Pembrolizumab + Trastuzumab + Chemotherapy for Esophageal Cancer

Recruiting in Palo Alto (17 mi)

+11 other locations

Overseen by Yelena Janjigian, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study to find out whether adding trastuzumab and pembrolizumab to standard chemotherapy is an effective treatment for resectable HER2+ esophagogastric cancer.

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.

What data supports the effectiveness of the drug combination of Pembrolizumab, Trastuzumab, and Chemotherapy for esophageal cancer?

Research shows that combining Pembrolizumab with Trastuzumab and chemotherapy can significantly reduce tumor size and improve response rates in patients with HER2-positive gastric or gastro-esophageal junction cancer, which is similar to esophageal cancer. Pembrolizumab has also been approved for use in esophageal cancer, indicating its potential effectiveness.

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Is the combination of Pembrolizumab, Trastuzumab, and Chemotherapy safe for humans?

Pembrolizumab and Trastuzumab have been used safely in humans for various cancers, including esophageal cancer, often in combination with chemotherapy. These treatments are generally considered safe, but like all cancer treatments, they can have side effects, which should be discussed with a healthcare provider.

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What makes the drug combination of pembrolizumab, trastuzumab, and chemotherapy unique for esophageal cancer?

This drug combination is unique because it combines pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with trastuzumab, a targeted therapy for HER2-positive cancers, and chemotherapy, potentially offering a more effective treatment for HER2-positive esophageal cancer compared to using these drugs individually.

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Eligibility Criteria

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.

Trial Timeline

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

Participant Groups

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.

Group I: Participants with Esophagogastric Cancer Experimental Treatment 4 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Pennsylvania (Data Collection Only) Philadelphia, PA

Memorial Sloan Kettering Cancer Center @ Suffolk-Commack (Limited protocol activity) Commack, NY

MD Anderson Cancer Center (Data Collection Only) Houston, TX

Massachusetts General Hospital (Data Collection Only) Boston, MA

More Trial Locations

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center Lead Sponsor

Genentech, Inc. Industry Sponsor

Merck Sharp & Dohme LLC Industry Sponsor

References

1. Italy 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. [2023] Therapies that target specific tumor drivers or immune checkpoints are increasingly explored for esophageal cancer patients. This review addresses developments in therapies with targeted anti-human epidermal growth factor receptor 2 (HER2) agents and immune checkpoint inhibitors in patients with stage IV esophageal cancer. First-line palliative treatment with the anti-HER2 agent trastuzumab in combination with chemotherapy has been approved for use in patients with HER2 positive gastro-esophageal adenocarcinoma. Neoadjuvant chemoradiotherapy plus perioperative trastuzumab however has not demonstrated a survival benefit in advanced esophageal cancer patients eligible for surgery. Potentially better responses are expected with dual agent anti-HER2 therapy instead of monotherapy. In the metastatic setting, the antibody-drug conjugate trastuzumab deruxtecan is effective after progression on trastuzumab. Nivolumab and pembrolizumab, antibodies blocking the programmed cell death 1 (PD-1) receptor on T cells, have recently gained approval for clinical use in esophageal cancer patients for specific indications. Synergistic effects might be achieved with combinations of immune checkpoint inhibitors that target PD-1 on T cells or PD ligand 1 (PD-L1) on tumor cells and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) receptor on T cells. Multiple clinical trials investigating combinations of targeted and immunotherapies, with or without (neo)adjuvant chemo(radio)therapy, for curative and palliative treatment, are underway, and are expected to deliver a long-awaited improvement in the prognosis of esophageal cancer patients.

2. China pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020] Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are recommended by the National Comprehensive Cancer Network (NCCN): trastuzumab for patients with esophageal/esophagogastric or gastric adenocarcinomas with HER2 overexpression and ramucirumab, a VEGFR-2 inhibitor, as a second-line therapy for metastatic disease. However, recent reports of increases in overall and progression-free survival for agents including pertuzumab, apatinib, and pembrolizumab will likely increase the use of targeted biologic therapy in clinical practice for esophageal and gastric malignancies.

3. England pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). [2021] To investigate the safety and activity of preoperative pembrolizumab combined with chemoradiotherapy for resectable oesophageal squamous cell carcinoma (ESCC) (ClinicalTrials.gov number, NCT03792347).

4. England pubmed.ncbi.nlm.nih.gov

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. [2022] Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6-19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023] Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

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

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. [2023] Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease.

8. England 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. [2021] Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer.

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

Immuno-oncology for esophageal cancer. [2021] Esophageal cancer (EC) is the seventh most common cancer, with a poor prognosis for metastatic EC patients and limited effective drugs for treatment. Nivolumab and pembrolizumab, monoclonal antibodies that inhibit interactions of PD-1 and its ligand (PD-L1), which induce lymphocyte activation, have antitumor activity. The ATTRACTION-3 trial compared nivolumab with taxane after first-line chemotherapy and demonstrated superior overall survival (OS) for esophageal squamous cell carcinoma. The KEYNOTE-181 trial that compared pembrolizumab with chemotherapy demonstrated superior OS for EC with a PD-L1 combined positive score ≥10. Trials to evaluate efficacy of combined cytotoxic agents and immune checkpoint inhibitors (ICI) as first-line chemotherapies, ICI-containing chemoradiotherapy, and pre/postoperative chemotherapy are ongoing and might provide important data to improve clinical outcomes.