Pembrolizumab + Trastuzumab + Chemotherapy for Esophageal Cancer

Recruiting at 11 trial locations

Overseen By Yelena Janjigian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Anti-PD-1, Anti-HER2, others

Disqualifiers: Metastatic disease, Immunodeficiency, Autoimmune disorders, 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: Unknown

Duration: 12-16 weeks

49 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for esophageal and stomach cancers with high levels of HER2, a protein that can promote cancer growth. The researchers aim to determine if adding two drugs, pembrolizumab (an immunotherapy drug known as KEYTRUDA) and trastuzumab (a targeted therapy drug), to standard chemotherapy can improve treatment outcomes. The trial seeks participants diagnosed with HER2+ esophageal, GEJ, or stomach cancer who have not received prior treatment for these conditions. Participants should be eligible for complete surgical removal of their primary tumor. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 does mention that you cannot be on systemic steroid therapy or other immunosuppressive treatments within 7 days before starting the trial, unless it's a low dose or specific type like inhaled corticosteroids. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that pembrolizumab and trastuzumab are likely to be safe for humans?

Research shows that adding pembrolizumab and trastuzumab to chemotherapy is generally safe for patients. Studies have found that this combination helps patients with HER2-positive gastric cancer live longer.

One study tested this combination with chemotherapy and supported it as a first-choice treatment for some patients. Reports indicate that most patients can handle this treatment without severe side effects.

However, like any treatment, some side effects may occur. Common ones include fatigue, nausea, or mild skin reactions. Serious side effects are less common but can happen. Discuss the potential risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for esophageal cancer?

Researchers are excited about combining pembrolizumab and trastuzumab with chemotherapy for treating esophageal cancer because it offers a new approach to targeting HER2-positive tumors. Unlike standard treatments that might only focus on chemotherapy, this combination leverages pembrolizumab, an immunotherapy drug, to boost the body's immune system to fight cancer cells. Trastuzumab, on the other hand, specifically targets the HER2 protein, which is overexpressed in some cancer cells, potentially making this combination more effective for patients with HER2-positive tumors. This targeted approach could lead to improved outcomes compared to traditional chemotherapy alone.

What evidence suggests that adding trastuzumab and pembrolizumab to standard chemotherapy could be an effective treatment for esophagogastric cancer?

Research has shown that combining pembrolizumab and trastuzumab with standard chemotherapy yields promising results for treating HER2-positive esophageal and gastric cancers. In this trial, participants will receive this combination, which studies have found significantly improves survival rates compared to using only trastuzumab and chemotherapy. Specifically, adding pembrolizumab increases the number of patients whose tumors shrink or disappear. Pembrolizumab enhances the immune system's ability to attack cancer cells, while trastuzumab targets the HER2 protein that promotes cancer growth. Together, they enhance the effectiveness of chemotherapy, offering hope for better treatment outcomes. ^{3 5 6 7 8}

Who Is on the Research Team?

Yelena Janjigian, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with HER2+ esophagogastric cancer who can potentially have their tumor completely removed by surgery. They must be in good physical condition (ECOG 0-1), agree to use contraception, and not be pregnant or breastfeeding. Their organs must function well enough to handle the treatments.

Inclusion Criteria

My esophageal or stomach cancer is HER2 positive.

My primary tumor can be completely removed by surgery.

I agree to use birth control and not donate sperm for 230 days after my last treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant pembrolizumab with trastuzumab and chemotherapy

12-16 weeks

Surgery

Participants undergo surgical resection of the tumor

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 18 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Trastuzumab

Trial Overview The study is testing if adding trastuzumab (a drug targeting HER2 proteins) and pembrolizumab (an immunotherapy drug) to standard chemotherapy improves outcomes for patients with resectable HER2+ esophagogastric cancer.

How Is the Trial Designed?

Group I: Esophagogastric Cancer Experimental Treatment 6 Interventions

Participants will have a diagnosis of resectable HER2+ (IHC 3+ or IHC 2+/FISH ratio \>2.0) esophageal, GEJ or gastric cancer.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

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

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]

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]

In the KEYNOTE-811 study, combining pembrolizumab with trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma significantly reduced tumor size and improved the objective response rate, indicating enhanced efficacy of this treatment regimen.

The study highlights that this combination therapy not only induces complete responses in some patients but also represents a promising advancement in the treatment of unresectable or metastatic HER2-positive cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Janjigian, YY., Kawazoe, A., Yañez, P., et al.[2022]

In a study of 55 patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with chemotherapy or radiotherapy showed favorable long-term survival outcomes, with a 12-month overall survival rate of 78.8%.

The treatment was found to be safe and manageable, with long-term adverse effects reported in only a small number of patients, indicating that pembrolizumab is a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. Wang, HC., Huang, X., Chen, J., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Preoperative treatment with pembrolizumab combined with chemoradiotherapy was found to be safe for 20 patients with resectable esophageal squamous cell carcinoma, with a high pathologic complete response (pCR) rate of 55.6%.

Despite some patients experiencing significant adverse events, including grade III lymphopenia in 65% of cases, the treatment did not delay surgery, indicating its feasibility for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Li, C., Zhao, S., Zheng, Y., et al.[2021]

Trastuzumab, an anti-HER2 agent, is approved for first-line treatment in HER2 positive gastro-esophageal adenocarcinoma, showing effectiveness when combined with chemotherapy, but not with neoadjuvant chemoradiotherapy for advanced cases.

Immune checkpoint inhibitors like nivolumab and pembrolizumab have been approved for specific uses in esophageal cancer, and combining these with other therapies may enhance treatment outcomes, with ongoing clinical trials exploring these combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction. Valkema, MJ., Mostert, B., Lagarde, SM., et al.[2023]

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 trial involving 37 patients with HER2-positive metastatic oesophagogastric cancer, the combination of pembrolizumab, trastuzumab, and chemotherapy resulted in 70% of patients being progression-free at 6 months, indicating promising efficacy.

The treatment was generally safe, with the most common adverse effect being neuropathy in 97% of patients, but no treatment-related deaths were reported, suggesting a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Janjigian, YY., Maron, SB., Chatila, WK., et al.[2021]

Citations

1. esmoopen.com esmoopen.com/article/S2059-7029(25)01411-5/fulltext

Pembrolizumab with trastuzumab and chemotherapy for ... While improving clinical outcomes, the addition of pembrolizumab to trastuzumab and chemotherapy did not negatively impact health-related ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8229851/

First-line pembrolizumab and trastuzumab in HER2-positive ... Adding trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer.

3. merck.com merck.com/news/keytruda-pembrolizumab-plus-trastuzumab-and-chemotherapy-significantly-improved-overall-survival-os-versus-trastuzumab-and-chemotherapy-alone-in-first-line-treatment-of-patients-with-her2-po/

KEYTRUDA® (pembrolizumab) Plus Trastuzumab and ... KEYTRUDA is the first anti-PD-1/L1 therapy in combination with trastuzumab and chemotherapy to demonstrate a statistically significant improvement in OS in ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06123338

NCT06123338 | A Study of Pembrolizumab With ... The purpose of this study to find out whether adding trastuzumab and pembrolizumab to standard chemotherapy is an effective treatment for resectable HER2+ ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.4013

Pembrolizumab plus trastuzumab and chemotherapy for ... Conclusions: Adding pembro to tras and chemo resulted in a substantial, statistically significant increase in ORR versus trastuzumab and chemo ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-her2-positive-gastric-or-gastroesophageal-junction-adenocarcinoma

FDA approves pembrolizumab for HER2 positive gastric or ... Additional outcome measures included overall response rate (ORR) and duration of response (DOR). A statistically significant improvement in OS ...

7. nature.com nature.com/articles/s41591-025-03979-y

Perioperative pembrolizumab, trastuzumab and FLOT in ... Here in the open-label, phase 2 IKF/AIO PHERFLOT trial, we evaluated the safety and efficacy of adding pembrolizumab and trastuzumab to FLOT ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2059702925014115

Pembrolizumab with trastuzumab and chemotherapy for ... Together with efficacy and safety data, these results support the use of pembrolizumab plus trastuzumab and chemotherapy as a first-line treatment option for ...