Belzutifan: The HIF-2 Alpha Blocker for Von Hippel-Lindau Tumours and Paraganglioma

Table of Contents

1. One Pill Aimed at One Protein
2. Von Hippel-Lindau Disease Breaks the Oxygen Gauge
3. From the 2019 Nobel Work to a Drug
4. Trial Results in Von Hippel-Lindau Tumours
5. Trial Results in Kidney Cancer
6. Trial Results in Pheochromocytoma and Paraganglioma
7. What the FDA Has Approved
8. The Boxed Warning Covers Harm in Pregnancy
9. Anemia, Low Oxygen and Other Label Hazards
10. What Is Not Known
11. Key Research Papers
12. Connections
13. Featured Videos

One Pill Aimed at One Protein

Every cell needs to know how much oxygen it has. When oxygen runs short, a family of proteins called hypoxia-inducible factors turns on genes that help the cell cope, such as genes that build new blood vessels and genes that tell the body to make more red blood cells. These proteins work in pairs. The FDA label describes the active form as hypoxia-inducible factor 2 alpha joined to a partner, hypoxia-inducible factor 1 beta, and that pair then switches on genes tied to cell growth, new blood vessels and tumour growth (FDA label).

Belzutifan fits into a pocket inside hypoxia-inducible factor 2 alpha. A 2022 crystal structure of the protein pair with the drug bound shows it sitting in that pocket and destabilizing the pair from a distance, an effect called allosteric. In tests on cells it blocked the protein's activity at a very low concentration (PubMed PMID: 36167425). With the pair broken up, the growth genes are read less.

That is a different approach from older kidney cancer drugs. The blood-vessel drugs block one product of this pathway, a signal called vascular endothelial growth factor. Belzutifan acts further up the chain, on the switch itself (PubMed PMID: 36106637).

The trials on this page gave 120 mg by mouth once a day, the same dose in nearly every study. A randomized dose study in 154 people with advanced clear cell kidney cancer compared 120 mg with 200 mg. Responses were about the same, 23.7% and 23.1%, and severe treatment-related side effects were also about the same, 46.1% and 46.2% (PubMed PMID: 39233312). The higher dose did not add benefit.

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Von Hippel-Lindau Disease Breaks the Oxygen Gauge

Von Hippel-Lindau disease is an inherited condition caused by a faulty copy of the von Hippel-Lindau tumour suppressor gene. It passes through families in a dominant pattern, which means one altered copy inherited from a parent is enough to raise the risk (PubMed PMID: 21386872). The tumours it causes most often are blood-vessel-rich growths in the retina, brain and spinal cord called hemangioblastomas, clear cell kidney cancer, and pheochromocytoma, a tumour of the adrenal gland (PubMed PMID: 21386872). Paragangliomas and pancreatic tumours are also part of the picture (PubMed PMID: 36106637, PubMed PMID: 34818478).

It is rare. The first nationwide estimate, from Denmark, put it at 1 in 46,900 people and 1 in 27,300 live births. The same study found that as many as 25% of people who met the diagnostic criteria had never been diagnosed, and that 87% of carriers had developed signs of the disease by age 60 (PubMed PMID: 27966541).

What goes wrong inside the cell

The von Hippel-Lindau gene makes the protein that tags hypoxia-inducible factor for destruction when oxygen is present. William Kaelin's 2022 review describes it as the part of the cell's disposal machinery that recognizes this one target (PubMed PMID: 36106637). In a healthy cell with plenty of oxygen the tag goes on, the protein is broken down, and the low-oxygen genes stay quiet.

When the gene is damaged, nothing tags the protein. It builds up even though oxygen is normal, so the cell behaves as though it were starving for oxygen. Researchers call this state pseudohypoxia, meaning false low oxygen. The result is constant growth and blood-vessel signals, which fits the blood-vessel-rich tumours of this disease.

The kidney adds a further twist. Damage to the same gene also defines clear cell kidney cancer in people with no inherited disease, and laboratory work points to the type 2 form of the protein as the driver of those tumours (PubMed PMID: 27595394, PubMed PMID: 36106637). That overlap made the tumours of the inherited disease natural candidates for blocking this pathway (PubMed PMID: 36301191).

The long-standing management of these tumours has been surveillance and repeated surgery. In the main von Hippel-Lindau trial of belzutifan, participants had a median age of 41, and 77% had already had surgery for their kidney tumours (FDA label).

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From the 2019 Nobel Work to a Drug

The 2019 Nobel Prize in Physiology or Medicine went to William Kaelin, Peter Ratcliffe and Gregg Semenza for showing how cells sense and adapt to oxygen (PubMed PMID: 31832511). Their full story is on the Kaelin, Ratcliffe and Semenza page. The steps that lead most directly to belzutifan are these.

1. 1995, the switch. Guang Wang and Gregg Semenza purified hypoxia-inducible factor 1 from cells, the protein that turns on the erythropoietin gene under low oxygen, and found it is made of two parts (PubMed PMID: 7836384). Erythropoietin is the hormone that tells bone marrow to make red blood cells, which becomes important again in the side effects below.
2. 1999, the link to the disease. Peter Ratcliffe's group showed in cells that when the von Hippel-Lindau protein is missing, the alpha part of hypoxia-inducible factor stays stable and active. Restoring the protein brought back normal oxygen-dependent breakdown (PubMed PMID: 10353251). A rare inherited tumour disease and the oxygen switch turned out to be one story.
3. 2001, the sensor. The same group found that the von Hippel-Lindau protein recognizes its target only after an enzyme adds a small chemical mark to it. The enzyme has an absolute need for oxygen and iron, which suggested it acts directly as the cell's oxygen sensor (PubMed PMID: 11292861).
4. 2009, the pocket. Hypoxia-inducible factor 2 had been regarded as undruggable (PubMed PMID: 27595394). Crystal structures then showed an unexpectedly large internal cavity in the alpha protein. Small molecules from a chemical screen fit inside, and one of them changed how tightly the protein pair held together in a test tube (PubMed PMID: 19129502).
5. 2016, the mouse tumours. A blocker called PT2399 was tested on human clear cell kidney tumours grown in mice. It held back tumour growth in 10 of 18 tumour lines, and worked better than the standard drug sunitinib in that setting. Some tumours with the gene damage did not respond, and long treatment led to resistance through mutations in the drug's target and in its partner protein (PubMed PMID: 27595394).
6. 2019, the molecule. A first compound in people, PT2385, showed promise, but the body broke it down too quickly and too unevenly. Moving the fluorine atoms on the molecule slowed that breakdown, and the result, first called PT2977, became belzutifan (PubMed PMID: 31282155).
7. 2021, the first human data. In the first-in-human trial, 25% of 55 people with heavily treated advanced clear cell kidney cancer had a tumour response, and median time without worsening was 14.5 months. Blood erythropoietin fell at every dose, a measure that tracked drug levels in the blood (PubMed PMID: 33888901). After 41.2 months of median follow-up the response figure was unchanged at 14 of 55 (PubMed PMID: 38008031).

The same biology has produced drugs that push in the opposite direction. Kaelin's review notes that pills blocking the oxygen-sensing enzyme keep hypoxia-inducible factor switched on and raise red blood cells. Five of these have been approved in various countries for anemia in chronic kidney disease (PubMed PMID: 36106637).

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Trial Results in Von Hippel-Lindau Tumours

The evidence here comes from one trial, LITESPARK-004. It enrolled 61 adults with the inherited disease and at least one measurable kidney tumour, with no tumour larger than 3 cm that needed immediate surgery and no spread. Everyone received belzutifan 120 mg daily. There was no comparison group, so the trial shows what happened to tumours on the drug but not how those people would have fared on watchful waiting and surgery.

The main measure was objective response, meaning scans read by an independent committee showed a tumour shrink by a set amount or disappear. More people reached that mark with longer follow-up, so the figures rise between reports.

Sources for the table: the first report (PubMed PMID: 34818478), the 50-month kidney update (PubMed PMID: 40228516), the pancreatic analysis (PubMed PMID: 38393723) and the brain and spinal cord analysis (PubMed PMID: 39284337).

The FDA's own summary used narrower groups for the same trial, counting only tumours measurable at the start. On that basis it reported responses in 63% of 24 people with brain and spinal cord hemangioblastomas and 83% of 12 with pancreatic neuroendocrine tumours. Kidney responses took a median of 8 months to appear (PubMed PMID: 35727604).

In the first report, the most common side effects were anemia in 90% and fatigue in 66%. Seven of the 61 stopped treatment, four by their own choice, one for a side effect, one for disease progression, and one died of an acute fentanyl toxicity (PubMed PMID: 34818478). At about 50 months, 36 of the 61 were still on treatment, and 18% had a severe treatment-related side effect. Seven had severe anemia and one had a serious treatment-related intracranial hemorrhage. None had a life-threatening or fatal treatment-related event (PubMed PMID: 40228516).

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Trial Results in Kidney Cancer

Most people with clear cell kidney cancer do not have the inherited disease; the gene damage, when present, arises in the tumour. Those trials have a different shape, because they enrolled people whose cancer had already resisted other drugs, or who had just had surgery. See Kidney Cancer and Renal Cell Carcinoma for the disease itself.

Belzutifan alone against everolimus: LITESPARK-005

This phase 3 open-label trial assigned 746 people with advanced disease, already treated with immune checkpoint and blood-vessel drugs, to belzutifan or everolimus. The results were mixed in an instructive way (PubMed PMID: 39167807).

• Time without worsening: the median was 5.6 months in both groups. At 18 months, however, 24.0% on belzutifan and 8.3% on everolimus were alive and free of progression, a statistically significant gap.
• Tumour response: 21.9% against 3.5%.
• Survival: median 21.4 months against 18.1 months, which did not meet the trial's bar for significance (hazard ratio 0.88). The later analysis on the FDA label gives 21 months against 18 months, hazard ratio 0.92, again not statistically significant (FDA label).
• Harms: severe side effects of any cause were about equal at 61.8% and 62.5%, while 5.9% and 14.7% stopped treatment because of side effects.

Belzutifan with lenvatinib against cabozantinib: LITESPARK-011

This phase 3 open-label trial assigned 747 people, whose cancer had progressed after immune checkpoint treatment, to belzutifan plus lenvatinib or to cabozantinib (PubMed PMID: 42586114). Median time without worsening was 14.8 months against 10.7 months (hazard ratio 0.70), a significant difference. Median survival was 34.9 months against 27.6 months (hazard ratio 0.85), which was not significantly different. Severe side effects were common in both groups, at 84% and 83%. Treatment-related side effects led to two deaths in the combination group and one in the cabozantinib group. The label reports a separate analysis with slightly different figures, 14.6 months against 10.6 months, with responses in 53% against 40% (FDA label).

Belzutifan added after surgery: LITESPARK-022

This phase 3 double-blind trial moved the drug much earlier (PubMed PMID: 42384869). After kidney cancer surgery, 1,841 people at raised risk of the cancer returning received the immune drug pembrolizumab with either belzutifan or a placebo, for up to a year. An estimated 80.7% with belzutifan and 73.7% with placebo were free of disease at 24 months (hazard ratio 0.72), a significant difference. Overall survival did not differ significantly at this interim look, with only 29% of the events the final analysis needs: 96.2% and 95.7% at 24 months. Severe side effects occurred in 52.1% and 30.2%. So adding belzutifan delayed recurrence in this analysis, at a cost of more severe side effects, and it is not yet known whether people live longer.

Smaller and negative studies

• With cabozantinib, single-group phase 2 data: 30.8% of 52 previously treated people responded, and one treatment-related death was reported (PubMed PMID: 37011650). In 50 previously untreated people, 70% responded (PubMed PMID: 39756444). Neither group had a comparison arm.
• Glioblastoma, a brain cancer: a phase 1 cohort with recurrent disease found that belzutifan alone had no anti-tumour activity, although laboratory models had pointed to a role for this protein in that cancer (PubMed PMID: 42058763).

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Trial Results in Pheochromocytoma and Paraganglioma

Pheochromocytomas grow in the core of the adrenal gland and paragangliomas grow from related nerve-linked cell clusters elsewhere in the body. Many release stress hormones that drive up blood pressure. The basics are on the Pheochromocytoma and Paraganglioma pages, and the Paraganglioma page has a short note on this trial.

The reason to try this drug is the same false low-oxygen state. A group of these tumours, known as cluster 1, carries damage in the succinate dehydrogenase genes or the von Hippel-Lindau gene, both of which leave hypoxia-inducible factor 2 alpha switched on. This group carries the highest risk of spread (PubMed PMID: 42573142). The trial report says most metastatic cases are driven by this pathway (PubMed PMID: 41124218).

LITESPARK-015

This phase 2 international trial gave 72 people with advanced tumours that surgery could not cure belzutifan 120 mg daily, with no comparison group. The FDA label states none had a history of von Hippel-Lindau disease (FDA label). At a median follow-up of 30.2 months (PubMed PMID: 41124218):

• Tumour response: 26% had a confirmed response, and the label states all were partial, with no tumour disappearing entirely.
• Disease control: 85% had a response or stable disease.
• Duration: the median response lasted 20.4 months, and median time without worsening was 22.3 months.
• Survival: 76% were alive at 24 months. Without a comparison group, this cannot be credited to the drug on its own.
• Blood pressure medicines: of the 60 people taking them, 19 (32%) cut the daily dose of at least one by half or more for at least 6 months.
• Harms: 99% had a treatment-related side effect, 22% had grade 3 anemia, and 11% had a serious treatment-related side effect.

Responses came slowly, with a median of 11.0 months to appear, according to the label (FDA label). A review notes that the links between a tumour's specific gene changes and its response have not been firmly shown (PubMed PMID: 42573142).

Rare cases with a gene fault in the target itself

In a few people, the gene for hypoxia-inducible factor 2 alpha itself is altered so that it stays active. A 2021 report described one such person, with several paragangliomas and too many red blood cells, whose tumours responded quickly and durably while high blood pressure, headaches and the red cell excess resolved (PubMed PMID: 34818480). A later retrospective series of 5 patients with this kind of tumour reported partial responses in 4 and stable disease in 1 (PubMed PMID: 41043588). These are very small, uncontrolled reports.

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What the FDA Has Approved

All of the entries below are U.S. approvals, as stated in FDA notices, FDA approval summaries and the current label, revised in 2026 (FDA label).

The label lists the adult dose as 120 mg by mouth once a day. For children 12 and older with pheochromocytoma or paraganglioma, it lists 120 mg at 40 kg or more and 80 mg below 40 kg. After surgery for kidney cancer the label sets a limit of 54 weeks; for the other uses treatment continues until the disease progresses or side effects become unacceptable. Children's use was extended from adult trial data plus drug-level data. Safety and effectiveness have not been established in children with von Hippel-Lindau disease or kidney cancer, or in those under 12 with pheochromocytoma or paraganglioma (FDA label).

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The Boxed Warning Covers Harm in Pregnancy

The FDA's most prominent warning, the boxed warning, is on this label for one hazard, harm to an unborn baby (FDA label). Anemia and low oxygen are serious listed warnings, covered in the next section, but they are not in the box.

• The finding: given to pregnant rats during the period when organs form, belzutifan caused death of embryos and fetuses, lower fetal weight and skeletal malformations, at exposures as low as 0.2 times those in humans at the 120 mg dose. There are no data from pregnant women.
• Pregnancy status: the label directs prescribers to verify it before starting.
• Contraception: the label calls for effective non-hormonal contraception in females who can become pregnant, during treatment and for 1 week after the last dose, because the drug can make some hormonal contraceptives ineffective. It also calls for effective contraception in males with female partners who can become pregnant, for the same period.
• Breastfeeding: there are no data on the drug in human milk. The label advises against breastfeeding during treatment and for 1 week after the last dose.
• Fertility: based on animal findings, including testicular damage in rats, the drug may impair fertility in males and females, and whether that reverses is unknown.

The contraceptive problem comes from a drug interaction. Belzutifan lowers blood levels of drugs cleared by the enzyme CYP3A4, and the label warns against combining it with sensitive drugs of that type where a small drop could make them fail (FDA label).

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Anemia, Low Oxygen and Other Label Hazards

These two main warnings are not random side effects. Anemia is regarded as an on-target effect of the drug (PubMed PMID: 40806229). Hypoxia-inducible factor 2 alpha helps switch on erythropoietin, the signal for making red blood cells (PubMed PMID: 27595394), and blood erythropoietin fell at every dose in the first human trial (PubMed PMID: 33888901). The cause of the low oxygen is less well understood, according to a 2025 review (PubMed PMID: 40806229).

All figures in the table are from the FDA label (FDA label). Grade 3 means severe. Low oxygen and severe anemia were less common in the von Hippel-Lindau trial than in the advanced cancer trials. The people in that trial were younger and had no spread of disease, and the trials were not designed to compare these rates directly.

What the label says about managing them

• Anemia: the label describes severe anemia that can need a blood transfusion, starting at a median of 29 to 56 days across these trials. Hemoglobin is monitored before and during treatment, and the dose is held, cut or ended based on severity.
• Erythropoiesis-stimulating drugs: the label states the safety of these drugs for anemia in people with von Hippel-Lindau disease on belzutifan has not been established. It also notes that trials in people with cancer on chemotherapy linked them to higher risks of death and serious heart and blood vessel events.
• Low oxygen: the label describes severe low oxygen that may require stopping the drug, added oxygen or a hospital stay. Oxygen levels are monitored before and during treatment. A pulse oximeter reading under 88% is the label's threshold for acting, and life-threatening or recurrent symptomatic low oxygen means ending the drug for good. Patients are told to report signs at once.

Other hazards on record

• Heart damage with lenvatinib: the label warns of serious heart problems, including heart failure, with this combination. Grade 3 or higher heart problems occurred in 6% in LITESPARK-011. Safety has not been established in people whose heart pumping measure (left ventricular ejection fraction) is below 50%.
• Bleeding: in LITESPARK-005 the label records hemorrhage in 9%, including bleeding in the brain in 0.8%, with fatal hemorrhage in 0.5%. A 2025 case report described a fatal brain bleed within 72 hours of starting the drug in a person with von Hippel-Lindau hemangioblastomas. The authors called it the third post-marketing report of early bleeding from such tumours and suggested a rare but potentially serious side effect (PubMed PMID: 40381358). A case report cannot by itself establish cause.
• Inherited drug handling: people who are poor metabolizers through both of the enzymes UGT2B17 and CYP2C19 are estimated to reach about 3.2 times the usual drug exposure, which may raise side-effect risk (FDA label).
• Eye effects: LITESPARK-005 recorded visual impairment in 6% (FDA label).
• Common effects: fatigue, nausea, headache, dizziness and raised creatinine and glucose were among those reported in 20% or more of von Hippel-Lindau patients (PubMed PMID: 35727604).

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What Is Not Known

• Whether it extends life in advanced kidney cancer. Neither LITESPARK-005 nor LITESPARK-011 showed a statistically significant survival gain, and the survival data for the after-surgery use are still immature (PubMed PMID: 39167807, PubMed PMID: 42586114, PubMed PMID: 42384869).
• Whether it changes the long course of von Hippel-Lindau disease. The evidence is one single-group trial of 61 people with a median of about 50 months of follow-up. The published summaries do not report how many later operations were avoided, or lifetime outcomes, and the disease spans decades (PubMed PMID: 40228516).
• How it compares with no drug in pheochromocytoma and paraganglioma. LITESPARK-015 had no control group, and it included only 72 people (PubMed PMID: 41124218).
• Which tumours respond. Some tumours with the gene damage resisted a related compound in mice (PubMed PMID: 27595394). In pheochromocytoma and paraganglioma, firm links between gene changes and response remain to be shown (PubMed PMID: 42573142).
• How to overcome resistance. Reviews describe emerging resistance through mutations in the drug's target pocket and in its partner protein, and the full limits of this drug class are only starting to be explored (PubMed PMID: 36301191).
• Why low oxygen happens. The 2025 review describes the cause as not well understood and discusses possible mechanisms from laboratory studies (PubMed PMID: 40806229).
• Whether early brain and spinal bleeds are caused by the drug, since the evidence is a handful of case reports in tumours that are themselves blood-vessel-rich (PubMed PMID: 40381358).
• Long-term effects in younger people, including fertility, whose reversibility is unknown (FDA label). Safety and effectiveness in children with von Hippel-Lindau disease have not been established (FDA label).

The main trials on this page were funded by the drug's manufacturer, some with National Cancer Institute support.

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Key Research Papers

1. Ren X, Diao X, Zhuang J, Wu D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol Pharmacol. 2022;102(6). PubMed PMID: 36167425
2. Kaelin WG. Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer. J Clin Invest. 2022;132(18):e162480. PubMed PMID: 36106637
3. Agarwal N, Brugarolas J, Ghatalia P, George S, Haanen JB, Gurney H, et al. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann Oncol. 2024;35(12):1148-1156. PubMed PMID: 39233312
4. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617-23. PubMed PMID: 21386872
5. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021;385(22):2036-2046. PubMed PMID: 34818478
6. Binderup ML, Galanakis M, Budtz-Jørgensen E, Kosteljanetz M, Luise Bisgaard M. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark. Eur J Hum Genet. 2017;25(3):301-307. PubMed PMID: 27966541
7. Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112-117. PubMed PMID: 27595394
8. Toledo RA, Jimenez C, Armaiz-Pena G, Arenillas C, Capdevila J, Dahia PLM. Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia. Endocr Rev. 2023;44(2):312-322. PubMed PMID: 36301191
9. Zhang Q, Yan Q, Yang H, Wei W. Oxygen sensing and adaptability won the 2019 Nobel Prize in Physiology or medicine. Genes Dis. 2019;6(4):328-332. PubMed PMID: 31832511
10. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270(3):1230-7. PubMed PMID: 7836384
11. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271-5. PubMed PMID: 10353251
12. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468-72. PubMed PMID: 11292861
13. Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009;106(2):450-5. PubMed PMID: 19129502
14. Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma. J Med Chem. 2019;62(15):6876-6893. PubMed PMID: 31282155
15. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. PubMed PMID: 33888901
16. Jonasch E, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort. Eur J Cancer. 2024;196:113434. PubMed PMID: 38008031
17. Srinivasan R, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, Oudard S, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 2025;26(5):571-582. PubMed PMID: 40228516
18. Else T, Jonasch E, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, et al. Belzutifan for von Hippel-Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study. Clin Cancer Res. 2024;30(9):1750-1757. PubMed PMID: 38393723
19. Iliopoulos O, Iversen AB, Narayan V, Maughan BL, Beckermann KE, Oudard S, et al. Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024;25(10):1325-1336. PubMed PMID: 39284337
20. Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors. Clin Cancer Res. 2022;28(22):4843-4848. PubMed PMID: 35727604
21. Choueiri TK, Powles T, Peltola K, de Velasco G, Burotto M, Suarez C, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024;391(8):710-721. PubMed PMID: 39167807
22. Motzer RJ, McDermott R, Park SH, Burotto M, Iacovelli R, Verzoni E, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026;408(10557):808-820. PubMed PMID: 42586114
23. Choueiri TK, Motzer RJ, Karam JA, Yip W, Suárez C, Ye D, et al. Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma. N Engl J Med. 2026;395(1):32-43. PubMed PMID: 42384869
24. Choueiri TK, McDermott DF, Merchan J, Bauer TM, Figlin R, Heath EI, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023;24(5):553-562. PubMed PMID: 37011650
25. Choueiri TK, Merchan JR, Figlin R, McDermott DF, Arrowsmith E, Michaelson MD, et al. Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study. Lancet Oncol. 2025;26(1):64-73. PubMed PMID: 39756444
26. Strowd RE, de la Fuente M, Bauer TM, Papadopoulos KP, Chen K, Perini RF, et al. Phase 1 LITESPARK-001 study of belzutifan in participants with advanced solid tumors: Results of the glioblastoma expansion cohort. Neurooncol Adv. 2026;8(1):vdaf242. PubMed PMID: 42058763
27. Jimenez C, Waguespack SG, Kaplan J, Habra MA, Varghese J. Belzutifan, A Hypoxia-Inducible Factor 2-Alpha Inhibitor, for Patients with Advanced Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab. 2026;dgag324. PubMed PMID: 42573142
28. Jimenez C, Andreassen M, Durand A, Moog S, Hendifar A, Welin S, et al. Belzutifan for Advanced Pheochromocytoma or Paraganglioma. N Engl J Med. 2025;393(20):2012-2022. PubMed PMID: 41124218
29. Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, et al. Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome. N Engl J Med. 2021;385(22):2059-2065. PubMed PMID: 34818480
30. Alkaissi H, Talvacchio S, Derkyi A, Gubbi S, Pappo A, Gordon CM, et al. Belzutifan for HIF2A-Related Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data. Endocr Pract. 2026;32(2):201-205. PubMed PMID: 41043588
31. Fallah J, Heiss BL, Joeng HK, Weinstock C, Gao X, Pierce WF, et al. FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma. Clin Cancer Res. 2024;30(22):5003-5008. PubMed PMID: 39248780
32. Kucharczyk J, Bhatt A, Bauer L, Economides M. Belzutifan-Associated Hypoxia: A Review of the Novel Therapeutic, Proposed Mechanisms of Hypoxia, and Management Recommendations. Int J Mol Sci. 2025;26(15):7094. PubMed PMID: 40806229
33. Shepherd STC, Kelly-Morland C, Drage S, Brady AF, Macwana R, Pickering L, et al. Fatal intracranial haemorrhage shortly after belzutifan initiation in von Hippel-Lindau (VHL) disease-associated haemangioblastoma. ESMO Open. 2025;10(5):105109. PubMed PMID: 40381358

Official Sources

1. DailyMed: FDA prescribing information for belzutifan tablets, revised 2026
2. FDA notice, December 14, 2023: advanced renal cell carcinoma
3. FDA notice, May 14, 2025: pheochromocytoma or paraganglioma
4. FDA notice, June 12, 2026: treatment after kidney cancer surgery
5. FDA supplement approval letter, NDA 215383/S-013: combination with lenvatinib

PubMed Topic Searches

1. PubMed: belzutifan and von Hippel-Lindau disease
2. PubMed: belzutifan and renal cell carcinoma
3. PubMed: belzutifan and pheochromocytoma or paraganglioma
4. PubMed: resistance to HIF-2 alpha inhibitors
5. PubMed: belzutifan, anemia and hypoxia

Connections

• Drugs — the parent section
• Paraganglioma — the tumour, its genes and its other treatments
• Pheochromocytoma — the adrenal form of the same tumour family
• Kidney Cancer — the disease and the wider treatment picture
• Renal Cell Carcinoma — the urology view, including staging and surgery
• Kaelin, Ratcliffe and Semenza — the 2019 Nobel laureates behind the oxygen-sensing science
• Neuroendocrine Tumors — the wider family of pancreatic neuroendocrine tumours
• How Your Body Makes Red Blood Cells (EPO) — an animation of the signal this drug lowers

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