Based on encouraging preliminary data, researchers at Mayo Clinic in Rochester, Minn., are leading a randomized multi-site phase II study for adults with metastatic, recurrent, or locally advanced unresectable gastric or gastroesophageal (GE) junction adenocarcinoma that tests a novel serial approach to treating these cancers, using immunotherapy, anti-angiogenic therapy, and chemotherapy.

The primary goal of the study, SEQUEL (HCRN-GI18-333), is to evaluate the best overall response rate of the chemotherapy drug paclitaxel plus the vascular endothelial growth factor-2 (VEGF-2) inhibitor ramucirumab plus either alternating or concurrent pembrolizumab, a PD-1 inhibitor, following induction pembrolizumab in these types of cancer.

Researchers believe immunotherapy drugs, like pembrolizumab, might make tumors more sensitive to treatment with chemotherapy and drugs that target blood formation.

The study is now open to accrual at Mayo Clinic in Rochester, Minn.

“We hope we will identify a new treatment and management approach to merging immunotherapy with standard therapy in a way that makes it the most tolerable and has the highest anti-tumor effect,” said Harry Yoon, MD, sponsor-investigator of the study and a medical oncologist at Mayo Clinic. “Single agent immunotherapy only works in about 10 to 20 percent of people. So, 80 or 90 percent are not responding to immunotherapy. We think you have to combine the immunotherapy with other therapies, but it works best when done in a certain way, and that is what this study is testing.

“What is unique about this trial is how the treatment is individualized to the patient throughout the course of the study,” Dr. Yoon continued. “We developed a way that we believe is best for knowing when to move from one segment of therapy to the next, and back again, to maximize quality of life and tumor control. We learned these valuable lessons during a pilot study from our patients, who are benefitting from this treatment approach.”

Currently, there is no single first-line treatment for metastatic gastric and GE junction cancer, and the prognosis is poor. About 30 percent of people with these cancers initially have some response to treatment, but the majority of these patients will later experience a worsening of their disease, called disease progression. Second-line treatment often consists of ramucirumab and paclitaxel or other chemotherapy regimens. Patients whose tumor expresses a protein called PD-L1 may undergo a third-line treatment of pembrolizumab.

Pembrolizumab is a monoclonal antibody that blocks the PD-1 pathway that cancer cells use to hide from the body’s immune system. By blocking this pathway, pembrolizumab helps the body’s immune system recognize and fight cancer cells. Pembrolizumab is approved by the U.S. Food & Drug Administration (FDA) to treat several types of cancer, including certain types of gastric or GE junction cancers.

Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor-2 (VEGFR-2). VEGFR-2 plays a role in the formation of blood vessels that cancer cells use to grow. Ramucirumab is FDA approved to treat several cancers, including certain types of gastric or GE junction cancers.

Paclitaxel is approved by the FDA to treat several types of cancer.

Combining these drugs for the treatment of advanced gastric or GE junction cancers is not FDA approved and should be considered investigational.

The study will enroll up to 58 subjects, age 18 or older, who have metastatic, recurrent, or locally advanced unresectable gastric or GE junction adenocarcinoma.

All participants will begin the study by receiving immunotherapy with pembrolizumab. Patients who started immunotherapy are also eligible.  They will continue to receive pembrolizumab as long as their disease does not progress. Subjects whose disease progresses during induction therapy will move to the combination therapy portion of the study. Subjects who experience only mild progression and are tolerating therapy well may be eligible to continue receiving induction immunotherapy at the researcher’s discretion.

During the combination therapy portion of the study, subjects with disease progression will be randomly assigned to one of two treatment groups, called arms.

Subjects in Arm A will receive ramucirumab and paclitaxel alternating with pembrolizumab. Subjects in Arm B will receive ramucirumab and paclitaxel with concurrent pembrolizumab.

Subjects in both arms will continue the combination therapy as long as their disease does not progress and they do not experience severe side effects. Subjects may choose to discontinue treatment at any time, in consultation with their doctor.

Blood and tissue will be collected to support correlative research. Studying blood and tissue samples can help researchers identify how cancer cells respond to treatment, and why certain patients’ tumors respond better to treatment than others.

The study is supported by Merck Sharp and Dohme Corp.

For more information about this research study, including full eligibility requirements, visit www.clinicaltrials.gov (study #NCT04069273).

About Hoosier Cancer Research Network 

Hoosier Cancer Research Network (formerly known as Hoosier Oncology Group) conducts innovative cancer research in collaboration with academic and community physicians and scientists across the United States. The organization provides comprehensive clinical trial management and support, from conception through publication. Created in 1984 as a program of the Walther Cancer Institute, Hoosier Cancer Research Network became an independent nonprofit clinical research organization in 2007. Since its founding, Hoosier Cancer Research Network has conducted more than 230 trials in a variety of cancer types and supportive care, resulting in more than 350 publications. More than 9,000 subjects have participated in Hoosier Cancer Research Network clinical trials.