed the game in cancer treatment for many people. Some people respond exceptionally well to these drugs (“overrides”), achieving a sustained response (sustained treatment effect) with 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 (cancer hyperprogression) leading to a lower than expected survival rate. Hyperprogression was first described as a ‘disease flare’ that occurred during treatment with Opdivo (nivolumab) in 2016.
Definition
At the moment, there is no universally accepted definition of hyperprogression. For this reason, it is also difficult to determine the exact frequency of this phenomenon as it may vary depending on the definition used. The definitions used in the research include:
Time to Treatment Failure (TTF) less than 2 months.
Increase in tumor burden by more than 50% (increase in growth and / or increase in metastases) compared to scans performed before the initiation of immunotherapy.
Change in tumor growth rate greater than 50%.
Changing the tumor growth rate is perhaps the most accurate (tumor growth kinetics), but requires looking at the growth rate before initiating immunotherapy and comparing it with the growth rate (progression rate) after initiation of treatment. When other treatments are used prior to immunotherapy (when immunotherapy is used as second-line treatment or after), scans may be available to make these calculations, but when immunotherapy drugs are used first-line, a comparison may not be possible.
Symptomatic hyperprogression may be suspected when the cancer progresses dramatically and rapidly after initiating immunotherapy.
Hyperprogression and pseudo-progression
When tumor growth is evident after initiating immunotherapy, it is important to try to distinguish it from other phenomena sometimes seen with these drugs: pseudoprogression. Pseudoprogression is defined as the initial increase in apparent tumor size (or number of metastases) after initiation of immunotherapy, before size reduction occurs. Pseudoprogression was reported in 0.6% to 5.8% of people depending on the study and the type of cancer.
Nowotwory i leczenie, w których odnotowano hiperprogresję
Hyperprogression is most common in people treated with checkpoint inhibitors. These include drugs targeting PD-1 (programmed cell death), PD-L1 (programmed cell death ligand) and CTLA-4 (T4-associated cytotoxic antigen). Examples of drugs in this category include:
Opdivo (nivolumab): PD-1
Keytruda (pembrolizumab): PD-1
Libtayo (cemiplimab): PD-1
Tecentriq (atezolizumab): PD-L1
Imfinzi (durvalumab): PD-L1
Bavencio (avelumab): PD-L1
Yervoy (ipilimumab): CTLA-4
Cancers that have reported hyperprogression to these drugs include:
Non-small cell lung cancer
Melanoma
Colon cancer
Bladder cancer
Head and neck cancer (squamous cell carcinoma)
Ovarian cancer
Lymphomas
Occurrence and influence of hyperprogression
The incidence of hyperprogression with checkpoint inhibitors varies both with the type of cancer and with the measurement (which definition is used). Overall, frequency estimates ranged from 2.5% to 29.4% .1
A 2018 study published in JAMA looked at the prevalence of hyperprogression in people with advanced non-small cell lung cancer. This study found that 13.8% of those treated with immunotherapy experienced hyperprogression compared to 5.1% of those treated with chemotherapy alone. Pseudoprogression was observed in 4.6%. As for the effects of hyperprogression, this phenomenon was associated with a worse experience; life expectancy was only 3.8 months in those who experienced hyperprogression compared to 6.2 months in those who did not.
Mechanism of hyperprogression
Several theories have been proposed to explain the phenomenon of hyperprogression, but at present this is not well understood. Some researchers have postulated that an immune mechanism may underlie the response, and checkpoint inhibitors paradoxically trigger an immune suppression rather than an immune response.
It has 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 from people who have experienced hyperprogression have been 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 the tumors, or the “tumor microenvironment”). The theory is that checkpoint inhibitors can bind to this Fc receptor on macrophages, causing them to behave in a tumor-promoting manner.
That said, the exact mechanism remains unknown, and research is ongoing hopefully will enable researchers to explore ways to predict when hyperprogression may occur and find ways to prevent it.
Risk factors
Unfortunately, there are currently no simple tests (biomarkers) available to predict which patients may experience hyperprogression, although several potential risk factors have been noted. Some studies have found that hyperprogression is more common in people with a greater tumor burden (larger tumors or more metastases), but others do not. Some have found it to be more common in people with poor performance status, but others have not. Head and neck cancers appear to be more common in older adults (but not seen in other studies) as well as in people who have relapsed in areas previously treated with radiation.1
Tests to predict who is more likely to respond to checkpoint inhibitors (such as PD-L1 levels) do not seem to have any association (currently) with hyperprogression.
Specific genetic changes in cancer cells
People with tumors that carry specific genetic changes (changes such as mutations and rearrangements) appear to be at higher risk of hyperprogression.
People with tumors carrying EGFR mutations may experience more hyperprogression with an incidence of 20% in one study. The risk was significantly higher in people who had MDM2 enhancements (50%) and MDM4 enhancements (67%). Tumors with DNMT3A alterations also appear to increase the risk of 4
Testing for genomic changes such as EGFR inhibitors is now recommended for anyone with non-small cell lung cancer, particularly lung adenocarcinoma, but is not routinely performed for anyone with tumors treated with immunotherapy and therefore needs to be learned a lot. More widespread use of tests such as next-generation sequencing (tests that look at a large number of possible genetic changes in tumors) could help define them, as well as other genetic risk factors in the future.
Diagnosis
Diagnosing hyperprogression can be difficult. As checkpoint inhibitors can sometimes lead to a sustained response, it is important not to jump to diagnosis and stop treatment too quickly. At the same time, since hyperprogression is associated with lower survival, it is important to catch it as soon as possible. Hyperprogression may be suspected when the tumor grows during imaging studies or when the person experiences a significant worsening of symptoms.
When will it happen?
Hyperprogression can occur rapidly and has been documented as early as two days after the administration of an immunotherapy dose. A 2019 case report reported a patient with lung cancer whose lung tumor had grown from 40 millimeters to 57 millimeters two days after receiving Keytrude.
Biopsy results
A biopsy of a tumor that appears to be hyperprogressive may help distinguish pseudoprogression from hyperprogression, but is invasive. Therefore, clinical judgment is most often used to make a diagnosis.
The possibility of using liquid biopsy samples (blood tests to detect acellular circulating tumor DNA) has been raised, although this is still not well understood. While it was predicted that acellular DNA should decrease if it is pseudoprogression and increase if it is hyperprogression, clinical trials are needed to answer this question.
Symptoms and imaging tests
Assessing a person’s overall health and symptoms is critical in making a diagnosis of hyperprogression.
If an increase in tumor size (and / or an increase in metastasis) is noticed on imaging studies, this should be correlated with the clinical symptoms. If symptoms worsen (for example, increased pain, deterioration in general health, etc.), immediate discontinuation of the immunotherapy drug may be necessary. However, if people appear to be stable or improving in terms of symptoms, immunotherapy can often be carefully continued with frequent visits to monitor symptoms and scans.
If symptoms worsen, imaging tests should be performed immediately. An increase in tumor size may indicate hyperprogression. Even if the scan is correct, there are other causes for the deterioration (such as side effects of immunotherapy medications) to be considered.
Certainly every person is different, and any decision to continue or stop immunotherapy will require looking at the individual’s specific circumstances.
Differential diagnosis
Both pseudoprogression and interstitial lung disease (a potential complication of immunotherapy) may appear early to be similar to hyperprogression and should be considered in the differential diagnosis.
Management and treatment
If hyperprogression is suspected, immunotherapy should be discontinued immediately. However, the next steps are not well defined as phenonenone is relatively new. In addition, following the onset of hyperprogression, many people become very sick and may not tolerate additional therapies well. It is generally believed that the immediate use of chemotherapeutic drugs (such as taxol (paclitaxel)) that affect the cell cycle may be the next step for those who are able to tolerate further treatment.
Prognosis
As noted earlier, hyperprogression includes not only faster tumor growth, but also a lower survival rate than might be expected (in at least one study).
Prevention
At present, it is difficult to predict who will develop hyperprogression on immunotherapy drugs and, therefore, when to question the use of these drugs. It is also not known if there are other ways to lower the risk. There are some concerns about an increased rate of hyperprogression in people with EGFR mutations, but most researchers do not think this is a reason to avoid drugs altogether. On the contrary, the possibility that the use of these drugs may cause a sustained response (and increase life expectancy) should still be considered.
A word from Labtech
Hyperprogression is a difficult phenomenon that is becoming increasingly worrying due to the widespread use of anti-cancer immunotherapeutic drugs. On the one hand, stopping the checkpoint inhibitors immediately if hyperprogression occurs in a critical case as the condition can reduce survival, but it is important not to throw the proverbial baby out with the bathwater; if it is pseudo-progressive instead of hyperprogressive, drug withdrawal may result in discontinuation of potentially life-saving therapy.
Since there is no simple diagnostic test that can distinguish hyperprogression from pseudoprogression or other side effects of immunotherapeutic drugs, careful and individual clinical evaluation is necessary.
The same clinical judgment is needed in deciding whether to use immunotherapy drugs in people who may be at higher risk; such as those that have tumors with EGFR mutations or MDM2 / MDM4 lesions. A better understanding of the incidence of hyperprogression compared to the incidence of sustained responses in those carrying these changes could make it more pronounced.
We’ll probably learn a lot more in the near future. Evaluating liquid biopsies as well as tumor biopsies performed during hyperprogression will help scientists better understand the underlying mechanism. Further research will hopefully also help doctors better predict who may develop this serious complication of cancer treatment. It is also believed that anti-hyperprogression medications (such as MDM2 inhibitors) may be an option in the future.