Advanced or Recurrent Endometrial Cancer Patients Have New Hopeful Combination Therapy Option

Dostarlimab-gxly is approved for metastatic and recurrent endometrial cancer in cases where chemotherapy did not not work. It is also approved as part of a first treatment for patients who have a specific set of genetic mutations called mismatch repair-deficiency (dMMR) or microsatellite instability-high (MSI-H). These genetic factors are associated with a much greater response to the check-point inhibitor class of drugs.

For gynecologic oncologists like Dr. Deanna Gerber, this is very exciting news:

“Treatment of metastatic or recurrent endometrial cancer is relatively difficult for us as oncologists,” says Dr. Gerber from NYU Langone Hospital–Long Island, Perlmutter Cancer Center. “So any advances in the way that we treat endometrial cancer are always welcome.”

Related: Next-Generation Sequencing Helps Understand Genetic Mutations in Endometrial Cancer 

What Is Endometrial Cancer?

Endometrial cancer is sometimes referred to as uterine cancer. It starts in the inner lining of the uterus, called the endometrium, according to the American Cancer Society.

The lifetime risk of an American woman developing endometrial cancer is about 2.8%. Around 60,000 new cases are diagnosed every year in the US.

Who Benefits From This Combination Therapy?

A study published in 2023 showed that dostarlimab-gxly is incredibly effective for metastatic or recurrent endometrial cancer patients who are mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), when used in combination with chemotherapy.

Here is what all that means:

• Metastatic or recurrent endometrial cancer means your cancer is advanced or has come back.
• Mismatch repair deficiency (dMMR) means your cells have a genetic mutation that inhibits your DNA’s ability to correct replication errors. This can result in an increased risk of certain cancers. But it also means you tend to respond well to immunotherapy. It is now standard to test for dMMR when diagnosed with endometrial cancer.
• Microsatellite instability-High (MSI-H) means there is a big accumulation of dMMR errors, silencing other proteins’ abilities to stop cancer cells from multiplying. DMMR/MSI-H cancers appear to be uniquely susceptible to immune checkpoint inhibitors like dostarlimab-gxly.
• The chemotherapies given approval “in combination” with dostarlimab-gxly are carboplatin and paclitaxel.

Related: SurvivorNet Clinical Trial Finder

The Benefits of Immunotherapy for Endometrial Cancer

For many years, treatment of advanced or recurrent endometrial cancer has not changed much, according to Dr. Gerber. But recently, immunotherapies have helped significantly expand effective treatment options for this group of patients:

“The addition of immunotherapy such as dostarlimab to standard chemotherapy has shown a progressive progression-free survival benefit and overall survival benefit in all endometrial cancer patients. Especially those who have mismatch repair (dMMR),” Dr. Gerber says.

• Progression free-survival means the amount of time until your cancer comes back or progresses.
• Overall survival is the measurement from the time of diagnosis until someone passes away from the disease.

A study showed the median progression-free survival was 30.3 months versus 7.7 months for those not given the drug. Overall survival at 24 months was  71% in the immunotherapy group  compared with 56% in the other group.

How Dostarlimab-gxly is Administered

According to the FDA, the dosage for dostarlimab-gxly is as follows:

• 500 mg every 3 weeks for 6 doses with carboplatin and paclitaxel, followed by 1,000 mg monotherapy every 6 weeks until disease progression or unacceptable toxicity, or up to 3 years.
• Dostarlimab-gxly should be administered before chemotherapy when administered on the same day.
• Administered as an IV infusion in conjunction with chemotherapy every three weeks before it is administered alone (as a monotherapy) for an additional 6 weeks. This will be done until the cancer has come back or if side effects become too much.
• Depending on your cancer center, it will be administered at the hospital or a outpatient infusion center.

Side effects could include:

• Gastrointestinal issues
• Fatigue
• Anemia
• Rash
• Hypertension

“Before and after you’re treated with any new agent you will be checking in with your oncologist,” Dr. Gerber says. “So that we can assess your toxicities or any side effects and make sure that we’re addressing them appropriately and determining if it’s safe for you to continue with the treatment.”

Related: Understanding the Different Types of Endometrial Cancer

Another Hopeful Combination Therapy

A separate immune checkpoint inhibitor combination therapy also could be helpful for some advanced endometrial cancer patients. A study with pembrolizumab (brand name Keytruda) used in combination with chemotherapies paclitaxel (brand name Abraxane) and carboplatin injections showed very similar results to the dostarlimab-gxly combination therapy.

In the pembrolizumab-chemotherapy study, dMMR patients who received immunotherapy and chemotherapy saw a 70% reduction in risk of disease progression at the 12-month follow up. Those who were mismatch repair proficient (pMMR) who received the immunotherapy-chemotherapy combo lived on average 13.1 months without their cancer progressing. That’s compared to 8.7 months for those who received only chemotherapy.

PMMR disease makes up “a large chunk of endometrial cancer patients,” said Dr. Ramez Eskander, lead author of the study and gynecologic oncologist at UCSan Diego Health.

He added that experts in the field “haven’t been able to identify effective therapeutic strategies” for this population.

But with this study, the researchers “saw a 46% reduction in the risk of disease progression or death” for pMMR patients.

“Hopefully these findings will translate into our ability to incorporate immunotherapy for both the dMMR and the pMMR patients,” Dr. Eskander said.

“The magnitude of the benefit that was seen for many of these patients was profound,” said Dr. Carol Aghajanian, chief of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center. Dr. Aghajanian oversaw the trial and was the study’s senior author.

The pembrolizumab-chemo combination therapy is not yet approved by the FDA, but pembrolizumab alone is FDA-approved to be used in dMMR advanced or recurrent endometrial cancers in cases where chemotherapy does not work. If the combination therapy is approved, Dr. Gerber sees it as just another opportunity to benefit her patients:

“Having two new drugs approved in this setting for advanced or recurrent endometrial cancer is great because at certain times an insurance company may approve one and won’t approve another. And so having different options is always great for the patient.”

Questions to Ask Your Doctor

• Is my endometrial cancer mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H)
• How can that impact my treatment options?
• What are the potential benefits of this therapy?
• What are the potential side effects?
• How can we modify treatment if my side effects are bad?

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