Pembrolizumab + Lenvatinib for Skin and Kidney Cancers with Brain Metastases

Overseen By Kira Pavlik

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must be taking: Anti-PD-1/PD-L1

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Symptomatic brain metastases, Active infection, Autoimmune disease, 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: 3

Duration: up to 2 years

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 2, Simon's 2-stage designed study with 2 cohorts of anti-PD-1/PD-L1 experienced patients with untreated brain metastases: 1) melanoma and 2) renal cell carcinoma (RCC).

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

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received anti-cancer therapy within 14 days before starting the trial and should not be on high doses of steroids or immunosuppressive therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of pembrolizumab and lenvatinib for treating skin and kidney cancers with brain metastases?

Research shows that the combination of pembrolizumab and lenvatinib has been effective in treating advanced gastric cancer, renal cell carcinoma, and urothelial carcinoma, suggesting potential benefits for other cancers as well. This combination has shown antitumor activity and is considered a standard treatment for certain types of kidney cancer. ^{1 2 3 4 5}

Is the combination of pembrolizumab and lenvatinib generally safe for humans?

The combination of pembrolizumab and lenvatinib has been studied in various cancers and has shown a manageable safety profile, meaning that while there are side effects, they can generally be managed with appropriate care. ^{2 4 6 7 8}

How is the drug combination of pembrolizumab and lenvatinib unique for treating skin and kidney cancers with brain metastases?

The combination of pembrolizumab and lenvatinib is unique because it pairs an immune checkpoint inhibitor (pembrolizumab) with a multikinase inhibitor (lenvatinib), which together enhance the body's immune response against tumors. This combination has shown promise in treating various cancers, including renal cell carcinoma, by improving anti-tumor activity compared to using either drug alone. ^{1 2 3 5 6}

Research Team

Harriet Kluger, MD

Principal Investigator

Professor of Medicine

Eligibility Criteria

Adults with melanoma or renal cell carcinoma (RCC) and untreated brain metastases who've had at least two doses of anti-PD-1/PD-L1 drugs. They must not be pregnant, agree to contraception, have a life expectancy over 3 months, stable blood pressure, good organ function, and an ECOG status of 0-1. Exclusions include symptomatic brain metastases, recent cancer treatments or vaccines, serious infections or bleeding risks.

Inclusion Criteria

You are expected to live for at least 3 more months.

I have received at least 2 doses of a drug targeting PD-1/PD-L1 in my treatment for melanoma or kidney cancer.

My organs are functioning well.

Exclusion Criteria

I have symptoms from melanoma or kidney cancer that has spread to my brain.

You had a positive pregnancy test within 3 days before the study starts.

I have had serious heart issues, like a heart attack or unstable angina, in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab 200mg IV every 3 weeks in combination with lenvatinib 20 mg PO daily for up to 2 years

up to 2 years

Every 3 weeks for pembrolizumab administration

Response Assessment

First response assessment at 6 weeks with MRI of the brain and CT body scans, followed by repeat imaging at 12 weeks and every 12 weeks thereafter

6 weeks for initial assessment, then every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The trial is testing Pembrolizumab combined with Lenvatinib in patients who have previously received PD-1/PD-L1 inhibitors but now have untreated brain metastases from either melanoma or RCC. It's a phase 2 study designed to evaluate the effectiveness and safety of this combination therapy.

Participant Groups

Group I: Cohort 2: Renal Cell Carcinoma Experimental Treatment 2 Interventions

Participants who are Renal Cell Carcinoma (PD-1/PD-L1 experienced).

Group II: Cohort 1: Melanoma Experimental Treatment 2 Interventions

Participants who are melanoma (PD-1/PD-L1-experienced)

Lenvatinib is already approved in United States, European Union for the following indications:

Approved in United States as Lenvima for:

• Differentiated Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Lenvima for:

• Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Kisplyx for:

• Renal Cell Carcinoma

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Merck Sharp & Dohme LLC

Industry 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

Findings from Research

In a phase 2 trial involving 29 patients with advanced gastric cancer, the combination of lenvatinib and pembrolizumab resulted in a promising objective response rate of 69%, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with the most common grade 3 adverse events being manageable, such as hypertension and proteinuria, and no serious treatment-related complications or deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Kawazoe, A., Fukuoka, S., Nakamura, Y., et al.[2020]

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 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 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]

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 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 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, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. [2020]

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

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

4. Switzerland 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. [2023]

5. 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]

6. Germany pubmed.ncbi.nlm.nih.gov

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

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]