Belzutifan vs Everolimus for Renal Cell Carcinoma

Not currently recruiting at 220 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS metastases, Cardiac disease, Hypertension, Hepatic impairment, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 78 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new treatment, belzutifan (also known as Welireg or MK-6482), outperforms the existing treatment, everolimus, for individuals with renal cell carcinoma—a type of kidney cancer that has spread or cannot be surgically removed. The goal is to identify which treatment helps patients live longer without cancer progression. Participants should have renal cell carcinoma that has worsened despite previous treatments with specific cancer drugs. This trial may suit those who have tried other treatments without success and seek new options. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong or moderate inhibitors and inducers of CYP3A4, for the duration of the study. If you are on these medications, you will need to discuss with your doctor about discontinuing them before participating.

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

Previous studies have shown that belzutifan is well-tolerated in treating certain kidney tumors. It is already approved for conditions like von Hippel-Lindau syndrome, indicating a well-understood safety profile. Common side effects include fatigue and low red blood cell counts, but these are usually manageable.

Everolimus also has a proven safety record. Research indicates it is generally well-tolerated, though some patients may experience side effects like mouth sores or infections. More serious side effects are less common, with only a small number of patients needing to adjust their dose.

Overall, both treatments have demonstrated relative safety, with side effects that doctors can often manage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Belzutifan is unique because it targets a protein called hypoxia-inducible factor 2-alpha (HIF-2α), which plays a role in tumor growth. This is different from current treatments for renal cell carcinoma, like Everolimus, which typically target mTOR pathways. Researchers are excited about Belzutifan because its novel mechanism of action could offer a new approach to slowing disease progression, potentially providing benefits to patients who don’t respond well to existing therapies.

What evidence suggests that this trial's treatments could be effective for renal cell carcinoma?

Studies have shown that belzutifan can be effective for kidney cancer, known as renal cell carcinoma (RCC). One study found that nearly half of the patients experienced tumor shrinkage with belzutifan. Other research has indicated that patients went longer without their cancer worsening, a measure called progression-free survival (PFS). In this trial, some participants will receive belzutifan to evaluate its effectiveness. Everolimus, a standard treatment for RCC, has helped many patients achieve longer overall survival (OS). Other participants in this trial will receive everolimus to compare both treatments and determine which one extends life without cancer progression. ^{6 7 8 9 10}

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 renal cell carcinoma who've had no more than three prior treatments, are not pregnant or breastfeeding, and agree to use contraception. They must have progressed after treatment with specific cancer drugs (PD-1/L1 inhibitors and VEGF-TKIs) and have good organ function. Exclusions include other active cancers within 3 years, brain metastases, significant heart issues, allergies to the study drugs, recent major surgery or certain medications.

Inclusion Criteria

I am not pregnant or breastfeeding and, if able to have children, I agree to use contraception as advised.

My kidney cancer worsened after treatment with PD-1/L1 and VEGF-TKI.

My kidney cancer cannot be surgically removed and has spread.

Exclusion Criteria

I cannot take pills by mouth or have a condition that affects how my body absorbs medication.

I haven't had any cancer treatment with antibodies in the last 4 weeks.

I have not had major surgery in the last 3 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Non-randomized participants received up to 120 mg of belzutifan QD

Not specified

Treatment

Randomized participants received either 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or discontinuation

Up to approximately 78 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 49 months

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Everolimus

Trial Overview The study aims to see if Belzutifan improves survival without cancer progression compared to Everolimus in patients with advanced kidney cancer. It's a head-to-head comparison of these two drugs' effectiveness over time.

How Is the Trial Designed?

Group I: Safety Run-In Experimental Treatment 1 Intervention

Non-Randomized participants enrolled into the Safety Run-in received up to 120 mg of belzutifan QD.

Group II: Belzutifan Experimental Treatment 1 Intervention

Randomized participants received 120 mg of belzutifan orally once daily (QD), until disease progression or discontinuation.

Group III: Everolimus Active Control 1 Intervention

Randomized participants received 10 mg of Everolimus orally QD, until disease progression or discontinuation.

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?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Everolimus, an oral mTOR inhibitor, significantly improves progression-free survival in patients with clear cell renal cancer, increasing it from a median of 1.9 months to 4.9 months in a phase III trial with a hazard ratio of 0.33 (P < 0.001).

The treatment is generally well-tolerated, with mild to moderate side effects that can be managed, and it has been approved as a validated option for patients who have progressed on VEGFR inhibitors, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Coppin, C.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12509838/

59: Real-World efficacy and safety of belzutifan in sporadic ... The disease control rate was 64%. The median OS was 6.93 months (95% CI: 3.75-12.58). The median PFS was 3.09 months (95% CI 2.53-5.72). AEs of ...

2. welireghcp.com welireghcp.com/von-hippel-lindau/efficacy/

Efficacy Data for WELIREG® (belzutifan) | VHL Disease Nearly half of patients achieved tumor reduction in VHL disease–associated RCC with WELIREG · MEDIAN DURATION OF RESPONSE WAS NOT REACHED · NCCN Clinical Practice ...

3. targetedonc.com targetedonc.com/view/interim-efficacy-data-favor-belzutifan-lenvatinib-in-advanced-rcc

Interim Efficacy Data Favor Belzutifan/Lenvatinib in ... The combination of belzutifan and lenvatinib showed significant PFS improvement in advanced RCC patients compared to cabozantinib. Although OS ...

4. 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 ... LITESPARK-011 and LITESPARK-022 trials showed significant PFS and DFS improvements in RCC with belzutifan combinations, surpassing cabozantinib ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39307587/

Belzutifan Efficacy and Tolerability in Patients with ... This study confirms that belzutifan can be effective and safe, even after other treatments have not worked. Keywords: Belzutifan; Clear cell; ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40920370/

The Safety Profile of Belzutifan in Renal Tumors The efficacy and side effects of belzutifan are well-documented from clinical trials, however, real-world data examining the incidence and ...

7. academic.oup.com academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyaf274/8249253?searchresult=1

The safety profile of belzutifan in renal tumors: real-world data ... Belzutifan is a HIF-2ɑ inhibitor approved for the treatment of tumors in von Hippel-Lindau (VHL) syndrome and sporadic metastatic clear cell renal cell ...

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

Merck & Co., Inc., Rahway, NJ, USA and ... The trial enrolled an estimated 708 patients who were randomized to receive WELIREG (120 mg orally once daily) plus LENVIMA (20 mg orally once ...

9. 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 ... The safety profiles of WELIREG and LENVIMA in this trial ... WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma ...

10. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e16531

Safety and efficacy profile of belzutifan, a hypoxia-inducible ... Belzutifan is a novel drug that inhibits HIF-2α which in turn results in anti-tumor effects of the drug against ccRCC.