Pembrolizumab + Trastuzumab + Chemotherapy for Gastric Cancer

Not currently recruiting at 237 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding pembrolizumab, an immunotherapy drug, to the standard treatment of trastuzumab and chemotherapy is more effective and safer for individuals with HER2-positive gastric cancer. Researchers compare different combinations of these treatments to identify the best option for controlling cancer growth and improving survival rates. Individuals with untreated HER2-positive gastric cancer, particularly if the cancer is advanced or has spread, may be suitable candidates for this study. As a Phase 3 trial, this study serves as the final step before FDA approval, providing participants an opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that combining pembrolizumab and trastuzumab with chemotherapy is generally well-tolerated. Studies have demonstrated that this treatment significantly improves survival in patients with HER2-positive gastric cancer. The side effects of pembrolizumab, when used with trastuzumab and chemotherapy, align with known effects of each drug individually.

Reported side effects are typical for chemotherapy and immunotherapy, such as tiredness, nausea, and an increased risk of infections. However, the combination did not present any unexpected safety issues, suggesting it is as safe as other standard treatments for this cancer type.

The FDA has approved pembrolizumab in this combination for HER2-positive gastric cancer, supporting its safety. While clinical trials continue to assess its efficacy, current data provide a reassuring safety profile for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine pembrolizumab, a powerful immunotherapy, with trastuzumab and chemotherapy to tackle gastric cancer. Unlike the standard of care, which typically involves chemotherapy and trastuzumab only, pembrolizumab works by helping the immune system recognize and attack cancer cells more effectively. This combination approach could potentially enhance the body's ability to fight cancer by not just targeting the cancer cells directly with chemotherapy but also boosting the immune response. Additionally, the use of pembrolizumab in combination with trastuzumab in different chemotherapy regimens, like SOX in Japan, brings a tailored approach that might improve outcomes for specific patient groups.

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

Research has shown that adding pembrolizumab to trastuzumab and chemotherapy can improve outcomes for patients with HER2-positive gastric cancer. In this trial, some participants will receive pembrolizumab with trastuzumab and chemotherapy, while others will receive a placebo with trastuzumab and chemotherapy. Studies have found that the combination including pembrolizumab extends patient survival compared to trastuzumab and chemotherapy alone. Additionally, pembrolizumab with trastuzumab and chemotherapy slows cancer growth. This combination has demonstrated lasting benefits, offering hope for effectively managing advanced gastric cancer. Overall, these findings suggest that adding pembrolizumab could significantly enhance treatment success for this condition. ^{1 2 5 6 7}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/n/niceta0983/

Pembrolizumab with trastuzumab and chemotherapy ... - NCBI The clinical experts explained that treatment aims to slow progression of the disease, extend life, and maintain or improve quality of life for ...

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. nejm.org nejm.org/doi/abs/10.1056/NEJMc2408121

Pembrolizumab in HER2-Positive Gastric Cancer The addition of pembrolizumab to trastuzumab and chemotherapy in patients with gastric cancer improved both progression-free and overall survival.

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

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

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8728435/

Safety and efficacy of HER2 blockade by trastuzumab-based ... Trastuzumab-based palliative chemotherapy for HER2-positive gastric cancer: a single-center real-world data. BMC Cancer. 2021;21:325. doi: 10.1186/s12885 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03615326

Study Details | NCT03615326 | Pembrolizumab/Placebo ... The study will compare the efficacy and safety of pembrolizumab plus trastuzumab in combination with standard of care (SOC) chemotherapy versus trastuzumab ...