Lenvatinib + Pembrolizumab + Chemotherapy for Gastroesophageal Cancer

(LEAP-015 Trial)

Not currently recruiting at 229 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Corticosteroids, Immunosuppressive drugs

Disqualifiers: CNS metastases, Autoimmune disease, HIV, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for advanced gastroesophageal cancer, which affects the stomach and the tube connecting it to the mouth. The researchers aim to determine if adding two drugs, lenvatinib (a targeted therapy) and pembrolizumab (an immunotherapy), to standard chemotherapy can help patients live longer and slow cancer growth more effectively than chemotherapy alone. Eligible participants have advanced gastroesophageal cancer that cannot be surgically removed and is not HER-2 positive, meaning it lacks a certain protein that can influence treatment options. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering patients access to promising treatments.

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, it mentions that participants must have adequately controlled blood pressure, which may imply continuing antihypertensive medications. 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 combining lenvatinib and pembrolizumab with chemotherapy has been studied for safety in patients with advanced cancers. These studies found that this treatment helped patients live longer without their cancer worsening.

However, some patients experienced side effects. Common issues included stomach problems like an upset stomach or diarrhea. Considering these side effects is important for those thinking about joining a trial with this treatment.

The safety of this treatment is still under study, but as it is in a later phase of clinical trials, evidence suggests it is generally well-tolerated. Additionally, pembrolizumab is already approved for other conditions, providing some reassurance about its safety. Always discuss with your doctor what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of lenvatinib, pembrolizumab, and chemotherapy for gastroesophageal cancer because it offers a multi-faceted approach to treatment. Unlike standard chemotherapy, this combination includes pembrolizumab, an immunotherapy that helps the body's immune system attack cancer cells more effectively. Lenvatinib, a targeted therapy, works by inhibiting pathways that cancer cells use to grow and spread, adding another layer of attack against the cancer. This innovative combination aims to improve outcomes by addressing the cancer from multiple angles, potentially leading to better survival rates and quality of life for patients.

What evidence suggests that the treatments in this trial could be effective for gastroesophageal cancer?

This trial will compare two treatment approaches for advanced gastroesophageal cancer. One group of participants will receive a combination of lenvatinib, pembrolizumab, and chemotherapy. Studies have shown that this combination significantly increases the time patients live without their cancer worsening and reduces tumor size. Another group will receive chemotherapy alone. Research indicates that adding pembrolizumab to standard chemotherapy has demonstrated strong effects against tumors. Overall, these findings suggest that the combination treatment may be more effective than chemotherapy alone for this type of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic gastroesophageal adenocarcinoma who haven't had treatment for it before. They should have a good performance status, not be pregnant or breastfeeding, and willing to use effective contraception. People can't join if they've had certain treatments, surgeries recently, other cancers within 5 years, severe allergies to study drugs, uncontrolled health issues like high blood pressure or diarrhea.

Inclusion Criteria

My cancer can be measured on scans.

My cancer is a type that started in the stomach or esophagus and has spread.

My organs are functioning well.

Exclusion Criteria

I needed treatment for fluid buildup in my chest or abdomen recently.

I have a history of hepatitis B or active hepatitis C.

I am at risk for or have had significant GI bleeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Approximately 12 participants are treated with lenvatinib in combination with pembrolizumab and chemotherapy to assess dose-limiting toxicities

3 weeks

Frequent monitoring visits

Main Study Treatment

Participants receive lenvatinib plus pembrolizumab plus chemotherapy or chemotherapy alone

Up to 2 years

Regular visits every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 31 months

What Are the Treatments Tested in This Trial?

Interventions

• 5-FU
• Capecitabine
• Lenvatinib
• Leucovorin
• Oxaliplatin
• Pembrolizumab

Trial Overview The trial tests the combination of Lenvatinib plus Pembrolizumab with chemotherapy against chemotherapy alone in patients with gastroesophageal cancer. It aims to see if this combo improves overall survival and slows disease progression compared to just chemo.

How Is the Trial Designed?

Group I: Lenvatinib + Pembrolizumab + Chemotherapy Experimental Treatment 6 Interventions

Participants receive lenvatinib administered orally (PO) every day (QD) in combination with pembrolizumab intravenously (IV) every 6 weeks (Q6W) plus chemotherapy with either capecitabine and oxaliplatin (CAPOX) or chemotherapy with 5-FU, leucovorin, and oxaliplatin (mFOLFOX6). Induction with lenvatinib 8 mg QD plus pembrolizumab (400 mg Q6W) plus chemotherapy (CAPOX or mFOLFOX6) will be administered for 2 cycles (approximately 12 weeks), followed by consolidation with lenvatinib 20 mg QD plus pembrolizumab (400 mg Q6W) for 16 cycles. A cycle is 6 weeks (42 days).

Group II: Chemotherapy Experimental Treatment 4 Interventions

Participants receive chemotherapy with either CAPOX Q3W or mFOLFOX6 Q2W. A cycle is 6 weeks (42 days).

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

Approved in United States as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in European Union as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in Canada as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Japan as Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead 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

Eisai Inc.

Industry Sponsor

Trials

524

Recruited

161,000+

Founded

Eisai Inc. was established in 1995 as the U.S. subsidiary of Eisai Co., Ltd.

Headquarters

Woodcliff Lake, NJ, USA

Known For

Neurology and Oncology

Top Products

Aricept (donepezil), Lenvima (lenvatinib), Leqembi (lecanemab), Halaven (eribulin)

Lynn Kramer

Eisai Inc.

Chief Medical Officer since 2019

MD

Tatsuyuki Yasuno

Eisai Inc.

Chief Executive Officer since 2023

MBA from Kellogg School of Management, Northwestern University; Bachelor of Political Science from Waseda 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 a phase III study involving 232 patients with advanced oesophageal, gastric, and pancreatic cancer, the FLP chemotherapy regimen showed comparable efficacy to the FP regimen, with similar tumor response rates and overall survival times.

The FLP regimen had a significant safety advantage, with lower rates of severe mucositis (4.5% vs. 16.4% in FP), suggesting it may be a preferable alternative for patients requiring first-line chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial). Duffour, J., Bouché, O., Rougier, P., et al.[2013]

In a phase III trial (KEYNOTE-590), pembrolizumab combined with cisplatin and fluorouracil (FP) showed superior efficacy compared to FP alone for treating advanced esophageal cancer, resulting in a mean gain of 0.86 life-years and 0.77 quality-adjusted life-years (QALYs).

The cost-effectiveness analysis indicated that pembrolizumab plus FP is a viable treatment option, with an incremental cost-effectiveness ratio of $147,097 per QALY, which is acceptable given the willingness-to-pay threshold of $150,000 per QALY in the US healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective. Qu, T., Zhang, S., Zhong, Y., et al.[2022]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

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]

In a phase III trial involving 1,886 patients with stage III colon cancer, the combination of capecitabine and oxaliplatin (XELOX) demonstrated a manageable safety profile, with treatment-related adverse events occurring at similar rates to the standard treatment of fluorouracil/leucovorin (FU/LV).

Patients receiving XELOX experienced less diarrhea and alopecia but had higher rates of neurosensory toxicity and hand-foot syndrome compared to those on FU/LV, indicating that while XELOX is generally well-tolerated, it may have specific side effects that need monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. Schmoll, HJ., Cartwright, T., Tabernero, J., et al.[2022]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

In a phase II trial involving 111 patients with metastatic gastroesophageal adenocarcinoma, the combination of FOLFIRI and ramucirumab did not meet the primary endpoint of a 6-month overall survival rate of ≥65%, achieving only 54%.

While overall survival rates were similar between FOLFIRI plus ramucirumab and paclitaxel plus ramucirumab, FOLFIRI showed better objective response rates and progression-free survival, particularly in patients previously treated with docetaxel, suggesting potential for further investigation in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel - results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO. Lorenzen, S., Thuss-Patience, P., Pauligk, C., et al.[2023]

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 meta-analysis of 1231 patients, pembrolizumab and paclitaxel showed no significant difference in effectiveness for treating advanced gastroesophageal cancer, with similar objective response rates.

Both treatments can be considered viable options for patients, as they provide comparable time to response and similar rates of partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. Swed, S., Shaheen, N., Hafez, W., et al.[2022]

Biologic therapies, particularly those targeting HER2 and VEGF, are showing promise in treating esophageal and gastric cancers, with trastuzumab and ramucirumab currently recommended by the NCCN for specific patient groups.

Recent studies indicate that other agents like pertuzumab, apatinib, and pembrolizumab may improve overall and progression-free survival, suggesting a growing role for targeted biologic therapies in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. Samson, P., Lockhart, AC.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00748

The Phase III, Randomized LEAP-015 Study Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or ...

2. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-015-trial-evaluating-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-combination-with-chemotherapy-in-patients-with-certain-types-of-ga/

Merck and Eisai Provide Update on Phase 3 LEAP-015 ... The KEYTRUDA plus LENVIMA-based regimen demonstrated a statistically significant improvement in progression-free survival (PFS), one of the study's dual ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4001

Lenvatinib plus pembrolizumab and chemotherapy versus ... Pembrolizumab plus lenvatinib and chemotherapy vs chemotherapy provided statistically significant improvement in PFS and ORR in pts with advanced unresectable ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572187/

LEAP-014: first-line lenvatinib + pembrolizumab + ... Pembrolizumab has shown antitumor activity in patients with advanced esophageal cancer, and the addition of pembrolizumab to standard-of-care chemotherapy may ...

5. pulmonologyadvisor.com pulmonologyadvisor.com/news/mixed-results-for-pembrolizumab-lenvatinib-in-advanced-gastroesophageal-cancer-trial/

Mixed Results for Pembrolizumab/Lenvatinib in Advanced ... Findings showed at the interim analysis, pembrolizumab/lenvatinib treatment statistically significantly improved PFS and objective response rate ...

6. nature.com nature.com/articles/s41598-025-99773-4

Gastrointestinal adverse events associated with Lenvatinib ... Existing studies confirm that gastrointestinal AEs are prevalent among patients receiving lenvatinib alone or in combination with pembrolizumab ...

7. onclive.com onclive.com/view/pembrolizumab-plus-lenvatinib-and-chemo-misses-os-end-point-in-gastroesophageal-adenocarcinoma

Pembrolizumab Plus Lenvatinib and Chemo Misses OS ... Pembrolizumab plus lenvatinib with chemotherapy did not significantly improve overall survival in HER2-negative gastroesophageal adenocarcinoma ...

8. eisai.com eisai.com/news/2025/news202505.html

Eisai and Merck & Co., Inc., Rahway, NJ, USA Provide ... The LENVIMA plus KEYTRUDA-based regimen demonstrated a statistically significant improvement in progression-free survival (PFS), one of the study's dual ...