Lenvatinib + Pembrolizumab + Fulvestrant for Breast Cancer

Recruiting at 6 trial locations

Overseen By Komal Jhaveri, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: LHRH agonists

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

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new treatment combination for individuals with ER+ (estrogen receptor-positive), HER2- (human epidermal growth factor receptor 2-negative) metastatic breast cancer. The study tests whether the combination of three drugs—lenvatinib (a cancer treatment), pembrolizumab (an immunotherapy), and fulvestrant (a hormone therapy)—is safe and effective, with minimal side effects. Candidates who have tried at least one hormone therapy and a CDK 4/6 inhibitor (a type of cancer treatment) but have not undergone more than two chemotherapy treatments in the metastatic stage might be suitable. Participants should also have manageable brain metastases, if present, and a tumor sample available for testing. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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, you should discuss your current medications with the trial team to ensure they don't interfere with the study treatments.

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

Research has shown that the combination of lenvatinib, pembrolizumab, and fulvestrant might be safe and effective, with only mild side effects reported. These treatments have been studied for other conditions, providing evidence of their safety. For instance, lenvatinib and pembrolizumab have been used together in treating other types of cancer, and fulvestrant is a known treatment for breast cancer.

Other studies have found that pembrolizumab, a drug that helps the immune system fight cancer, is well-tolerated when used with different medications. Lenvatinib, which blocks cancer cell growth, has also been tested with other drugs like letrozole without major safety issues.

This trial is in its early stages (Phase 1/2), so researchers are still assessing the safety of this combination specifically for breast cancer. Early trials mainly focus on safety, and any serious side effects will be closely monitored. However, since these drugs are already used in other treatments, there is some reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination because it brings together three powerful agents that each have a unique way of fighting breast cancer. Lenvatinib works by blocking specific proteins that cancer cells need to grow, while pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. Fulvestrant, on the other hand, is a hormone therapy that targets the estrogen receptor to slow down or stop the growth of cancer cells. This combination could potentially offer a more comprehensive attack on unresectable, locally advanced, or metastatic ER+/HER2- breast cancer, unlike traditional treatments that often focus on just one mechanism at a time.

What evidence suggests that this trial's treatments could be effective for ER+/HER2- metastatic breast cancer?

Research has shown that a combination of three drugs—lenvatinib, pembrolizumab, and fulvestrant—may help treat ER+/HER2- metastatic breast cancer. In this trial, participants will receive this combination treatment. Lenvatinib, a targeted therapy, and pembrolizumab, an immunotherapy, together can enhance the body's ability to fight cancer. Fulvestrant, a hormone therapy, blocks estrogen, which some breast cancers need to grow. Early results suggest this combination might be effective and cause only mild side effects. This new approach is under investigation because current treatments for this type of breast cancer often prove insufficient. Researchers hope this combination could lead to better outcomes for patients. ^{1 2 3 4 6}

Who Is on the Research Team?

Sherry Shen, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with ER+/HER2- metastatic breast cancer who have stable brain metastases, not pregnant or breastfeeding, and have had no more than two chemotherapy treatments in the metastatic setting. They must agree to contraception if applicable and have adequate organ function. People can't join if they've used certain immune therapies, VEGF inhibitors like lenvatinib before, or had recent vaccines or other cancer treatments.

Inclusion Criteria

Additional requirements for pregnancy testing during and after study intervention

You are expected to live for at least 12 more weeks.

A WOCBP must have a negative urine pregnancy test within 72 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Exclusion Criteria

Your heart's electrical activity is too slow.

I cannot swallow pills.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lenvatinib, pembrolizumab, and fulvestrant to assess safety and effectiveness

24 weeks

Pembrolizumab every 6 weeks, Fulvestrant every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants may continue treatment to determine long-term safety and efficacy

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Fulvestrant
• Lenvatinib
• Pembrolizumab

Trial Overview The study tests a combination of three drugs: Lenvatinib, Pembrolizumab, and Fulvestrant for safety and effectiveness in treating ER+/HER2- metastatic breast cancer. It aims to find out if this drug mix causes only mild side effects while being an effective treatment option.

How Is the Trial Designed?

Group I: Lenvatinib, Pembrolizumab, and Fulvestrant Experimental Treatment 3 Interventions

This is an open-label phase Ib/II trial of lenvatinib (20mg orally PO daily) plus pembrolizumab (400mg IV Q6W) plus fulvestrant (500mg IM Q4W) in patients with unresectable, locally advanced/metastatic ER+/HER2- breast cancer.

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

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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 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 phase II LEAP-004 study involving 103 patients with advanced melanoma who had disease progression on PD-1 inhibitors, the combination of lenvatinib and pembrolizumab achieved an objective response rate of 21.4%, indicating its potential effectiveness in this challenging population.

The treatment demonstrated a median progression-free survival of 4.2 months and an overall survival of 14.0 months, with a manageable safety profile, including a 45.6% incidence of grade 3-5 adverse events, primarily hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. Arance, A., de la Cruz-Merino, L., Petrella, TM., et al.[2023]

The combination of pembrolizumab and lenvatinib has shown promising efficacy in treating advanced endometrial cancer, with previous trials indicating improved objective response rates and survival outcomes compared to standard chemotherapy.

This ongoing phase 3 trial aims to determine if pembrolizumab plus lenvatinib is superior to the chemotherapy regimen of paclitaxel plus carboplatin in newly diagnosed patients, with a target enrollment of about 875 participants and results expected in 2022.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Marth, C., Tarnawski, R., Tyulyandina, A., et al.[2022]

In a phase 2 study involving 54 patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab resulted in a 39.6% objective response rate at week 24, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with serious adverse events occurring in 30% of patients, including one treatment-related death; however, the safety profile was consistent with previous studies of the individual drugs, except for a higher incidence of hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Makker, V., Rasco, D., Vogelzang, NJ., et al.[2020]

In a phase 2 study involving 38 patients with pleural mesothelioma, the combination of pembrolizumab and lenvatinib resulted in a promising objective response rate of 58%, indicating significant anti-tumor activity after prior chemotherapy.

However, the treatment was associated with considerable toxicity, with 26% of patients experiencing serious treatment-related adverse events, including one death, highlighting the need for careful monitoring and supportive care during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. Douma, LH., Lalezari, F., van der Noort, V., 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06110793?draw=2&rank=1

A Study of Lenvatinib, Pembrolizumab, and Fulvestrant in ... The purpose of this study is to test whether the combination of lenvatinib, pembrolizumab, and fulvestrant is a safe and effective treatment that causes few ...

2. mskcc.org mskcc.org/cancer-care/clinical-trials/23-274

A Phase 1b/2 Study of Lenvatinib, Pembrolizumab, and ... Researchers are assessing the effectiveness of the combination of lenvatinib, pembrolizumab immunotherapy, and fulvestrant to treat advanced breast cancer.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-11123

Lenvatinib with Pembrolizumab and Fulvestrant for the ... Giving lenvatinib in combination with pembrolizumab and fulvestrant may be be safe and effective and cause few or mild side effects in patients with ER+ HER2- ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05181033

Lenvatinib+Letrozole Versus Fulvestrant in Metastatic ER+ ... The purpose of this study is to determine if the combination therapy of letrozole (an anti-hormonal drug) and lenvatinib (a targeted therapy), when compared to ...

5. researchgate.net researchgate.net/publication/392687567_Abstract_P4-08-05_A_Phase_IbII_trial_of_Lenvatinib_plus_Pembrolizumab_plus_Fulvestrant_in_ERHER2-_Metastatic_Breast_Cancer_MBC

Abstract P4-08-05: A Phase Ib/II trial of Lenvatinib plus ... Background: The prognosis for endocrine-resistant ER+/HER2- MBC remains poor and novel therapeutic strategies are urgently needed.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11557168/

Narrative review on efficacy and safety of anti- ... Another study (NCT03222856) (88) has found that the treatment of pembrolizumab plus eribulin leads to good treatment results among HR-positive, ...