Immunotherapy for newly diagnosed endometrial cancer

For the first time ever, investigators are studying immunotherapy for patients with newly diagnosed endometrial cancer. The trial uses pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor. The drug is currently approved by the Food and Drug Administration for treatment of advanced melanoma and metastatic non-small-cell lung cancer.

“Pembrolizumab has been studied in patients with relapsed endometrial cancer, but our trial is the first to use it as an initial treatment for the disease,” says Katherine Fuh, MD, PhD, a gynecologic oncologist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Investigators plan to enroll nine patients with type 2 endometrial cancer. Unlike patients with type 1 endometrial cancer, those with type 2 disease have a poor prognosis and a high risk of recurrence.

“The large majority of endometrial cancers are type 1, which is thought to be caused by excess estrogen, often in obese women,” says gynecologic oncologist Premal Thaker, MD, the trial’s principal investigator. “These cancers are most often detected early because the excess estrogen leads to vaginal bleeding.” Thaker notes that patients with type 2 endometrial cancer usually don’t have obesity or diabetes, or other comorbidities, and may not have a long period of bleeding. “They tend to be thin, otherwise healthy women, and their cancer has commonly spread outside the uterus by the time it is discovered,” Thaker says.

Endometrial cancers have high tumor-mutational burden. “These mutations can generate a novel protein sequence that will be recognized as foreign by the immune system,” Fuh says. “The new protein sequences, or neo-antigens, potentially can elicit an immune response against the cancer—a situation that informs our rationale for this trial.” Pembrolizumab, Fuh says, works by inhibiting tumors from evading the immune response and allowing the immune system to do its job.

Study participants will receive two cycles of intravenous pembrolizumab three weeks apart before undergoing surgery to remove the cancer. They will then receive standard treatment—usually a combination of chemotherapy and radiation—followed by four additional cycles of pembrolizumab as a maintenance therapy.

“Immunotherapy for gynecological cancers is still in its infancy,” Thaker says. “But lots of women are dying of advanced-stage endometrial cancers, and immunotherapy has the potential to prevent that.”

Investigators will compare the study participants’ outcomes to those of historical controls. They also will take two biopsies from each patient’s uterus—one before the initial pembrolizumab dose and a second at the time of surgery. By comparing the samples, they can determine whether the drug affects the cancer.

“There aren’t many other disease sites that lend themselves to getting multiple biopsies easily,” Thaker says. “But because we can, we have the ability to understand how this treatment impacts the tumor microenvironment. That is part of what makes this trial novel, and hopefully it ultimately will make an impact for patients.”