Belzutifan + Cabozantinib for Kidney Cancer

Not currently recruiting at 9 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Peloton Therapeutics, Inc.

Must not be taking: Anticoagulants, HIF2α inhibitors

Disqualifiers: Brain metastases, Hypertension, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of two oral medications, belzutifan (also known as Welireg or MK-6482) and cabozantinib (also known as Cabometyx), for treating advanced kidney cancer, specifically the clear cell type. Participants will either have never received treatment for their advanced kidney cancer or have previously tried immunotherapy. Ideal candidates have advanced or spreading kidney cancer with clear cell features and at least one measurable tumor. The goal is to determine how these medications work together to fight the cancer and improve patient outcomes. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on anticoagulant therapy, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining belzutifan and cabozantinib yields promising results for patients with advanced kidney cancer. These studies suggest that most patients tolerate the combination well. Some participants experienced side effects, but they were mostly manageable. Common side effects included fatigue and high blood pressure. Notably, the FDA has already approved belzutifan for certain types of kidney cancer, which adds confidence in its safety. Cabozantinib is also a well-established treatment with proven safety in kidney cancer. Overall, safety data from earlier studies support further testing of this combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Belzutifan and Cabozantinib for kidney cancer because these drugs target the disease in a novel way. Unlike traditional treatments like surgery or immunotherapy, Belzutifan works by inhibiting HIF-2α, a protein that helps cancer cells survive in low-oxygen environments. Meanwhile, Cabozantinib inhibits multiple tyrosine kinases that are involved in tumor growth and metastasis. Together, these drugs offer a one-two punch by starving cancer cells of the resources they need to thrive and spreading less aggressively, potentially leading to more effective outcomes for patients.

What evidence suggests that this trial's treatments could be effective for kidney cancer?

Research has shown that combining belzutifan and cabozantinib holds promise for treating advanced clear cell renal cell carcinoma (ccRCC), a type of kidney cancer. This trial will evaluate the combination in two groups: treatment-naïve participants and those who have received prior immunotherapy. Studies have found that this combination can effectively shrink tumors or halt their growth, particularly in patients without previous treatment. Belzutifan has already received approval in several countries for treating advanced ccRCC, supporting its reliability. Earlier studies also demonstrated better disease control with this combination. This evidence suggests that belzutifan and cabozantinib together could be an effective treatment option for advanced kidney cancer. ^{1 3 5 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with advanced clear cell renal cell carcinoma (ccRCC). Participants should have measurable tumors, good performance status, and proper organ function. Some can't join if they've had certain treatments for ccRCC or major surgery recently, uncontrolled hypertension, active infections needing treatment, or are in another clinical trial.

Inclusion Criteria

Your AST and ALT levels in your blood are not more than 3 times the normal limit.

My kidney cancer is advanced or has spread and is mainly clear cell type.

You have at least one tumor that can be measured according to specific guidelines.

Exclusion Criteria

Is participating in another therapeutic clinical trial

I do not have any major health or mental conditions that could affect my trial participation.

I still have side effects from previous cancer treatments that haven't gone away.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive belzutifan and cabozantinib orally once daily

Up to approximately 2 years

Regular visits for monitoring and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Cabozantinib

Trial Overview The study tests the effectiveness and safety of combining two oral drugs: Belzutifan and Cabozantinib. It's an open-label Phase 2 study where all participants know which treatment they're getting and take the medications daily to treat advanced kidney cancer.

How Is the Trial Designed?

Group I: Belzutifan + Cabozantinib: Treatment Naïve (Cohort 1) Experimental Treatment 2 Interventions

Naïve participants will receive 120 mg belzutifan and 60 mg cabozantinib orally once daily (QD) at the same time.

Group II: Belzutifan + Cabozantinib: Prior Immunotherapy (Cohort 2) Experimental Treatment 2 Interventions

Participants who have received prior immunotherapy will receive 120 mg belzutifan and 60 mg cabozantinib orally QD at the same time.

Belzutifan is already approved in United States for the following indications:

Approved in United States as Welireg for:

• Advanced renal cell carcinoma (RCC) following a PD-1 or PD-L1 inhibitor and a VEGF TKI
• Von Hippel-Lindau disease-associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors

Who Is Running the Clinical Trial?

Peloton Therapeutics, Inc.

Lead Sponsor

Trials

8

Recruited

460+

Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Lead Sponsor

Trials

8

Recruited

460+

Published Research Related to This Trial

The combination of belzutifan and cabozantinib shows promising antitumor activity in patients with advanced clear cell renal cell carcinoma who have already undergone previous treatments.

This study highlights the potential of this drug combination as a new therapeutic option for patients with this challenging form of kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belzutifan Plus Cabozantinib Is Effective in Immunotherapy-Treated Renal Cell Carcinoma. [2023]

Cabozantinib has shown significant efficacy in treating advanced kidney cancer, with a 28% objective response rate and a median progression-free survival of 14.7 months based on a phase II trial involving patients with renal cancer.

The drug also demonstrated notable effectiveness in managing bone metastases, which is crucial for improving quality of life in patients, and further studies are planned to compare its effectiveness against standard VEGF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as a novel therapy for renal cell carcinoma. Vaishampayan, U.[2022]

Belzutifan (Welireg™) is an oral medication that inhibits HIF-2α and has been approved in the USA for treating patients with von Hippel-Lindau (VHL) disease who have associated renal cell carcinoma (RCC) and other tumors, marking a significant advancement in targeted cancer therapy.

Clinical studies are ongoing to evaluate the efficacy of belzutifan in treating other solid tumors, including clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine tumors (pNET), indicating its potential for broader applications in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belzutifan: First Approval. Deeks, ED.[2022]

Cabozantinib shows promising anti-tumor activity in patients with metastatic clear cell renal cell carcinoma (RCC), with a partial response observed in 28% of the 25 heavily pretreated participants.

The treatment demonstrated a median progression-free survival of 12.9 months and a median overall survival of 15.0 months, with a safety profile consistent with other similar therapies, indicating its potential as a viable option for advanced RCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Choueiri, TK., Pal, SK., McDermott, DF., et al.[2021]

Belzutifan, a first-in-class HIF-2α inhibitor, shows promising antitumor activity in patients with clear cell renal cell carcinoma (RCC) who have previously been treated, indicating its potential as a new treatment option.

The ongoing phase III study is comparing the combination of belzutifan with lenvatinib against cabozantinib in patients with advanced RCC who have progressed after anti-PD-1/PD-L1 therapy, addressing a significant need for effective treatments in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Motzer, RJ., Schmidinger, M., Eto, M., et al.[2023]

In a phase 2 study involving 52 patients with advanced clear cell renal cell carcinoma who had previously received immunotherapy, the combination of belzutifan and cabozantinib showed promising antitumour activity, with 30.8% of patients achieving a confirmed objective response, including one complete response.

The treatment was associated with manageable safety concerns, primarily hypertension (27% of patients), and serious treatment-related adverse events occurred in 29% of patients, indicating that while the combination therapy is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Choueiri, TK., McDermott, DF., Merchan, J., et al.[2023]

Cabozantinib (Cabometyx®) is now approved as a first-line treatment for advanced renal cell carcinoma (RCC) in treatment-naïve adults, expanding its use beyond patients who have already received VEGF-targeted therapy.

In a phase 2 trial, cabozantinib significantly improved median progression-free survival and objective response rates compared to the standard treatment sunitinib, while its side effects are manageable, similar to other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. Lyseng-Williamson, KA.[2020]

Citations

1. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-kidney-cancer/158330-asco-gu-2025-updated-results-from-the-phase-2-litespark-003-study-of-belzutifan-plus-cabozantinib-in-patients-with-advanced-clear-cell-renal-cell-carcinoma.html

Updated Results From the Phase 2 LITESPARK-003 Study ... Dr. Toni Choueiri presented updated results from the phase II LITESPARK-003 study of belzutifan plus cabozantinib in patients with advanced clear cell renal ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39756444/

Belzutifan plus cabozantinib as first-line treatment for ... Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03634540

NCT03634540 | A Trial of Belzutifan (PT2977, MK-6482) in ... This is an open-label Phase 2 study which will evaluate the efficacy and safety of belzutifan in combination with cabozantinib in participants with advanced ...

4. eisai.com eisai.com/news/2025/news202575.html

Merck & Co., Inc., Rahway, NJ, USA and ... WELIREG is approved in the U.S., European Union (EU), Japan and other countries for the treatment of adult patients with advanced clear cell RCC ...

5. onclive.com onclive.com/view/belzutifan-based-combinations-meet-dfs-pfs-end-points-in-renal-cell-carcinoma

Belzutifan-Based Combinations Meet DFS, PFS End Points ... These results mark belzutifan plus lenvatinib as the first treatment regimen to signfiicantly improved PFS vs cabozantinib following anti-PD-1/ ...

6. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00649-1/abstract

Belzutifan plus cabozantinib as first-line treatment for ... The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with ...

7. merck.com merck.com/news/merck-and-eisai-announce-welireg-belzutifan-plus-lenvima-lenvatinib-met-primary-endpoint-of-progression-free-survival-pfs-in-certain-previously-treated-patients-with-advanced-renal-c/

Merck and Eisai Announce WELIREG® (belzutifan) Plus ... WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component following a programmed death ...