Lenvatinib + Everolimus vs. Cabozantinib for Renal Cell Carcinoma

Not currently recruiting at 2 trial locations

Overseen By Paul Corn, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Lenvatinib, c-MET inhibitors, mTOR inhibitors

Disqualifiers: Other malignancies, Major surgery, HIV, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatment options for individuals with kidney cancer (renal cell carcinoma) that has spread and worsened after previous treatment. One group will receive a combination of lenvatinib and everolimus, while the other will take cabozantinib alone. These drugs block enzymes that aid tumor cell growth. The trial seeks participants with metastatic kidney cancer who have tried one or two treatments and experienced worsening after treatment with a PD-1/PD-L1 checkpoint inhibitor. As a Phase 2 trial, the 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 does not specify if you need to stop your current medications, but you cannot be on any anticancer therapies or systemic therapy for renal cell cancer when you join. It's best to discuss your current medications with the trial team.

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

Research has shown that using lenvatinib and everolimus together is safe for treating kidney cancer that has spread. This combination remains effective even for patients who have tried several other treatments. However, 42% of patients experienced high blood pressure, with 13% having severe cases.

Cabozantinib offers another option for treating advanced kidney cancer. It is generally well-tolerated, but like many cancer treatments, it can cause side effects such as diarrhea, tiredness, and high blood pressure.

Studies have demonstrated the safety of both treatments, but participants should be aware of possible side effects. Discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new ways to tackle renal cell carcinoma. Lenvatinib and everolimus, when combined, work by targeting specific pathways that help cancer cells grow and spread, potentially offering a dual-action approach. Meanwhile, cabozantinib targets different proteins involved in tumor growth and blood vessel formation, which is distinct from standard treatments like sunitinib or pazopanib. These unique mechanisms could lead to improved outcomes for patients by addressing cancer from multiple angles.

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

This trial will compare the effectiveness of two treatment options for advanced kidney cancer: the combination of lenvatinib and everolimus, and cabozantinib alone. Research has shown that using lenvatinib and everolimus together is promising, as this combination lowered the risk of cancer progression or death by 49% compared to cabozantinib alone in patients whose cancer progressed after PD-1 inhibitor treatment. Approximately 40% of patients experienced tumor shrinkage with this treatment.

Cabozantinib alone has also proven effective, reducing the risk of cancer progression or death by 34%, with about 40% of patients seeing a reduction in tumor size. Both treatments have shown potential, with lenvatinib and everolimus sometimes offering a slight advantage. Participants in this trial will be randomized to receive either the lenvatinib and everolimus combination or cabozantinib alone. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrew W Hahn, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced renal cell cancer that has spread and worsened after PD-1/PD-L1 checkpoint inhibitor treatment. They must have good organ function, no major psychiatric illness, and at least one measurable disease site. Excluded are those with uncontrolled blood pressure, recent surgery or injury, other medical conditions affecting study participation, severe allergies to trial drugs, certain heart problems, prior use of similar drugs, other cancers within 3 years (with exceptions), inflammatory bowel or serious liver disease.

Inclusion Criteria

Your blood clotting levels need to be within a certain range before you can join the study.

My organs and bone marrow are working well.

My cancer progressed after treatment with a PD-1/PD-L1 drug, or I had a severe reaction to it.

Exclusion Criteria

Patients with severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study

My blood pressure is not well-controlled.

You have high levels of protein in your urine, unless a specific urine test shows that the ratio of protein to creatinine is within a certain range.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive lenvatinib and everolimus or cabozantinib orally once daily. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Everolimus
• Lenvatinib

Trial Overview This phase II trial is testing the effectiveness of lenvatinib combined with everolimus versus cabozantinib alone in patients whose metastatic renal cell cancer has progressed despite previous treatments. The goal is to see which regimen better halts tumor growth by blocking enzymes needed for cell proliferation.

How Is the Trial Designed?

Group I: Arm A (lenvatinib, everolimus) Experimental Treatment 3 Interventions

Patients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (cabozantinib) Active Control 2 Interventions

Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11332639/

The efficacy and safety of cabozantinib in patients ... The cabozantinib group showed a 34% reduction in disease progression or death and higher tumor response rates (33%) compared to the sunitinib ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.479

Cabozantinib real-world effectiveness in the second-line ... Background: Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0929664625001172

Real-world study of cabozantinib treatment of advanced ... Overall, 40 % of patients treated with cabozantinib had a reduction in their tumor size and, on average, patients' cancer did not get worse for ...

4. winshipcancer.emory.edu winshipcancer.emory.edu/newsroom/articles/2025/winship-study-reveals-pre-surgical-cabozantinib-may-improve-outcomes-in-kidney-cancer.php

Pre-surgical cabozantinib may improve outcomes in ... 35% of patients (6 of 17) had a partial response, and 65% (11 of 17) had stable disease. One previously inoperable tumor became resectable, and ...

5. cancer.gov cancer.gov/news-events/cancer-currents-blog/2021/papillary-renal-cell-carcinoma-cabozantinib

Cabozantinib Slows Progression of Rare Kidney Cancer Two out of 44 people receiving cabozantinib (5%) had their tumors disappear entirely during treatment, known as a complete response. No complete ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2035716

Lenvatinib plus Pembrolizumab or Everolimus for ... Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib.

7. onclive.com onclive.com/view/lenvatinib-plus-everolimus-safe-effective-following-immunotherapy-in-clear-cell-rcc

Lenvatinib Plus Everolimus Safe, Effective Following ... Lenvatinib (Lenvima) in combination with everolimus (Afinitor) has proven to be safe and effective when used in the treatment of patients ...

8. lenvimahcp.com lenvimahcp.com/2nd-line-advanced-renal-cell-carcinoma/efficacy-results

NCCN recommendation - LENVIMA ® (lenvatinib) In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% ...

9. actionkidneycancer.org actionkidneycancer.org/lenvatinib-plus-everolimus-for-patients-with-metastatic-kidney-cancer/

Lenvatinib plus everolimus for patients with metastatic ... This study suggests that the lenvatinib plus everolimus combination is effective in heavily pre-treated patients with metastatic kidney cancer and is safe for ...

10. cda-amc.ca cda-amc.ca/sites/default/files/pcodr/Reviews2019/10140LenvatinibRCC_fnCGR_REDACT_Post_04Jan2019_final.pdf

pan-Canadian Oncology Drug Review Final Clinical ... The purpose of this review is to evaluate the efficacy and safety of lenvatinib (Lenvima) in combination with everolimus compared with ...