For Advanced Endometrial Cancer, Chemotherapy Plus Immunotherapy Improves Outcomes

Dr. Carol Aghajanian

Dr. Carol Aghajanian is Chief of Gynecologic Medical Oncology at MSK.

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,” says Dr. 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

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

In the group with MMR deficiency, the risk that their cancer would recur or progress was reduced by 70% when immunotherapy was added to their treatment. Even among patients whose tumors were MMR-proficient, adding immunotherapy reduced the risk of the cancer progressing by 46%. One year after starting the study, 38% of the patients in the chemotherapy-only group were free of cancer progression or death. However, among patients with tumors that were mismatch repair-deficient and who got chemotherapy plus immunotherapy, 74% continued to be free from cancer progression or death.

We know that we can have a greater impact on cancer by moving the most effective treatments earlier, before patients have had other treatments.
Carol Aghajanian gynecologic medical oncologist

“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.”

This research was supported by grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Funding was provided by Merck through a cooperative research and developmental agreement with the NCI. Merck also provided supplemental funding to NRG Oncology for this trial. Dr. Aghajanian and MSK co-author Roisin O’Cearbhaill are supported in part by grant P30CA008748 from the NCI.

Dr. Aghajanian has provided services to Blueprint Medicines (uncompensated).