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

Trial Summary

What is the purpose of this trial?

This study will be evaluating safety and efficacy of the combination of lenvatinib and pembolizumab neoaadjuvant therapy prior to surgical resection of locally advanced renal cell carcinoma with IVC tumor thrombus.

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.

What data supports the effectiveness of the drug combination Lenvatinib and Pembrolizumab for kidney cancer?

Research shows that the combination of Lenvatinib and Pembrolizumab improves survival rates and delays disease progression in patients with advanced kidney cancer compared to another drug, sunitinib. This combination has been effective in both clear-cell and non-clear-cell types of kidney cancer. ^{1 2 3 4 5}

What is known about the safety of Lenvatinib and Pembrolizumab in humans?

Lenvatinib and Pembrolizumab have been studied together in various cancers, including kidney and endometrial cancers. Common side effects include high blood pressure, low thyroid function, diarrhea, nausea, vomiting, loss of appetite, tiredness, and weight loss. These side effects are consistent with what is known about each drug when used alone. ^{2 3 4 6 7}

How is the drug combination of lenvatinib and pembrolizumab unique for kidney cancer treatment?

The combination of lenvatinib (a multikinase inhibitor) and pembrolizumab (an immune checkpoint inhibitor) is unique because it targets both cancer cell growth and the immune system, offering improved progression-free and overall survival compared to traditional treatments like sunitinib for advanced renal cell carcinoma. ^{2 3 4 8 9}

Research Team

Vitaly Margulis

Principal Investigator

University of Texas Southwestern Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

2. England 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. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. [2022]

4. England 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab versus sunitinib for advanced renal cell carcinoma: Japanese patients from the CLEAR study. [2023]

6. England 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. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

8. Australia pubmed.ncbi.nlm.nih.gov

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. [2022]