Targeted Therapies Take Aim at Endometrial Cancer

CURE, CURE® Women's Cancers 2021 Special Issue,

As more is learned about the biology of endometrial cancer, new treatment possibilities emerge.

When Jo Anne Schatz, 69, talks about the latest treatment she received for her endometrial cancer, she describes it as an “eraser.”

“It was amazing,” Schatz says. “It just wiped my cancer out.”

The drug, Keytruda (pembrolizumab), is a type of cancer treatment called immunotherapy, designed to harness a person’s immune system to identify and destroy the cancer. It is just one of the targeted treatments approved by the Food and Drug Administration (FDA) for or being developed for the treatment of endometrial cancer.

Unlike traditional chemotherapy, which acts against cancer cells and healthy cells alike, targeted treatments are aimed at specific aspects of the cancer cells.

Keytruda hitting its target is what Schatz credits with saving her life.

First Signs

Schatz, a former addiction specialist from Philadelphia, received a diagnosis of endometrial cancer in May 2015 after experiencing unexpected vaginal bleeding. She had never heard of the disease.

“My primary care doctor told me to contact my gynecologist; within two weeks, I was seeing a specialist at Fox Chase Cancer Center and headed in for a complete hysterectomy,” Schatz says.

Endometrial cancer is a disease in which cancer cells form inside the lining of the endometrium, or uterus. Vaginal bleeding and pelvic pain are common symptoms.

“Endometrial cancer is the most common of all gynecological cancers in the United States,” says Dr. Christina S. Chu, professor in the Department of Surgical Oncology at Fox Chase Cancer Center in Philadelphia. “Fortunately, the vast majority of endometrial cancers can be treated surgically with the removal of the uterus, ovaries, fallopian tubes and cervix. Most are cured with this surgery plus or minus radiation.”

Some patients — 13% — who receive a diagnosis of endometrial cancer, however, will have their disease recur. After surgery, Schatz underwent several rounds of radiation and chemotherapy to destroy any remaining cancer cells. After a brief remission, her cancer recurred, metastasizing to the peritoneal lining, and her physicians began to look for more targeted treatment options.

Find the Target

“When we started to get down to the genomic levels of these tumors, we realized that just because some endometrial cancers may look (similar) under the microscope, they may still behave biologically different based on genomic signature,” says Dr. Emily M. Ko, assistant professor of obstetrics and gynecology at Pennsylvania Hospital of Penn Medicine in Philadelphia. “Based on that genomic signature, there may be biologic pathways that we can target.”

That is what happened to Schatz, who was told that her type of endometrial cancer had a genetic component called MSI-high.

MSI stands for “microsatellite instability.” When disease is MSI-high, the cancer cells have a high number of mutations within microsatellites, which are short, repeated sequences of the DNA. These signify abnormalities in DNA repair, which can be targeted with certain drugs.

In 2017, the FDA approved Keytruda for use as a treatment for any solid tumor that was MSI-high, had progressed after prior treatment and had no satisfactory alternative treatment options.

“This was important for patients with endometrial cancer because (approximately) 30% of patients with endometrial cancer will have tumors that are MSI-high,” explains Dr. Shannon N. Westin, associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston.

One study evaluating the use of Keytruda in patients with MSI-high tumors showed that among a small group of women with endometrial cancers, more than half saw their tumor respond to the treatment, and the majority had at least some clinical benefit.

“A larger proportion of patients with endometrial cancer will have microsatellite-stable disease,” Westin says. “For those patients, there is a newer FDA-approved targeted therapy combining Keytruda with Lenvima (lenvatinib).”

Indeed, in late 2019, the FDA approved the immuno- therapy Keytruda with Lenvima for patients with endo- metrial cancer that is not MSI-high and whose disease has come back after prior chemotherapy. Lenvima is a multiple-receptor tyrosine kinase inhibitor. The drug works by blocking the action of abnormally activated proteins that signals cancer cells to multiply. A study of this combination showed that approximately one-third of endometrial tumors responded.

Finally, some patients with endometrial cancer may qualify for treatment with a drug targeting NTRK gene fusions, which are estimated to occur in only a small percentage of endometrial cancers. Rozlytrek (entrectinib) and Vitrakvi (larotrectinib) are approved for adults who have solid tumors with this specific genetic alteration.

Finding New Targets

“Not every endometrial cancer that comes back or spreads will have one of the characteristics to qualify for the currently available targeted treatments. These women may want to ask their physicians about potential alternatives,” Ko says.

Kim Bryant, 61, a former special education teacher from Texas, did just that when she was told in May 2019 that her endometrial cancer had spread. After receiving her diagnosis in March 2016, Bryant initially underwent surgery and radiation for the cancer. After its first recurrence a year later, she had additional surgery followed by radiation and chemotherapy.

“At that point, my local oncologist said he had done all he could and referred me to MD Anderson,” Bryant says. “I was given a choice between two trials. I was enrolled in one for about a year and my cancer progressed. I have had more success with the second trial.”

The second clinical trial is testing a three-drug combination of the hormone therapy Femara (letrozole); Afinitor (everolimus), a drug designed to target a protein called mTOR that promotes cell growth; and Kisqali (ribociclib), a CDK 4/6 inhibitor that is designed to interrupt the cell cycle that drives growth of cancer cells.

“CDK 4/6 inhibitors have been studied in breast cancer and are thought to potentially be synergistic when used with other hormonal drugs,” Ko says.

For her first clinical trial, Bryant had been making a four- hour drive once a week from Dallas to Houston to receive treatment. On the current trial, all three drugs are oral and can be taken at home.

“All three oral treatments (are) so much easier because there are no infusions,” Bryant says. “I only have to go down once every three months for bloodwork and other testing.”

Bryant remains on treatment and says that, so far, the cancer is responding well.

In addition to mTOR and CDK 4/6 inhibitors, clinical trials are also testing a class of drugs that inhibit poly (ADP-ribose) polymerase — more commonly known as PARP inhibitors. This class of drugs is approved for certain breast and ovarian cancers that have an inherited mutation in the BRCA gene

or have a certain genomic instability called homologous recombination deficiency (HRD), a type of DNA repair defect.

“There are a number of trials exploring these drugs alone or in combination with other targeted agents to see if there is activity in endometrial cancer,” Westin says. “Probably about 20% of endometrial cancers have mutations in BRCA or other abnormalities in HRD pathway members, but there may be other abnormalities in endometrial cancer that predict benefit, so none of the trials (is) being selective.”

There are also trials exploring other immunotherapy drugs that target a protein called PD-1 or PD-L1, immunotherapy drugs in combination with chemotherapy or other targeted agents, and agents targeted against other disease pathways such as the PI3K or MEK pathways, Westin says.

Why Target?

Right now, these targeted therapies are considered second- line treatments — given after a first disease recurrence — because they are not as effective as primary chemotherapy for most patients, according to Chu.

“Trials are ongoing to test targeted therapies in combination with chemotherapy in the first-line setting, though,” Chu says.

There have not been any completed clinical trials yet comparing the standard chemotherapy with these new targeted treatments, but they are in progress, according to Ko.

“What we are learning is that perhaps side effect profiles may be better in targeted treatment, meaning it may be worthwhile to consider an alternative targeted therapy up front in treatment rather than saving it for down the road,” explains Ko.

For example, immunotherapy drugs such Keytruda do not have the traditional side effects seen with chemotherapy, such as hair loss, nausea or vomiting. Because the drug works by attempting to stimulate the immune system, many of the side effects seen with Keytruda are related to the immune system, Chu says. Similarly, side effects seen with Lenvima, which works by affecting blood vessels, can be related to a patient’s blood vessels, such as high blood pressure.

Schatz says that during her treatment with Keytruda, she experienced muscle aches, pains and fatigue. Other common side effects associated with Keytruda include headache, fever, skin rash, constipation, loss of appetite and diarrhea.

“On chemotherapy, I was often sick for a full week, then a little better before preparing to go back for another treatment,” Schatz says. “On the trial, I was able to cook and care for myself and establish a routine.”

Bryant says that side effects during her most recent clinical trial also have been tolerable.

“I have had some decrease in appetite and some fatigue, but not enough that it keeps me from doing what I want to do,” Bryant says. “It has only slowed me down some.”

Many of the side effects related to targeted therapies can be managed easily if caught early, Westin says.

“This takes good communications between a patient and their health care team — and preparation — so that a patient knows what to look for,” Westin says.

In addition to a patient’s tumor having the right “target,” the health care team will consider these possible side effects in their decision on whether a patient might qualify for treatment with a targeted therapy.

“We look at the best data we have available, the tumor characteristics and the overall health of each patient to decide if a targeted therapy is best,” Ko says.

Advocacy

Schatz credits much of her progress not only to targeted therapy but also to advocating for herself and her treatment. She had one doctor who encouraged her to continue treatment, whereas another told her to stop. Since stopping treatment with Keytruda, Schatz has follow-up scans every four months, as well as other regular monitoring. “I am also healthier,” she says. “I am on a ‘cancer-fighting’ plant-based diet. I take it one day at a time, but I am grateful to be alive and can feel my creativity coming back.”

Bryant, too, has been able to maintain an upbeat, “glass-half-full” attitude throughout her cancer journey, she says.

“I have surrounded myself with my faith, family and friends,” she says.

Westin applauds patients such as Schatz and Bryant for raising their voices and sharing their stories about endometrial cancer.

“Other tumor types get more attention, but endometrial cancer is one of the only cancer types where the incidence is growing,” Westin says. “A lot of women with endometrial cancer will be cured, but we have to be aware of their sisters in diagnosis who do not do as well and together raise our voices to shine more light on this problem. Hopefully that will allow us to get more funding and more companies interested in exploring new agents to treat endometrial cancer.”

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