Treatments for advanced endometrial cancer have progressed and improved with the use of immunotherapy with chemotherapy.
In November 2021, Stephenie Black-Grant, a 50-year- old artist who lives in Orlando, Florida, was in Iowa caring for her father when she found a lump at the base of her neck near her collarbone. She soon learned she had a recurrence of the endometrial cancer that had been diagnosed years before. Her doctors planned to start this round of treatment with radiation followed by the immunotherapy drug Keytruda (pembrolizumab).
But the medical center’s radiation department was running behind and while it was able to map her egg-sized tumor, it couldn’t schedule her treatments. Finally, her doctor decided to start Keytruda while they waited.
“Before my second (Keytruda) treatment,” Black-Grant says, “the doctor comes into the exam room, she’s on her laptop while asking me questions about how I’m feeling. And me and the nurses are grinning because you can barely see the lump in my neck. So I was just waiting. She finally looks up and she almost falls off the freaking stool. It was hilarious. And I’m laughing. And when I laugh really hard, I still cough. So we are all just laughing and coughing and laughing.”
Black-Grant was already able to breathe a bit better, didn’t need morphine for her pain and was able to lie down again. She knew that at the very least, they’d have to remap the tumor if they planned to do radiation because it was much smaller. This was all from a single treatment of Keytruda.
Black-Grant’s experience is the result of some exciting new drugs and studies that are bringing about a shift in how doctors treat advanced endometrial cancer.
According to Dr. Linda R. Duska, gynecologic oncologist and professor of obstetrics and gynecology at the University of Virginia in Charlottesville, endometrial cancer is the most common gynecological cancer and is almost always symptomatic. It’s usually caught in the early stages by bleeding, staining or vaginal discharge in postmenopausal women and heavier bleeding or intermittent bleeding in premenopausal women. Cancers confined to the uterus can almost always be cured with surgery and radiation therapy.
Dr. Brian Slomovitz, director of gynecologic oncology at Mount Sinai Medical Center in Miami Beach, Florida, and professor at Florida International University, and the Uterine Cancer Clinical Trial Lead for GOG Foundation/ GOG Partners, says symptoms of advanced disease can include pelvic pain, abdominal swelling and an early sense of satiety or fullness.
An endometrial cancer diagnosis usually includes a uterine biopsy or sampling from a dilation and curettage procedure. Then the doctor may recommend scans to determine whether tumors have spread outside the uterus. If so, these patients receive a diagnosis of advanced disease.
Advanced and recurrent endometrial cancer cases have historically been treated with chemotherapy – combination carboplatin/ paclitaxel – and in some patients, trastuzumab and hormonal therapy.
Black-Grant’s story started 21 years earlier, in 2000, when heavy menstrual bleeding led to a diagnosis of uterine polyps that were treated with a dilation and curettage (D&C) procedure and progesterone tablets.
Then in 2017, Black-Grant began having pelvic discomfort and abdominal pressure. She started spotting, but her periods were still regular so she brushed it off. In 2020, her gynecologist performed a hysterectomy and removed three fibroids and a sizable uterine tumor. She received a diagnosis of stage 3, grade 3 advanced endometroid adenocarcinoma and had six months of chemotherapy as well as internal and external radiation that she described as painful and hard on her body.
According to Dr. Ramez N. Eskander, gynecologic oncologist and associate professor at the University of California San Diego, things began to change in uterine cancer research in 2013 when scientists began to understand the various subtypes of endometrial cancer. Among the discoveries, they found that certain tumors were categorized as hypermutated or mismatch repair deficient (dMMR) while others were less mutated or mismatch repair proficient (pMMR). Approximately 30% of endometrial cancers are dMMR, according to a study published in the journal Cancers.
In 2015, Eskander says Dr. Dung Le of Johns Hopkins Medicine presented a pivotal study that showed a type of immunotherapy medication called a checkpoint inhibitor (Keytruda) worked well on colon cancer tumors that were dMMR. Researchers hypothesized that these same checkpoint inhibitors would be effective for women with dMMR endometrial tumors.
In 2017, Keytruda received Food and Drug Administration approval for use on dMMR tumors found in any part of the body. This was big news, but what about people with tumors that were pMMR?
Duska says dMMR tumors that are hypermutated can be thought of as “hot” and pMMR tumors with fewer mutations as “cold”, implying that the higher number of mutations and resulting protein alterations can better stimulate the immune system and make immunotherapy more effective. Since we know that Keytruda works on hot tumors, we need to make cold tumors hot so that Keytruda works.
“There are different ways you can make a cold tumor hot,” Duska says. “You could do it with anything that disrupts the tumor’s microenvironment (the neighborhood of cells in which the tumor lives). So that can be radiation, chemotherapy or you could do it with a tyrosine kinase inhibitor, which is what lenvatinib (Lenvima) is.”
Dr. Vicky Makker, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, was the lead author on the KEYNOTE-775 trial for patients with advanced endometrial cancer who had experienced a recurrence after prior chemotherapy.
Half these patients received additional chemotherapy alone and the other half received Keytruda and Lenvima without chemotherapy. Overall, Keytruda plus Lenvima reduced the risk of disease progression by 44% and the risk of death by 38%. This worked for patients with dMMR or pMMR tumors.
According to Slomovitz, this shows that immunotherapy can be used in all patients with endometrial cancer as a second-line treatment after progressing on prior chemotherapy.
“Based on these studies, we need to investigate whether, at least in some patients, if immunotherapy can be moved to the first line,” he says.
In March 2023, the results of the NRG-GY018 trial, led by the National Cancer Institute with Eskander as lead author, were released. In the study of patients with advanced-stage endometrial cancer, one group started chemotherapy plus placebo. The other group received chemotherapy plus Keytruda.
The study found that 30% of the patients had dMMR tumors and of that group, 74% who received Keytruda were alive without progression of their cancer 12 months later while only 38% of the placebo group could say the same. But that wasn’t all. They also looked at the results for patients with pMMR tumors.
“Not only did we see a paradigm shift in the (dMMR) patients with that 70% reduction,” Eskander says, “but even in the (pMMR) patients, we saw statistically significant and clinically meaningful improvement in progression-free survival with a 46% reduction in the risk of disease progression or death.”
Around the same time, the RUBY study results were released at the European Society for Medical Oncology Virtual Plenary. This similar study found that using immunotherapy and chemotherapy for the treatment of advanced endometrial cancer previously treated with chemotherapy significantly improved progression-free survival (the time during and after treatment when a patient with cancer lives with the disease without worsening).
Eskander says the next step is to incorporate immunotherapy with chemotherapy-naive patients at initial diagnosis.
“Both RUBY and GY-018 were game- changing trials,” Slomovitz says. “Statistically, the results are some of the most convincing that we have seen in gynecologic cancers, ever. Not only were the results presented at major conferences on the same day, but they were also published in The New England Journal of Medicine simultaneously. As far as medical breakthroughs go, you can’t get better than that. We’re looking forward to FDA approval to incorporate immunotherapy in the first-line management for women with endometrial cancer.”
Trials such as LEAP-001 will determine if doctors can use a combination of Keytruda and Lenvima instead of chemotherapy for first-line management.
One study Slomovitz is watching is the LEAP trial that will determine whether Keytruda and Lenvima, the combination that is approved in the second-line setting, works better in a first-line setting than chemotherapy. Researchers are also investigating whether patients with dMMR tumors can be treated with Keytruda alone in the first-line setting and whether there are any biomarkers that would indicate who benefit from such treatment.
Duska expresses some caution.
“We were all very excited about the results from these trials,” she says. “It’s wonderful news for the MMR-deficient group for sure. In the MMR-proficient group, I think we still need to wait for the mature overall survival (the time from treatment until death of any cause) data from RUBY. I think we need to wait to see what things look like when we move immunotherapy into the front line instead of chemo. And then we need to think carefully about how we’re going to use immunotherapy in the second line if we’ve already used it in the first line.”
Black-Grant said the Keytruda did make her extremely tired, and she had frequent nausea, which was new for her. She also had some digestive and bowel issues that weren’t unusual but had become more bothersome. One side effect she really struggled with was itchy rashes.
“The side effects for immunotherapies, the checkpoint inhibitors, are well tolerated,” Slomovitz says. “Sometimes they can cause immune-related types of side effects like colitis, diarrhea or thyroiditis or cystitis, but in general they’re pretty well tolerated.”
Valerie Smith, a pseudonym to protect her privacy, was diagnosed with stage 3 clear cell advanced endometrial cancer in 2019 when she was in her late 50s, after years of symptoms and illnesses that required frequent doctors’ visits and painful procedures. She had surgery in February 2020 and underwent six chemotherapy treatments in the early days of the COVID-19 pandemic.
“It was overwhelming,” Smith says. “With mandatory isolation I was stripped of my ability to socially engage. I was experiencing isolation and a life-threatening event. It was traumatic.”
Smith says chemotherapy brought the usual side effects and hit her with nausea and vomiting that was hard to control even with antinausea meds.
Then she had 28 rounds of radiation that left her with the “most horrendous UTI (urinary tract infection) I’ve ever experienced.” She couldn’t even stand up to get to the medical center to provide a sample.
The one group that continues to be difficult to treat is women with high-risk histologies including uterine serous cancers and carcinosarcomas, Slomovitz says.
“Even though we’re getting better in the first-line management of all women with endometrial cancers,” Slomovitz says, “We still have very limited treatment options for those women with the aggressive histologies. And we find those types of histologies are more likely to affect Black women. That may be one
of the reasons why, in fact, Black women are more likely to die of this disease. We are committed to finding better treatment options for all women and to overcome disparities in our treatment options.”
Smith is one of these women. “No, the immunotherapies are not warranted in my case if there is a recurrence,” Smith says.
Finding out why Black and Hispanic women are more likely to receive a diagnosis of advanced or recurrent stage disease with high-risk histologies is something that Duska believes researchers need to explore further and understand so they can address the disparities. This is most likely to be done by helping Black and Hispanic women enroll in clinical trials.
Black-Grant never needed radiation the second time around. These days, she sees her oncologist a few times a year for scans that show she is still clear of disease.
Both women, Black-Grant and Smith, are active with the Endometrial Cancer Action Network for African-Americans (ECANA) and part of the Sister Study, which provides peer support to African- American women in treatment for endometrial cancer. Black-Grant is also on the ECANA board.
Smith is doing her best to recover physically, emotionally and financially. She wants all women to know that a cancer diagnosis isn’t anyone’s fault and that they should make sure they are receiving the best care possible.
“Because I didn’t know what I was doing at the onset,” Smith says. “And this was a total, total surprise. I did not receive the best care at the onset, so I had to become my own advocate, which is not an easy task.”
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