Research Rookies is an ongoing article series designed to help patients and caregivers understand research about pheo para. Articles provide a summary of published pheo para and related research. It’s written in easy-to-understand language focused on making us all better patient and caregiver advocates and providing much-needed hope to those affected. We also provide links to resources where you can find more information about these research topics.
Special thanks to Dr Emma Boehm MD PhD who has written this summary.
An accessible summary of the LITESPARK-015 clinical trial:
Text in orange is defined in the glossary at the end of this article.
Why was this study done?
This study was done to see whether a medication called belzutifan (“bell-zoo-tee-fan”) can control the growth of advanced and metastatic pheochromocytoma or paraganglioma (PPGL). A PPGL is called “advanced” when it cannot be completely removed with surgery and is “metastatic” when it has spread from where it first started growing to places such as bones, lymph nodes, the liver or the lungs (see glossary). People living with advanced or metastatic PPGL have limited treatments available to stop the cancer from growing.
Many different cancers grow because they have abnormally high levels of a signal called HIF-2α (hypoxia inducible factor 2α, see glossary). Belzutifan works by blocking HIF-2α to stop the cancer cells from growing and spreading. This has been effective for cancers that are part of the von Hippel Lindau (VHL) genetic condition because those cancers have very high levels of HIF-2α. VHL cancers effectively treated with belzutifan include kidney cancer (renal cell carcinoma), pancreas cancer (pancreatic neuroendocrine tumors) and nervous system cancers (hemangioblastomas). PPGLs also occur in people with the VHL genetic condition however belzutifan had not yet been tested for PPGL.
Research has found that PPGLs in many different people, not just those with the VHL genetic condition, can have high levels of HIF-2α and so might also be effectively treated with belzutifan. This is why the LITESPARK-015 trial aimed to test how effective belzutifan is for treating metastatic PPGLs.
Who was involved in the study?
The LITESPARK-015 study was an international clinical trial. The study was run by a partnership between the researchers and Merck, the drug company that makes belzutifan.
A total of 72 people with locally advanced PPGL (unable to be removed with surgery) or metastatic PPGL participated in the study. Participants were from 31 health care services in 12 different countries. All participants had PPGLs that were growing (progressing) in the 12 months before starting belzutifan.
The participants ranged from 22-77 years of age and just over half were male. Three quarters of participants previously had one or more treatments for their metastatic PPGL, for example chemotherapy or a form of targeted liquid radiation called radionuclide therapy. One third of the participants had PPGL as part of a genetic syndrome called SDHB. The most common places the PPGL had spread to were the lymph nodes and bones. Sixty percent had a history of high blood pressure (hypertension, see glossary) which had to be under control to be eligible for the study.
How was the study done?
This was a single-arm clinical trial meaning that all participants of the study received the drug belzutifan. There was no control (or placebo) group or alternative treatment to compare with.
All participants received at least one dose of belzutifan, which was given as a capsule. The dose was 120mg daily, but could be reduced to 80mg daily or 40mg daily if needed to decrease side effects.
The study looked at:
- Response of the PPGL to treatment. PPGL size was measured on CT or MRI scans performed before belzutifan was started and then every 8-12 weeks. PPGL response was defined as:
- Stable: The PPGL tumors stayed a similar size
- Partial response: The tumors reduced in size by at least 30%
- Progressive disease: The tumors increased in size by at least 20%
- How many participants had “disease control”, meaning that the PPGL was either stable or had reduced in size after belzutifan was started.
- How long the response lasted (response duration).
- How long participants lived after the first dose of belzutifan (survival).
- Side effects of belzutifan (safety).
- Whether there was a change in the medication required to control blood pressure after belzutifan was started.
- The effect of taking belzutifan on quality of life.
What were the results?
Belzutifan was effective to control the growth of the PPGLs in the participants of this study. About 1 in 4 (26%) participants treated with belzutifan had a partial response to treatment (PPGL significantly reduced in size). Over half of the participants had stable disease, meaning that the PPGL stopped growing. Overall, 85% of participants had disease control (either stable or partial response) after starting belzutifan. Half of those who responded had a response that lasted 20.4 months or more.
Belzutifan was also associated with an improvement in blood pressure for some of the participants who had disease control. One third of participants who had hypertension (20/60) had a reduction in the dose of medication needed to control blood pressure.
Importantly, the majority of participants reported a stable or improved quality of life during belzutifan treatment.
Belzutifan treatment had a high rate of side effects. Almost all (71 out of 72) participants experienced side-effects while taking belzutifan. Anaemia (low levels of red blood cells) was the most common side effect, occurring in 88% of participants. The anaemia was reported as severe, meaning a level where a blood transfusion or other treatment might be required, in about 1 in 5 (22%) of participants. Other common important side effects that happened in more than 1 in 10 participants were: feeling tired (fatigue), feeling short of breath (dyspnoea), low blood oxygen levels (hypoxia), feeling of whole body weakness (asthenia), nausea, swelling of the legs and headache.
How does this impact patients living with PPGL?
The results of the LITESPARK-015 trial show that belzutifan can be effective in controlling the growth of advanced or metastatic PPGL. Belzutifan treatment may also reduce the dose of medication required to control blood pressure. However, side-effects are common and people taking belzutifan may need to have regular checks for anaemia (low red blood cells) which can require treatment.
For patients who live in the United States of America, the results of this trial directly led to the FDA (Food and Drug Administration) approval of belzutifan for the treatment of locally advanced or metastatic PPGL in people over 12 years of age.
Belzutifan is now one of the possible options for treating advanced or metastatic PPGL. Other treatments include chemotherapy, radionuclide therapy or other targeted therapies such as cabozantinib and sunitinib (see Research Rookie Edition 4 for a summary of the FIRSTMAPP trial of sunitinib: https://pheopara.org/2024/05/research-rookie-edition-4).
The LITESPARK-015 study did not compare belzutifan to these other possible treatments. Because trials comparing between treatments are extremely difficult to do for people with ultra-rare cancer like PPGL, there is currently no research data to say which treatment is most effective. This means that people with PPGL and their doctors need decide between the options together. Future research is needed to find ways to predict which treatment is best for an individual living with advanced or metastatic PPGL to help make these important decisions.
Glossary
Advanced PPGL: A pheochromocytoma or paraganglioma that cannot be completely removed by surgery. An advanced PPGL might not have spread to distant places in the body (become metastatic) but it might have grown into nearby body structures (like nerves or blood vessels in the head, or large blood vessels in the abdomen) so surgery is too dangerous to perform.
HIF-2α: HIF-2α (hypoxia inducible factor 2α) is found in normal cells of the body and normally is active to help cells survive and grow when there are low oxygen levels. HIF-2α occurs at abnormally high levels in many types of PPGL. There are lots of reasons that HIF-2α can be high including DNA changes (like VHL gene changes) or build-up of other substances that trick the PPGL cell into acting as if oxygen levels are low with more signals to use energy, grow and spread. Belzutifan blocks HIF-2α activity.
Hypertension: Medical term for high blood pressure.
Lymph nodes: A lymph node is a small structure in the body that is part of the immune system. Lymph nodes are grouped together in nodes that are found throughout the body in places such as the neck, armpits, and groin. The cells in the lymph nodes help destroy harmful bacteria and viruses that may be in the lymph fluid, which is a liquid that flows throughout the body.
Metastatic PPGL: A PPGL that has spread from where it first started to grow (for example, the adrenal gland) to distant body structures like lymph nodes, bones, liver or lungs.