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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, Pembrolizumab (an immunotherapy drug) and Lenvatinib (a targeted therapy), for patients with certain skin and kidney cancers that have spread to the brain. Researchers aim to determine the effectiveness of these treatments for individuals who have already tried similar drugs. The trial seeks participants with melanoma or renal cell carcinoma with untreated brain metastases and previous use of anti-PD-1/PD-L1 therapies. If this describes your situation, this trial might be suitable. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

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.

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

Research has shown that the combination of pembrolizumab and lenvatinib has been tested in patients with melanoma and kidney cancer. For melanoma, studies have found benefits, but the side effects can be serious. About 59% of patients experienced severe side effects when taking these two drugs together. In patients with kidney cancer, around 25% experienced serious side effects, and some had to lower their lenvatinib dose due to these effects.

These treatments are currently in a phase 2 trial, indicating they have shown some safety in earlier trials but are still under close study. Pembrolizumab and lenvatinib have already received FDA approval for other uses, suggesting their safety is somewhat known, but new uses can present different risks. It is important to discuss possible side effects with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and lenvatinib because it offers a novel approach to treating skin and kidney cancers, especially when they've spread to the brain. Unlike traditional treatments that often focus solely on either the immune system or tumor growth, this combo targets both by using pembrolizumab to enhance the immune response against cancer cells and lenvatinib to inhibit blood vessel growth that tumors need. This dual action not only has the potential to improve efficacy but also tackles challenging cases where the cancer has metastasized to the brain, an area where many current treatments struggle. This innovative approach could provide new hope for patients with advanced melanoma and renal cell carcinoma.

What evidence suggests that this trial's treatments could be effective for skin and kidney cancers with brain metastases?

This trial will evaluate the combination of pembrolizumab and lenvatinib for treating melanoma and renal cell carcinoma (RCC) in patients with brain metastases. Research has shown that using pembrolizumab and lenvatinib together holds promise for treating melanoma, especially in patients unresponsive to other immunotherapy treatments. The LEAP-004 study found that this combination might help when other treatments fail. For RCC, studies indicate that pembrolizumab and lenvatinib are effective, with many patients experiencing significant tumor shrinkage. Real-world evidence supports their effectiveness in RCC, with many patients responding well. Overall, these treatments have demonstrated positive results for both melanoma and RCC, even when the cancer has spread to the brain. ^{3 6 7 8 9}

Who Is on the Research Team?

Harriet Kluger, MD

Principal Investigator

Professor of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11491429/

pembrolizumab and lenvatinib versus conventional ... The phase II LEAP-004 trial supported that pembrolizumab/lenvatinib could potentially overcome anti-PD-1/anti-CTLA-4 immunotherapy refractoriness.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04955743?cond=pembrolizumab&aggFilters=studyType:int&viewType=Table&rank=10

Study Details | Pembrolizumab and Lenvatinib in Patients ... The primary endpoint of this study is to determine the best intracranial response of combined pembrolizumab and lenvatinib in patients with untreated brain ...

3. academic.oup.com academic.oup.com/oncolo/article/29/10/e1364/7704479

Real-world outcomes of combined lenvatinib and anti-PD-1 in ... Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy.

4. merck.com merck.com/news/new-data-from-investigational-study-of-lenvima-lenvatinib-and-keytruda-pembrolizumab-combination-in-three-different-tumor-types-presented-at-the-society-for-immunotherapy-of-cancer/

New Data from Investigational Study of LENVIMA® ... The LENVIMA and KEYTRUDA combination demonstrated encouraging anti-tumor activity. These data support further evaluation of the combination.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04700072

Study Details | NCT04700072 | Substudy 02D: Safety and ... RANO-BM uses a combination of RECIST 1.1 and clinical data to assess response to treatment in brain metastases. Up to ~30 months. Brain metastasis duration of ...

6. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-012-trial-in-unresectable-non-metastatic-hepatocellular-carcinoma/

Merck and Eisai Provide Update on Phase 3 LEAP-012 ... The safety profile of the KEYTRUDA plus LENVIMA-based regimen was consistent with that observed in previously reported studies evaluating ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40885529/

Randomized, Double-Blind, Phase III LEAP-003 Study of ... Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab (HR, 0.72 ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00928-7/fulltext

Randomized, double-blind, phase III LEAP-003 study of ... Grade 3-5 treatment-related AEs occurred in 58.7% with lenvatinib + pembrolizumab versus 29.0% with placebo + pembrolizumab. •. Lenvatinib + ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9553

First-line lenvatinib plus pembrolizumab versus placebo ... Results of the global, phase 3 LEAP-003 study, showed that lenvatinib (len) + pembrolizumab (pembro) significantly improved PFS compared with pembro alone.