Neoadjuvant Lenvatinib + Pembrolizumab for Kidney Cancer

Overseen By Donna Mitchell

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Immunodeficiency, Active CNS metastases, others

Stay on Your Current Meds You can continue your current medications while participating

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

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, lenvatinib (a targeted therapy) and pembrolizumab (an immunotherapy), administered before surgery to evaluate their safety and effectiveness in treating advanced kidney cancer. The focus is on cases where the cancer has spread to the inferior vena cava, a large vein that carries blood to the heart. The trial seeks participants with a confirmed diagnosis of kidney cancer that may or may not be surgically removable. Those with kidney cancer and tumors in the vena cava might find this trial suitable. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant advancements in kidney cancer treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on certain treatments like systemic steroids or have received recent cancer therapies, you may need to adjust or stop those. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that the combination of lenvatinib and pembrolizumab is likely to be safe?

Research has shown that using lenvatinib and pembrolizumab together is generally safe for patients. In one study, this combination was administered to patients with advanced kidney cancer before surgery, helping to shrink the tumor without worsening the cancer. Another study found that this combination is safe for patients at high risk of cancer progression.

While side effects can occur with any treatment, studies so far have indicated that most people tolerate this combination well. Since these treatments have already been approved for other conditions, this adds some confidence in their safety. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for kidney cancer?

Researchers are excited about using lenvatinib and pembrolizumab for kidney cancer because they offer a fresh approach compared to traditional treatments like surgery, radiation, and chemotherapy. Lenvatinib is a targeted therapy that inhibits tumor blood vessel growth, while pembrolizumab is an immunotherapy that boosts the body's own immune response against cancer. This combination is especially promising because it tackles the cancer from two angles: cutting off its blood supply and enhancing immune attack, potentially leading to better outcomes than existing treatments alone.

What evidence suggests that this combination treatment could be effective for kidney cancer?

Research shows that using lenvatinib and pembrolizumab together holds promise for treating kidney cancer. In this trial, participants will receive neoadjuvant lenvatinib and pembrolizumab before surgical resection of locally advanced RCC with IVC tumor thrombus. Studies have found that this combination can significantly shrink tumors, with an average reduction of about 21.8% in the main kidney tumors. Importantly, these studies did not report any cases of cancer worsening during treatment. This suggests the treatment not only shrinks tumors but also helps prevent cancer progression. Early results also indicate that this combination is safe and effective for patients at high risk of cancer spreading. Overall, the evidence supports the potential effectiveness of this treatment for kidney cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Vitaly Margulis

Principal Investigator

University of Texas Southwestern Medical Center

Are You a Good Fit for This Trial?

Adults with advanced kidney cancer and blood clots in the inferior vena cava who are fit for surgery. They must have good organ function, not be pregnant or breastfeeding, agree to use contraception, and can't have had recent transfusions or certain treatments. Excluded if they have heart issues, high protein in urine, active infections, severe allergies to trial drugs, uncontrolled blood pressure or other conditions that could affect results.

Inclusion Criteria

I am a male and agree to use approved birth control methods for 90 days after my last treatment dose and not donate sperm.

My organs are functioning well.

My doctor thinks my tumor and related blood clot can or cannot be surgically removed.

Exclusion Criteria

I had radiotherapy less than 2 weeks before starting the study treatment.

Your heart takes too long to recharge between beats.

I have not received a live vaccine in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant lenvatinib (20 mg PO daily) for 12 weeks and pembrolizumab (200 mg IV every 3 weeks for four doses) prior to surgical resection

12 weeks

Surgery

Surgical resection of locally advanced RCC with IVC tumor thrombus

1 week

Adjuvant Treatment

Following surgery, patients receive adjuvant pembrolizumab (200 mg IV every 3 weeks for up to thirteen doses)

39 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of 90 day post-operative complications

13 weeks

Long-term Follow-up

Evaluation of post-operative survival outcomes including recurrence-free survival and overall survival

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The trial tests a combination of Lenvatinib and Pembrolizumab before surgery (neoadjuvant therapy) followed by kidney removal and clot extraction from the inferior vena cava. Afterward, patients receive additional Pembrolizumab treatment (adjuvant therapy). The goal is to assess how safe and effective this approach is for treating renal cell carcinoma with IVC tumor thrombus.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 4 Interventions

Patients receive neoadjuvant lenvatinib (20 mg PO daily) for 12 weeks and pembrolizumab (200 mg IV every 3 weeks for four doses) prior to surgical resection of locally advanced RCC with IVC tumor thrombus. Following surgery, patients will receive adjuvant pembrolizumab (200 mg IV every 3 weeks for up to thirteen doses).

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Published Research Related to This Trial

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]

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]

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]

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 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 a phase 3 trial with 1069 patients, the combination of lenvatinib and pembrolizumab significantly improved progression-free survival compared to sunitinib, with a median of 23.9 months versus 9.2 months, indicating a strong efficacy of this regimen.

Lenvatinib plus pembrolizumab also resulted in longer overall survival compared to sunitinib, while the combination of lenvatinib and everolimus did not show a survival advantage over sunitinib. However, both lenvatinib combinations had a high incidence of grade 3 or higher adverse events, similar to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Motzer, R., Alekseev, B., Rha, SY., et al.[2022]

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 subset analysis of the CLEAR study involving 73 Japanese patients with advanced renal cell carcinoma, the combination of lenvatinib and pembrolizumab showed significantly longer progression-free survival (22.1 months) compared to sunitinib (10.9 months).

The combination therapy also resulted in a higher objective response rate (69.0% vs. 45.2%) and longer median duration of response (20.3 months vs. 9.1 months), although it was associated with a higher incidence of grade ≥3 treatment-emergent adverse events (95.2% vs. 87.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab versus sunitinib for advanced renal cell carcinoma: Japanese patients from the CLEAR study. Eto, M., Takagi, T., Kimura, G., et al.[2023]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05733715

Neoadjuvant Pembrolizumab and Lenvatinib for Renal Cell ... This trial will generate preliminary data on immune pharmacodynamic outcomes and tumor response for neoadjuvant pembrolizumab +/- lenvatinib and is not powered ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4541

Neoadjuvant lenvatinib plus pembrolizumab for resectable ... Conclusions: Our data preliminarily demonstrated safety and efficacy of neoadjuvant ldLP in ccRCC at high-risk of progression. Results also ...

3. merck.com merck.com/news/keytruda-pembrolizumab-plus-lenvima-lenvatinib-demonstrates-durable-5-year-survival-benefit-versus-chemotherapy-for-patients-with-advanced-endometrial-carcinoma-following-one-prior-pla/

KEYTRUDA® (pembrolizumab) Plus LENVIMA® ... At five years, KEYTRUDA plus LENVIMA showed a 16.7% overall survival (OS) rate for these patients with mismatch repair proficient (pMMR) advanced ...

4. urotoday.com urotoday.com/conference-highlights/asco-2025/asco-2025-kidney-cancer/161016-asco-2025-neoadjuvant-lenvatinib-plus-pembrolizumab-for-resectable-clear-cell-renal-cell-carcinoma-pelur-a-prospective-phase-2-study.html

ASCO 2025: Neoadjuvant Lenvatinib plus Pembrolizumab ... During adjuvant therapy, three grade 3 adverse events were reported, including one case of rash, ALT/AST elevation, and acute kidney injury. The ...

5. cancernetwork.com cancernetwork.com/view/perioperative-lenvatinib-combo-shows-activity-in-advanced-clear-cell-rcc

Perioperative Lenvatinib Combo Shows Activity in ... Treatment elicited a median primary renal tumor size reduction of 21.8% (range, 3.4%-37.0%). There were no instances of disease progression ...