Belzutifan + Lenvatinib vs. Cabozantinib for Kidney Cancer

Not currently recruiting at 233 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Belzutifan, Lenvatinib, Cabozantinib, others

Disqualifiers: CNS metastases, Cardiac disease, 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 44 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of two drugs, belzutifan (also known as Welireg or MK-6482) and lenvatinib, is more effective than cabozantinib in treating advanced kidney cancer, specifically clear cell renal cell carcinoma. The researchers are examining how long patients live without their cancer worsening, as well as overall survival. Suitable candidates have kidney cancer that has spread or cannot be surgically removed, and their cancer has progressed after previous specific therapy. As a Phase 3 trial, this study represents the final step before FDA approval, providing patients with access to potentially effective treatment.

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that the combination of belzutifan and lenvatinib has a safety record similar to earlier findings. This combination is being tested for advanced kidney cancer. Patients who previously took belzutifan and lenvatinib generally tolerated the treatment well, experiencing side effects similar to those of other cancer treatments.

Cabozantinib, another treatment in this study, has already received approval for kidney cancer, indicating that its safety has been thoroughly studied. While it can have side effects, its past use provides some reassurance about its safety.

In summary, both treatment options have demonstrated safety in earlier studies. However, discussing the benefits and risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Belzutifan and Lenvatinib for kidney cancer because it offers a fresh approach compared to existing treatments. Unlike traditional therapies like Cabozantinib, which targets specific receptors to inhibit tumor growth, Belzutifan works by inhibiting HIF-2α, a protein that plays a role in cancer cell survival under low oxygen conditions. This new mechanism of action could potentially enhance treatment effectiveness by targeting cancer cells in a novel way. Moreover, when combined with Lenvatinib, which also targets tumor blood vessel growth, this duo might offer a powerful one-two punch against kidney cancer.

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

This trial will compare the combination of belzutifan and lenvatinib with cabozantinib for treating advanced kidney cancer. Research has shown that using belzutifan and lenvatinib together may help treat advanced kidney cancer, with studies finding that this combination helps patients live longer without their cancer worsening. This improvement is unlikely due to chance. The combination also proves more effective than cabozantinib, another treatment option in this trial. These findings suggest that belzutifan and lenvatinib could be a better option for managing advanced kidney cancer. ^{1 2 3 4 6}

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 have seen their cancer progress after anti-PD-1/L1 therapy. They should have measurable disease, a Karnofsky performance status of at least 70%, and no more than two prior systemic treatments. Participants must not be pregnant or breastfeeding and agree to use contraception.

Inclusion Criteria

My organs are working well.

Your disease can be measured using a specific set of criteria called RECIST 1.1 by the study doctor in your area.

I am a man who will not have sex or will use birth control during and after the treatment.

Exclusion Criteria

Known hypersensitivity or allergy to the active pharmaceutical ingredients or any component of the study intervention formulations

Your heart's electrical activity takes too long, more than 480 milliseconds.

I am currently being treated for an infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either belzutifan + lenvatinib or cabozantinib for advanced renal cell carcinoma

Up to approximately 44 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 44 months

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Cabozantinib
• Lenvatinib

Trial Overview The study tests the effectiveness of combining Belzutifan with Lenvatinib against Cabozantinib alone in treating renal cell carcinoma. The main goal is to see if the combination leads to longer survival without cancer progression compared to Cabozantinib.

How Is the Trial Designed?

Group I: Belzutifan + Lenvatinib Experimental Treatment 2 Interventions

Belzutifan 120 mg and lenvatinib 20 mg orally once a day

Group II: Cabozantinib Active Control 1 Intervention

Cabozantinib 60 mg orally once a day

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

Eisai Inc.

Industry Sponsor

Trials

524

Recruited

161,000+

Founded

Eisai Inc. was established in 1995 as the U.S. subsidiary of Eisai Co., Ltd.

Headquarters

Woodcliff Lake, NJ, USA

Known For

Neurology and Oncology

Top Products

Aricept (donepezil), Lenvima (lenvatinib), Leqembi (lecanemab), Halaven (eribulin)

Lynn Kramer

Eisai Inc.

Chief Medical Officer since 2019

MD

Tatsuyuki Yasuno

Eisai Inc.

Chief Executive Officer since 2023

MBA from Kellogg School of Management, Northwestern University; Bachelor of Political Science from Waseda University

Published Research Related to This Trial

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]

The LITESPARK-012 study is a phase III clinical trial designed to evaluate the safety and efficacy of combining pembrolizumab and lenvatinib with either belzutifan or quavonlimab for treating advanced clear cell renal cell carcinoma (ccRCC).

This research aims to determine if these novel triplet therapies can improve patient outcomes and potentially establish a new standard of care for advanced ccRCC, building on existing combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Choueiri, TK., Powles, T., Voss, MH., et al.[2023]

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]

The CLEAR trial showed that the combination of lenvatinib and pembrolizumab significantly improves progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to sunitinib in treatment-naïve metastatic clear-cell renal cell carcinoma.

Combination therapies involving immune checkpoint inhibitors, such as cabozantinib plus nivolumab and axitinib plus pembrolizumab, also demonstrated similar survival benefits and improved quality of life, making them recommended first-line treatments for advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care. Bedke, J., Albiges, L., Capitanio, U., et al.[2022]

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]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., 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]

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]

Citations

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

Merck & Co., Inc., Rahway, NJ, USA and ... At a pre-specified interim analysis, WELIREG plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in PFS ...

2. 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 ... At a pre-specified interim analysis, WELIREG plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in PFS compared to ...

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

Interim Efficacy Data Favor Belzutifan/Lenvatinib in ... A new trial shows that the combination of belzutifan and lenvatinib improves progression-free survival in advanced renal cell carcinoma patients ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04586231

NCT04586231 | A Study of Belzutifan (MK-6482) in ... This study will compare the efficacy and safety of belzutifan + lenvatinib versus cabozantinib in participants with advanced renal cell carcinoma (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 ... LITESPARK-011 and LITESPARK-022 trials showed significant PFS and DFS improvements in RCC with belzutifan combinations, surpassing cabozantinib ...

6. cancernetwork.com cancernetwork.com/view/lenvatinib-belzutifan-exhibits-durable-antitumor-activity-safety-in-ccrcc

Lenvatinib/Belzutifan Exhibits Durable Antitumor Activity ... Treatment with lenvatinib (Lenvima) in combination with belzutifan (Welireg) exhibited durable antitumor activity and a safety profile consistent with prior ...