Pembrolizumab + Lenvatinib + Chemo for Esophageal Cancer

Not currently recruiting at 266 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Previous therapy, Adenocarcinoma, CNS metastases, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination to determine if it can more effectively treat metastatic esophageal cancer. The study compares the effects of pembrolizumab (an immunotherapy drug) and chemotherapy alone to a combination of pembrolizumab, lenvatinib (a targeted therapy drug), and chemotherapy, focusing on which treatment extends patient survival. Individuals with a confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus, who have not yet received treatment, might be suitable candidates for this trial. As a Phase 3 trial, it represents the final step before FDA approval, offering patients access to potentially groundbreaking treatments.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you must have adequately controlled blood pressure with or without antihypertensive medications, and there are restrictions on certain treatments like immunosuppressive therapy and live vaccines. It's best to discuss your specific medications with the trial team.

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 your blood pressure should be controlled with or without medication, and there are restrictions on certain treatments like immunosuppressive therapy and live vaccines before starting the trial.

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

Research shows that the combination of pembrolizumab and lenvatinib, when used with chemotherapy, is generally well-tolerated by patients. In earlier studies, patients experienced manageable side effects, meaning reactions were usually not severe or unexpected for cancer treatments. The LEAP-014 trial also found side effects at acceptable levels, encouraging for potential participants.

Overall, other studies have demonstrated that the combination of pembrolizumab and lenvatinib has a reasonable safety profile. Those considering participation should note that these treatments have been studied extensively, though individual reactions can vary. Discussing any concerns with a doctor is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine pembrolizumab, an immune checkpoint inhibitor, with lenvatinib, a targeted therapy, and traditional chemotherapy. Pembrolizumab helps the immune system attack cancer cells more effectively, while lenvatinib targets specific pathways that tumors use to grow and spread. This combination is unique because it brings together immune system activation and targeted therapy, potentially offering a more comprehensive attack on esophageal cancer compared to standard chemotherapy alone. This approach could lead to improved outcomes by tackling the cancer from multiple angles, which is why researchers are eager to see the results.

What evidence suggests that this trial's treatments could be effective for esophageal cancer?

Research has shown that using pembrolizumab with lenvatinib and chemotherapy yields promising results for treating esophageal cancer. In this trial, one group will receive pembrolizumab, lenvatinib, and chemotherapy, which led to significant tumor shrinkage in 86% of patients in previous studies. Another group will receive pembrolizumab with chemotherapy alone. Previous research indicates that 67% of patients remained alive after 12 months when treated with lenvatinib, pembrolizumab, and chemotherapy. However, this combination did not significantly increase survival time compared to pembrolizumab with chemotherapy alone, with average survival times of 17.6 months versus 15.5 months. Despite these mixed results, the combination of pembrolizumab and lenvatinib shows potential in improving treatment response for esophageal cancer. ^{2 5 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 metastatic squamous cell carcinoma of the esophagus. Participants must have controlled blood pressure, adequate organ function, and agree to contraception if applicable. Exclusions include adenocarcinoma of the esophagus, significant bleeding risks, recent major surgery or radiotherapy, active infections like Hepatitis B/C or HIV, weight loss over 20% in last 3 months, and certain cardiovascular diseases.

Inclusion Criteria

My organs are functioning well.

My blood pressure is 150/90 or lower, and my medication hasn't changed in the last week.

I am not pregnant, breastfeeding, and if able to have children, I use effective birth control or practice abstinence.

Exclusion Criteria

I have received treatment for advanced esophageal cancer that cannot be surgically removed.

I have cancer that has spread to my brain or spinal cord.

I have had serious heart problems in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Participants receive pembrolizumab plus lenvatinib plus FP or TP to assess dose-limiting toxicities, safety, and tolerability

3 weeks

Induction Treatment

Participants receive pembrolizumab plus lenvatinib plus chemotherapy for initial treatment

12 weeks

Consolidation Treatment

Participants receive pembrolizumab and lenvatinib until progressive disease or discontinuation

96 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 53 months

What Are the Treatments Tested in This Trial?

Interventions

• 5-FU
• Cisplatin
• Lenvatinib
• Oxaliplatin
• Paclitaxel
• Pembrolizumab

Trial Overview The study tests pembrolizumab plus lenvatinib with chemotherapy against pembrolizumab with chemotherapy alone in first-line treatment for metastatic esophageal cancer. The goal is to see which combination improves overall survival (OS) and progression-free survival (PFS) better.

How Is the Trial Designed?

Group I: Part 2: Pembrolizumab + Lenvatinib + Chemotherapy Experimental Treatment 8 Interventions

In the induction phase, participants receive pembrolizumab 400mg intravenously (IV) every 6 weeks (Q6W) for 2 cycles (each cycle length = 6 weeks) plus Lenvatinib 8 mg orally (PO) once daily (QD) plus chemotherapy with FP (cisplatin 80 mg/m\^2 and 5-FU 4000 mg/m\^2) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2) IV every 3 weeks for 4 administrations or mFOLFOX6 (oxaliplatin 85 mg/m\^2, 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2, and leucovorin 400 mg/m\^2 \[or levoleucovorin 200 mg/m\^2\] once every 2 weeks \[Q2W\] for 6 administrations at the investigator's discretion (approximately 12 weeks). In the consolidation phase, participants receive pembrolizumab 400 mg IV Q6W for 16 cycles (each cycle length = 6 weeks) and Lenvatinib 20 mg PO until progressive disease or discontinuation (approximately 96 weeks).

Group II: Part 1: Pembrolizumab + Lenvatinib + Chemotherapy Experimental Treatment 5 Interventions

In the induction phase, participants receive pembrolizumab 400mg intravenously (IV) every 6 weeks (Q6W) for 2 cycles (each cycle length = 6 weeks) plus Lenvatinib 8 mg orally (PO) once daily (QD) plus chemotherapy with FP (cisplatin 80 mg/m\^2 and 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2) IV every 3 weeks for 4 administrations at the investigator's discretion (approximately 12 weeks). In the consolidation phase, participants receive pembrolizumab 400 mg IV Q6W for 16 cycles (each cycle length = 6 weeks) and Lenvatinib 20 mg PO until progressive disease or discontinuation (approximately 96 weeks).

Group III: Part 2: Pembrolizumab + Chemotherapy Active Control 6 Interventions

Participants receive pembrolizumab 400 mg IV every 6 weeks for 18 cycles (each cycle length = 6 weeks, approximately 2 years) plus chemotherapy with FP (cisplatin 80 mg/m\^2 IV Q3W for up to 6 administrations \[up to \~18 weeks\] and 5-FU 4000 mg/m\^2 IV Q3W for up to 35 administrations \[up to \~2 years\]) or TP (paclitaxel 175 mg/m\^2 and cisplatin 75 mg/m\^2 Q3W for up 6 administrations \[up to \~18 weeks\]) or in combination with mFOLFOX6 (oxaliplatin 85 mg/m\^2, 5-FU 400 mg/m\^2 followed by 2400 mg/m\^2 and leucovorin 400 mg/m\^2 \[or levoleucovorin 200 mg/m\^2\] IV Q2W for up to 52 administrations \[approximately 2 years\]).

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 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]

Nivolumab and pembrolizumab, both PD-1 inhibitors, have shown improved overall survival in patients with esophageal cancer, particularly in trials like ATTRACTION-3 and KEYNOTE-181, which involved patients with esophageal squamous cell carcinoma and those with high PD-L1 expression, respectively.

Ongoing trials are exploring the effectiveness of combining immune checkpoint inhibitors with traditional chemotherapy and radiotherapy, which may lead to better treatment options and outcomes for esophageal cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immuno-oncology for esophageal cancer. Yamamoto, S., Kato, K.[2021]

Esophageal cancer, particularly adenocarcinoma, is increasingly common, with over half of patients presenting with metastatic disease, making palliative chemotherapy a crucial treatment option.

Recent studies show that weekly irinotecan and cisplatin is a highly effective and less toxic regimen for treating both adenocarcinoma and squamous cell carcinoma, while paclitaxel also shows promise with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in esophageal cancer. Enzinger, PC., Ilson, DH., Kelsen, DP.[2022]

In a feasibility study involving 16 patients with oesophageal cancer, the combination of paclitaxel, cisplatin, and 5-fluorouracil (5-FU) showed significant activity, with 25% of patients achieving pathological complete remission after surgery.

However, the treatment regimen resulted in high levels of toxicity, with 62.5% of patients experiencing severe side effects, leading to the conclusion that this specific dosing schedule is not safe for routine clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of preoperative combined modality treatment for locally advanced operable oesophageal carcinoma: toxicities and long-term outcome. Mukherjee, S., Abraham, J., Brewster, A., et al.[2019]

A 65-year-old female patient with metastatic endometrial cancer developed grade 2 esophagitis likely related to lenvatinib treatment, which was characterized by dysphagia and mucosal lacerations in the esophagus.

The patient's symptoms improved significantly after stopping lenvatinib and starting a proton pump inhibitor (PPI), allowing for a successful resumption of lenvatinib at a reduced dose without recurrence of esophagitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esophagitis as a complication of the combination of lenvatinib and pembrolizumab for advanced endometrial cancer: A case report. Fellouah, M., Auclair, MH., Fortin, S., et al.[2023]

In a study of 28 patients with unresectable or recurrent esophageal squamous cell carcinoma (ESCC), the combination of S-1 and paclitaxel (S1/PTX) showed a response rate of 14.8%, with a median overall survival time of 306 days, indicating some clinical efficacy in this difficult-to-treat population.

While S1/PTX was generally well-tolerated, severe neutropenia occurred in 13 patients, highlighting the need for monitoring blood counts during treatment, although most non-hematological side effects were mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Trial of S-1 and Paclitaxel in Unresectable or Postoperative Recurrent Esophageal Squamous Cell Carcinoma Pretreated by Fluorouracil, Cisplatin, and Docetaxel Chemotherapy. Nakajima, Y., Kawada, K., Tokairin, Y., et al.[2019]

In a phase II trial involving 61 patients with advanced esophageal cancer, the combination of paclitaxel, cisplatin, and fluorouracil (5-FU) demonstrated significant antitumor activity, achieving a 48% overall response rate and a notable 20% complete response rate in patients with squamous cell carcinoma.

While the treatment showed substantial efficacy, it also resulted in severe but manageable toxicity, with 46% of patients requiring dose adjustments and 48% needing hospitalization due to side effects, highlighting the need for further optimization of dosing and scheduling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. Ilson, DH., Ajani, J., Bhalla, K., 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]

Esophageal cancer is rapidly increasing in the U.S. and is aggressive, with poor survival rates from traditional treatments like surgery or chemoradiation alone.

New trials at Memorial Sloan-Kettering Cancer Center are exploring the use of weekly paclitaxel/cisplatin and irinotecan/cisplatin, which may reduce gastrointestinal toxicity while maintaining efficacy, compared to traditional cisplatin/5-FU regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy in esophageal cancer: the Memorial experience. Anderson, SE., Minsky, BD., Bains, M., et al.[2018]

In a study of 22 patients with advanced esophageal squamous cell cancer, a chemotherapy regimen combining continuous infusional paclitaxel and 5-FU resulted in a promising overall response rate of 68.2%, with 2 complete responses and 9 partial responses.

The treatment was well-tolerated, with manageable side effects such as marrow depression, alopecia, and fatigue, indicating that this low-dose continuous infusion approach could be a safe option for patients who are not candidates for surgery or radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study on continuous infusional paclitaxel and 5-Fu as first-line chemotherapy for patients with advanced esophageal cancer. Gu, M., Li, SY., Huang, XE., et al.[2022]

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]

The combination of Nedaplatin and 5-fluorouracil (5FU) showed a response rate of 60% in assessable patients and 52.9% in all patients with advanced esophageal cancer, indicating significant efficacy in treating this condition.

The treatment was generally safe, with only three cases of grade 3 toxicity reported, suggesting that the combination therapy is well tolerated by patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new combination chemotherapy with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for advanced esophageal cancers. Yoshioka, T., Gamoh, M., Shineha, R., et al.[2019]

Citations

1. 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 ...

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

Lenvatinib plus pembrolizumab and chemotherapy versus ... Median follow-up was 32.2 mo (range 19.0 – 41.7) in pts with PD-L1 CPS ≥1 and 31.8 mo (range, 19.0 – 41.7) in all pts. ... ORR was 59.5% vs 45.4% ...

3. onclive.com onclive.com/view/lenvatinib-plus-pembrolizumab-and-chemotherapy-fails-to-improve-os-in-advanced-escc

Lenvatinib Plus Pembrolizumab and Chemotherapy Fails ... The 12- and 24-month OS rates were 67% and 36% in the investigational arm vs 63% and 31% in the control arm, respectively. “Lenvatinib plus ...

4. curetoday.com curetoday.com/view/lenvima-combo-fails-to-extend-survival-in-esophageal-cancer

Lenvima Combo Fails to Extend Survival in Esophageal ... The median OS in the Lenvima arm was 17.6 months versus 15.5 months in the chemoimmunotherapy arm. The 12- and 24-month OS rates were 65% and 34 ...

5. targetedonc.com targetedonc.com/view/lenvatinib-pembrolizumab-plus-chemotherapy-shows-manageable-toxicity-in-mescc

Lenvatinib/Pembrolizumab Plus Chemotherapy Shows ... The ORR by BICR was 86% in the lenvatinib/pembrolizumab plus FP cohort, including 1 complete response and 5 partial responses. No patients had ...

6. 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 ...

7. eisai.com eisai.com/news/2025/news202573.html

LENVIMA® (lenvatinib) Plus KEYTRUDA® ... In the primary analysis, the median OS was 17.4 months (95% CI, 14.2-19.9) for LENVIMA plus KEYTRUDA versus 12.0 months (95% CI, 10.8-13.3) for ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK603321/

Pembrolizumab (Keytruda) in Combination With Lenvatinib ... At the January 10, 2019, data cut-off date, the median OS was 16.4 months (95% CI, 13.5 to 25.9). The survival probabilities of patients at 12, 18, and 24 weeks ...