Chemotherapy plus immunotherapy improves outcomes in patients with advanced endometrial cancer

Endometrial cancer, which makes up about 90% of uterine cancers, will be diagnosed in more than 65,000 people in the United States this year. It is the fourth most common cancer in women and is one of the few cancers that is increasing in incidence and mortality. Unfortunately, very few treatments have been developed specifically for endometrial cancer.

Now, new research published March 27, 2023, in The New England Journal of Medicine finds adding the immunotherapy drug pembrolizumab (Keytruda^®) to standard chemotherapy greatly improves patient outcomes in both patients whose tumors have a genetic alteration leading to mismatch repair (MMR) deficiency and those whose tumors are classified as MMR-proficient. The trial was sponsored by the National Cancer Institute and conducted by NRG Oncology, a National Clinical Trials Network group. Physician-scientist Carol Aghajanian, MD, Chair of the NRG Oncology Gynecologic Cancer Committee and Chief of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center (MSK), oversaw the trial.

The magnitude of the benefit that was seen for many of these patients was profound."

Dr. Carol Aghajanian, the paper's senior author

The results were also presented at the Society of Gynecologic Oncology's annual meeting by the paper's first author, Ramez Eskander, MD, of the University of California San Diego.

Endometrial cancer clinical trial results and MMR patient representation

There were 816 patients enrolled in the multicenter international trial. They were divided into two independent cohorts (groups): those with tumors that were MMR-deficient and those with tumors that were MMR-proficient.

There was a 70% improvement in progression-free survival (the time it takes for the cancer to recur or progress) in the group with MMR deficiency. Even among patients whose tumors were MMR-proficient, adding the immunotherapy reduced the risk of the cancer progressing by 46%.

"Endometrial tumors are very heterogeneous," Dr. Ahgajanian says, noting these cancers include many different kinds of cells. "It is important to know the molecular type of a patient's tumor when studying this disease."

All of the patients had advanced or metastatic (stage 3 or 4) cancer. Some were newly diagnosed and some had seen their cancer return after earlier treatments -; surgery or a combination of surgery and radiation, surgery and chemotherapy, or all three treatments.

The side effects of the treatment were as previously reported for chemotherapy and pembrolizumab.

Previous MSK research showed checkpoint inhibitor immunotherapy could work against MMR-deficient tumors

Pembrolizumab is a type of immunotherapy drug called a checkpoint inhibitor. The immune system has checkpoints, like brakes, which prevent immune cells from attacking a person's own body. A checkpoint inhibitor takes the brakes off the immune system, enabling it to better see and fight cancer. Research led by MSK physician-scientist Luis Diaz Jr., MD, Head of MSK's Division of Solid Tumor Oncology, has shown that patients whose tumors have MMR defects are more likely to respond to checkpoint inhibitors.

Endometrial cancer has one of the highest rates of MMR defects among all solid tumors.

Advancing research on new endometrial cancer treatments

Based on the research of Dr. Diaz and others, pembrolizumab is already approved for patients with MMR defects who have failed other treatments, regardless of what type of cancer they have. "This treatment is different, because it looks at giving immunotherapy earlier in the course of disease," Dr. Aghajanian explains. "We know that we can have a greater impact on cancer by moving the most effective treatments earlier, before patients have had other treatments."

She adds that, currently, other than immune checkpoint inhibitors for patients with MMR-deficient tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, only one treatment has been approved by the U.S. Food and Drug Administration specifically for endometrial cancer. That treatment, a combination of pembrolizumab and the targeted drug lenvatinib (Lenvima^®), was approved in 2021 based on a clinical trial led by MSK gynecologic oncologist Vicky Makker, MD.

Dr. Aghajanian stresses the importance of doing more research on endometrial cancer. "Despite it being the fourth most common cancer among women, endometrial cancer is ranked 24th in terms of the amount of funding it receives from the National Cancer Institute," she says. "There is still so much we don't know."