Pembrolizumab for Esophageal Cancer

Recruiting at 175 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Immunosuppressants, Steroids, Anti-PD-1

Disqualifiers: Autoimmune disease, Active infection, HIV, others

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: 3

Duration: 52 weeks

703 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the efficacy and safety of treatment with definitive chemoradiotherapy (dCRT) + pembrolizumab (MK-3475) compared to treatment with dCRT + placebo with respect to Event-free Survival (EFS) and Overall Survival (OS) in: * participants whose tumors express Programmed Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 * participants whose tumors express PD-L1 CPS ≥1 * all participants The primary study hypotheses are that dCRT+ pembrolizumab is better than dCRT + placebo with respect to: * EFS in participants whose tumors express PD-L1 CPS ≥10 * EFS in participants whose tumors express PD-L1 CPS ≥1 * EFS in all participants * OS in participants whose tumors express PD-L1 CPS ≥10 * OS in participants whose tumors express PD-L1 CPS ≥1 * OS in all participants

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive therapy or have received certain vaccines recently, you may need to discuss this with the study team.

What data supports the effectiveness of the drug Pembrolizumab for esophageal cancer?

Research shows that combining 5-fluorouracil (5-FU) and cisplatin with radiotherapy has been effective in treating esophageal cancer, with studies indicating promising response rates. Additionally, the use of similar drug combinations in chemoradiotherapy has been shown to improve outcomes compared to surgery alone. ^{1 2 3 4 5}

Is Pembrolizumab safe for treating esophageal cancer?

The studies mention that treatments involving 5-fluorouracil (5-FU) and cisplatin, which are sometimes used with Pembrolizumab, can have significant toxic effects, especially in elderly patients with esophageal cancer. However, a phase I trial with a 5-FU derivative showed it was generally safe when used with radiotherapy. ^{6 7 8 9 10}

What makes the pembrolizumab treatment for esophageal cancer unique?

Pembrolizumab is unique for esophageal cancer treatment because it is an immunotherapy drug that helps the immune system fight cancer cells, and it is used in combination with chemotherapy drugs like cisplatin and fluorouracil, which are standard treatments. This combination has shown superior effectiveness compared to chemotherapy alone for advanced esophageal cancer. ^{1 3 11 12 13}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with esophageal cancer who can't have surgery, are not pregnant or breastfeeding, and agree to use effective contraception. They should be in good physical condition (ECOG 0-1), have proper organ function, and no recent heart attacks or active infections like HIV or hepatitis.

Inclusion Criteria

I am not expected to need surgery to remove a tumor during the study.

My doctor thinks I am a good candidate for combined chemotherapy and radiation.

I am a male willing to use effective birth control or am unable to father children, and will not donate sperm during and for 90 days after the study.

Exclusion Criteria

I have had treatment for esophageal cancer before.

I haven't had major surgery in the last 28 days and don't expect to need any during the study.

I have been treated for an autoimmune disease in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab or placebo with chemotherapy and radiotherapy for up to approximately one year

52 weeks

Every 3 weeks for 8 cycles, then every 6 weeks for 5 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term follow-up

Participants are monitored for event-free survival and overall survival

Up to 72 months

Treatment Details

Interventions

• 5-FU
• Cisplatin
• Levoleucovorin
• Oxaliplatin
• Pembrolizumab
• Radiotherapy

Trial Overview The study tests if adding pembrolizumab to standard chemoradiotherapy improves survival compared to a placebo plus the same therapy. It focuses on patients whose tumors express certain levels of PD-L1 protein.

Participant Groups

Group I: Pembrolizumab+FP or FOLFOX Therapy+Radiotherapy Experimental Treatment 7 Interventions

Participants receive pembrolizumab 200 mg on Day 1 of each 3-week cycle for 8 cycles followed by pembrolizumab 400 mg on Day 1 of each 6-week cycle for 5 cycles PLUS either: * FP therapy: cisplatin 75 mg/m\^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-fluorouracil (5-FU)\] 1000 mg/m\^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m\^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gray \[Gy\] in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR * FOLFOX therapy: oxaliplatin 85 mg/m\^2 AND either leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m\^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by intravenous (IV) infusion. Total treatment duration is approximately 1 year.

Group II: Placebo+FP or FOLFOX Therapy+Radiotherapy Placebo Group 7 Interventions

Participants receive placebo on Day 1 of each 3-week cycle for 8 cycles followed by placebo on Day 1 of each 6-week cycle for 5 cycles PLUS either: * FP therapy: cisplatin 75 mg/m\^2 on Day 1 of Weeks 1, 5, 8 and 11 PLUS 5-FU 1000 mg/m\^2 per day on Days 1-4 of Weeks 1, 5, 8 and 11 OR 800 mg/m\^2/day on each of Days 1-5 at Weeks 1, 5, 8, and 11 PLUS radiotherapy (either 50 Gy in 25 fractions OR 60 Gy in 30 fractions) on Days 1-5 of each 3-week cycle OR * FOLFOX therapy: oxaliplatin 85 mg/m\^2 AND either leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 PLUS either 5-FU 400 mg/m\^2 on Day 1 of Weeks 1, 3, 5, 7, 9 and 11 OR 5-FU 800 mg/m\^2 per day on Days 1 and 2 of Weeks 1, 3, 5, 7, 9 and 11 PLUS radiotherapy (50 Gy in 25 fractions) on Days 1-5 of each 3-week cycle. All treatments except radiotherapy are given by IV infusion. Total treatment duration is approximately 1 year.

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

Findings from Research

In a phase II trial involving 24 patients with resectable esophageal carcinoma, the combination of neoadjuvant therapy using paclitaxel, carboplatin, 5-fluorouracil, and conformal radiotherapy resulted in a 57% pathologic complete response rate, indicating significant effectiveness in shrinking tumors before surgery.

The treatment showed a median overall survival of 31 months and a disease-free survival rate of 57% at 3 years, although some patients experienced significant side effects, including esophagitis and hypotension, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiotherapy for esophageal cancer using weekly Paclitaxel and Carboplatin plus infusional 5-Fluorouracil. Gannett, DE., Wolf, RF., Takahashi, GW., et al.[2022]

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 Phase II trial involving 30 elderly patients with esophageal cancer, concurrent chemoradiotherapy (CCRT) using S-1 demonstrated a 2-year overall survival rate of 45.1%, surpassing the target of 35%.

The treatment was associated with mild toxicity, with no grade 4 toxicities or treatment-related deaths, indicating that S-1 may be a safer alternative to conventional platinum-based therapies for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. Ji, Y., Du, X., Tian, Y., et al.[2022]

The maximum tolerated dose (MTD) of S-1, an oral 5-FU derivative, was determined to be 80 mg/m², with a recommended dose of 70 mg/m² for further studies, indicating a safe dosing range for elderly patients with esophageal cancer.

The treatment regimen showed promising efficacy, with an endoscopic complete response in 66.7% of patients, a median progression-free survival of 20 months, and a median overall survival of 29 months, suggesting that S-1 combined with radiotherapy is an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. Ji, Y., Qiu, G., Sheng, L., et al.[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]

In a phase 2 study involving 42 patients with advanced esophageal cancer, the combination of docetaxel, cisplatin, and 5-fluorouracil (DCF-R) showed a clinical complete response rate of 52.4%, indicating significant efficacy in treating this condition.

While DCF-R was effective, it also led to considerable side effects, including high rates of leukopenia and neutropenia, suggesting that while the treatment is promising, careful monitoring for these toxicities is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2). Higuchi, K., Komori, S., Tanabe, S., 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 study of 39 patients with locally advanced esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with neoadjuvant chemotherapy resulted in a high objective response rate of 87.2% and a disease control rate of 100%.

The treatment led to significant surgical outcomes, with a major pathological response rate of 68.2% and a complete pathological response rate of 45.5% among those who underwent radical surgery, while maintaining a manageable safety profile with only 15.4% experiencing severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. Lin, W., Huang, Y., Zhu, L., et al.[2023]

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]

References

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

Neoadjuvant chemoradiotherapy for esophageal cancer using weekly Paclitaxel and Carboplatin plus infusional 5-Fluorouracil. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Weekly Chemotherapy of 5-Fluorouracil plus Cisplatin Concurrent with Radiotherapy for Esophageal Squamous Cell Carcinoma Patients with Postoperative Locoregional Recurrence: Results from a Phase II Study. [2021]

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

Combined modality therapy in esophageal cancer: the Memorial experience. [2018]

4. China pubmed.ncbi.nlm.nih.gov

Does chemotherapy regimen matter in the neoadjuvant treatment of esophageal cancer? [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Phase I Study of Definitive Radio-chemotherapy with Cisplatin, 5-Fluorouracil and Cetuximab for Unresectable Locally Advanced Esophageal Cancer. [2017]

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

A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. [2022]

7. China pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. [2022]

8. Greece pubmed.ncbi.nlm.nih.gov

Paclitaxel and Carboplatin Versus Cisplatin and 5-Fluorouracil in Concurrent Chemoradiotherapy in Patients With Esophageal Cancer. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Pilot study of preoperative combined modality treatment for locally advanced operable oesophageal carcinoma: toxicities and long-term outcome. [2019]

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

Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2). [2022]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]

12. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. [2023]

13. New Zealand 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. [2022]