Pembrolizumab + Trastuzumab + Chemotherapy for Gastric Cancer

Recruiting at 191 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Steroids, Diuretics, Immunosuppressants, others

Disqualifiers: CNS metastases, Autoimmune disease, Cardiac disease, 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: 3

Duration: Up to 63 months

738 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

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

Research shows that adding pembrolizumab to trastuzumab and chemotherapy significantly reduces tumor size and improves response rates in HER2-positive gastric cancer. Trastuzumab combined with chemotherapy has already been shown to improve survival in HER2-positive gastric cancer patients. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Trastuzumab, and Chemotherapy safe for treating gastric cancer?

The combination of chemotherapy drugs like 5-FU, capecitabine, and cisplatin with trastuzumab has been studied for gastric cancer, showing some survival benefits but also high rates of side effects like neutropenia (low white blood cell count) and neutropenic fever. S-1, another chemotherapy drug, combined with cisplatin, has shown a favorable safety profile compared to 5-FU, with common side effects including anemia, vomiting, and fatigue. Safety data for Pembrolizumab in this specific combination is not detailed in the provided studies. ^{2 6 7 8 9}

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

This drug combination is unique because it targets HER2-positive gastric cancer by combining pembrolizumab, an immune checkpoint inhibitor, with trastuzumab, which targets the HER2 protein, and chemotherapy, potentially improving outcomes for patients with this specific type of cancer. ^{3 10 11 12 13}

What is the purpose of this trial?

The study will compare the efficacy and safety of pembrolizumab plus trastuzumab in combination with standard of care (SOC) chemotherapy versus trastuzumab in combination with SOC chemotherapy in participants with HER2-positive gastric cancer. The primary hypotheses of the study are that pembrolizumab plus trastuzumab in combination with chemotherapy is superior to trastuzumab plus chemotherapy in terms of 1) progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), and 2) overall survival (OS).

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with untreated advanced HER2+ gastric or GEJ adenocarcinoma. Participants must have measurable disease, be in good physical condition (ECOG 0-1), and expect to live more than 6 months. They should have proper organ function and agree to use contraception. Exclusions include recent radiotherapy, other active cancers within 5 years, autoimmune diseases treated in the past 2 years, infections needing systemic therapy, poorly controlled diarrhea, significant cardiac issues or hypersensitivities.

Inclusion Criteria

Has measurable disease as defined by RECIST 1.1 as determined by the site investigator

I agree to use contraception as required.

My cancer is advanced stomach or GEJ cancer that has not been treated and is HER2 positive.

Exclusion Criteria

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

I have another cancer that has gotten worse or needed treatment in the last 5 years.

I have had fluid buildup needing drainage or water pills in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab or placebo plus trastuzumab in combination with standard of care chemotherapy every 3 weeks

Up to 63 months

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 63 months

Treatment Details

Interventions

• 5-FU
• Capecitabine
• Cisplatin
• Oxaliplatin
• Pembrolizumab
• Placebo
• S-1
• Trastuzumab

Trial Overview The study tests if pembrolizumab plus trastuzumab with standard chemotherapy works better for HER2+ gastric cancer than just trastuzumab with chemotherapy. It measures how long patients live without their cancer getting worse (PFS) and overall survival (OS). Patients are randomly assigned to receive either the new combination of drugs or the current standard treatment.

Participant Groups

Group I: Japan Trastuzumab + S-1 Plus Oxaliplatin Experimental Treatment 4 Interventions

Participants received matched placebo to pembrolizumab IV Q3W plus trastuzumab (8mg/kg loading dose, 6mg/kg maintenance thereafter) IV Q3W in combination with SOX chemotherapy.

Group II: Japan Pembrolizumab + Trastuzumab + S-1 Plus Oxaliplatin Experimental Treatment 4 Interventions

Participants received 200 mg pembrolizumab IV every 3 weeks (Q3W) plus trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance thereafter) IV Q3W in combination with SOX chemotherapy.

Group III: Global Pembrolizumab + Standard of Care First Course Experimental Treatment 6 Interventions

Participants received 200 mg pembrolizumab IV every 3 weeks (Q3W) plus trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance thereafter) IV Q3W in combination with investigator's choice of FP or CAPOX chemotherapy.

Group IV: Global Standard of Care Active Control 6 Interventions

Participants received matched placebo to pembrolizumab IV Q3W plus trastuzumab (8mg/kg loading dose, 6mg/kg maintenance thereafter) IV Q3W in combination with investigator's choice of FP or CAPOX chemotherapy.

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 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

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

Findings from Research

In Korea, patients with advanced gastric cancer who undergo D2 resection benefit from postoperative adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin, indicating a potential effective treatment strategy in this population.

Trastuzumab is now part of the standard chemotherapy for gastric cancers that overexpress the HER2 protein, highlighting the importance of targeted therapies in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for advanced gastric cancer: review and update of current practices. Park, SC., Chun, HJ.[2023]

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]

Pembrolizumab (Keytruda) received FDA accelerated approval for treating recurrent gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1, based on a multicenter trial involving 259 patients, showing a 13.3% overall response rate.

The treatment was associated with common side effects like fatigue and decreased appetite, and serious adverse reactions included pneumonia and pulmonary embolism, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1. Fashoyin-Aje, L., Donoghue, M., Chen, H., et al.[2021]

In a study of 44 previously untreated patients with advanced gastric cancer, the combination of cetuximab and XELOX chemotherapy resulted in a significant overall response rate of 52.3%, with median progression-free survival of 6.5 months and overall survival of 11.8 months.

The treatment was generally safe, with most side effects being mild to moderate (grade 1 or 2), such as anemia and asthenia, and serious hematologic toxicities were rare, indicating that cetuximab combined with XELOX is a viable first-line option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Kim, C., Lee, JL., Ryu, MH., et al.[2021]

The Phase III KEYNOTE-811 study is designed to evaluate the efficacy and safety of pembrolizumab combined with trastuzumab and chemotherapy in patients with advanced HER2-positive gastric cancer, a group with limited treatment options and poor prognosis.

Pembrolizumab has shown promising antitumor activity in previous studies, suggesting that its combination with trastuzumab and chemotherapy could improve outcomes for patients with this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Chung, HC., Bang, YJ., S Fuchs, C., et al.[2021]

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]

References

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

Targeted Therapies in Advanced Gastric Cancer. [2021]

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

Advanced gastric cancer: an update and future directions. [2021]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Chemotherapy for advanced gastric cancer: review and update of current practices. [2023]

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

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study). [2022]

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

A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. [2021]

8. England pubmed.ncbi.nlm.nih.gov

The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP). [2021]

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

Pharmaceutical care for patients undergoing s-1 plus Cisplatin therapy for unresectable recurrent gastric cancer. [2013]

10. England pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. [2021]

11. England pubmed.ncbi.nlm.nih.gov

A remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy: A report of two cases. [2023]

12. 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]

13. Japan pubmed.ncbi.nlm.nih.gov

[A Case in Which Trastuzumab Combined Chemotherapy Was Effective for Recurrence of Post-Operative Gastric Cancer with Partial HER2 Overexpression]. [2020]