Drug Combinations for Kidney Cancer

Not currently recruiting at 343 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Steroids, Immunosuppressants, others

Disqualifiers: CNS metastases, Cardiac disease, 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 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new drug combinations to treat advanced clear cell renal cell carcinoma (ccRCC), a specific type of kidney cancer. Researchers aim to determine if adding either belzutifan (also known as Welireg, an experimental treatment) or quavonlimab to the usual treatment of pembrolizumab and lenvatinib can help patients live longer without their cancer worsening. The trial seeks participants diagnosed with ccRCC who have not yet received systemic treatment for their advanced condition. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to groundbreaking advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants must not have received prior systemic therapy for advanced kidney cancer and should have controlled blood pressure, with or without medication.

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

Research shows that the treatments in this clinical trial are generally well-tolerated by patients. Studies have found that using pembrolizumab with lenvatinib is a common approach for treating advanced kidney cancer, known for its effectiveness and manageable side effects.

The combination of pembrolizumab with belzutifan and lenvatinib has also undergone testing. Results suggest it is safe, with side effects similar to those of other cancer treatments, such as tiredness and high blood pressure. The approval of belzutifan for certain kidney cancers supports its safety.

Similarly, the combination of pembrolizumab with quavonlimab and lenvatinib is under study. Research indicates it is well-tolerated, though it can cause side effects like diarrhea and nausea, common to many cancer treatments.

Overall, these treatments have been through several studies, demonstrating their safety, though side effects can occur. Discussing any concerns with healthcare professionals is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for kidney cancer because they explore innovative drug combinations and mechanisms. Unlike standard treatments, these combinations include pembrolizumab, an immune checkpoint inhibitor, paired with lenvatinib, a tyrosine kinase inhibitor, with or without the addition of belzutifan or quavonlimab. Belzutifan is particularly interesting because it inhibits HIF-2 alpha, a protein involved in cancer cell survival, offering a fresh approach to combating kidney cancer. Quavonlimab adds another layer of immune modulation, potentially enhancing the body's ability to fight cancer. These unique combinations aim to improve patient outcomes by attacking cancer cells from multiple angles.

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

Studies have shown that combining pembrolizumab and lenvatinib, one of the treatment arms in this trial, effectively treats advanced clear cell renal cell carcinoma (ccRCC). This combination helps patients live longer without cancer progression and improves overall survival. Another arm in this trial will test adding belzutifan to pembrolizumab and lenvatinib, with early research suggesting it might enhance these benefits by increasing the treatment's tumor-fighting ability. Additionally, the trial includes an arm testing pembrolizumab/quavonlimab with lenvatinib, with hopes for similar or better results. While each combination appears promising, ongoing research in this trial will determine their effectiveness compared to the current standard treatment. ^{1 3 4 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 who haven't had systemic therapy for it. They must have good organ function, controlled blood pressure, and agree to contraception if applicable. Exclusions include other active cancers within 3 years, recent major surgery or radiotherapy, certain heart diseases, lung conditions like interstitial disease or pneumonitis, uncontrolled infections including HIV or Hepatitis B.

Inclusion Criteria

I started treatment for bone loss at least 2 weeks before joining the study.

My blood pressure is under control, with or without medication.

My organs are functioning well.

Exclusion Criteria

I have had or currently have lung inflammation treated with steroids.

I have a history of Hepatitis B.

I have not had major surgery within the last 4 weeks, except for kidney removal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab in combination with belzutifan and lenvatinib, or pembrolizumab/quavonlimab in combination with lenvatinib, or pembrolizumab and lenvatinib alone. Pembrolizumab is administered IV every 6 weeks for up to 18 administrations (~2 years), while belzutifan, quavonlimab, and lenvatinib are administered orally daily until disease progression or discontinuation.

Up to approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments for progression-free survival and overall survival.

Up to approximately 66 months

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Lenvatinib
• Pembrolizumab
• Pembrolizumab/Quavonlimab

Trial Overview The study tests the effectiveness of pembrolizumab combined with belzutifan and lenvatinib or a combo of pembrolizumab/quavonlimab with lenvatinib against just pembrolizumab plus lenvatinib in treating kidney cancer. It aims to see which combination leads to longer survival without disease progression.

How Is the Trial Designed?

Group I: Pembrolizumab/Quavonlimab + Lenvatinib Experimental Treatment 2 Interventions

Participants will receive pembrolizumab/quavonlimab (co-formulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered IV Q6W for up to 18 administrations (up to \~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.

Group II: Pembrolizumab + Belzutifan + Lenvatinib Experimental Treatment 3 Interventions

Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 18 administrations (up to \~2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.

Group III: Pembrolizumab + Lenvatinib Active Control 2 Interventions

Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 18 administrations (up to \~2 years). Lenvatinib will be administered orally QD until progressive disease 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

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

In a phase 1b study involving 6 Japanese patients with metastatic solid tumors, the combination of lenvatinib and pembrolizumab was well-tolerated, with no dose-limiting toxicities reported.

The treatment showed promising antitumor activity, with an objective response rate of 33.3%, particularly in patients with urothelial cancer, indicating potential efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Kitano, S., Fujiwara, Y., Shimizu, T., et al.[2022]

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]

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

In the CLEAR study involving 352 patients, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common adverse reactions including fatigue (63.1%), diarrhea (61.9%), and hypertension (56.3%).

Most adverse reactions occurred within approximately 5 months of starting treatment, and effective management strategies such as monitoring and dose modifications were identified to ensure patient safety and support ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Motzer, R., George, S., Merchan, JR., et al.[2023]

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

In a phase 3 study involving 1069 patients with advanced renal cell carcinoma, the combination of lenvatinib and pembrolizumab showed similar or better health-related quality of life (HRQOL) outcomes compared to sunitinib, particularly in terms of time to definitive deterioration.

Patients receiving lenvatinib plus pembrolizumab experienced longer median times to deterioration in quality of life measures, indicating that this combination therapy not only improves survival but also maintains a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Motzer, R., Porta, C., Alekseev, B., et al.[2023]

The combination of lenvatinib and pembrolizumab demonstrated promising antitumor activity in patients with metastatic renal cell carcinoma (RCC), with an objective response rate of 72.7% in treatment-naive patients and 55.8% in those previously treated with immune checkpoint inhibitors, based on a study of 143 patients.

While the treatment showed efficacy, it also had a manageable safety profile, with 57% of patients experiencing grade 3 treatment-related adverse events, primarily hypertension, and 7% experiencing grade 4 events, indicating that careful monitoring is necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lee, CH., Shah, AY., Rasco, D., et al.[2022]

In the KEYNOTE-B61 trial involving 158 patients with advanced non-clear-cell renal cell carcinoma, the combination of pembrolizumab and lenvatinib demonstrated a 49% objective response rate, indicating significant antitumor activity as a first-line treatment.

The safety profile was consistent with previous studies, with 51% of patients experiencing grade 3-4 treatment-related adverse events, primarily hypertension, but no deaths were attributed to the treatment itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Albiges, L., Gurney, H., Atduev, V., et al.[2023]

A 49-year-old man with advanced metastatic renal cell carcinoma was successfully treated with a combination of lenvatinib and pembrolizumab, leading to the disappearance of lung metastases and significant shrinkage of the primary tumor.

Following this combination therapy, a robot-assisted radical nephrectomy was performed, resulting in complete surgical remission, highlighting the effectiveness of this treatment strategy for metastatic renal cell carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. Sato, H., Sazuka, T., Fujimoto, A., 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04736706

NCT04736706 | A Study of Pembrolizumab (MK-3475) in ... The goal of this study is to evaluate the efficacy and safety of pembrolizumab plus belzutifan plus lenvatinib or pembrolizumab/quavonlimab plus lenvatinib ...

2. merck.com merck.com/news/merck-announces-keytruda-pembrolizumab-plus-welireg-belzutifan-met-primary-endpoint-of-disease-free-survival-dfs-in-certain-patients-with-clear-cell-renal-cell-carcinoma-rcc-follow/

Merck Announces KEYTRUDA® (pembrolizumab) Plus ... First combination regimen to demonstrate improvement in DFS compared to KEYTRUDA monotherapy for these patients in the adjuvant setting.

3. 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 ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37882432/

LITESPARK-012: pembrolizumab plus lenvatinib with or ... This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab ...

5. onclive.com onclive.com/view/lenvatinib-plus-belzutifan-demonstrates-antitumor-activity-in-advanced-ccrcc

Lenvatinib Plus Belzutifan Demonstrates Antitumor Activity ... The combination of lenvatinib (Lenvima) and belzutifan (Welireg) produced antitumor activity with a manageable safety profile in patients with locally advanced ...

6. 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 ...

7. 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/ ...