Future Looks Bright in Endometrial Cancer, With Exciting Emerging Agents and Targets

Shannon N. Westin, MD, MPH, FACOG

The treatment of patients with endometrial cancer is shifting away from the use of chemotherapy to more novel modalities, according to Shannon N. Westin, MD, MPH, FACOG, as the disease offers the opportunity for more personalized approaches.

"The bottom line is that we're hitting a dead end with chemotherapy. There is certainly still a benefit to our patients [with this approach], but we're really moving into a different direction," said Westin. "We have the opportunity in endometrial cancer to be more focused, based on the molecular expression of a patient. Of all the gynecologic cancers, this is one of the better opportunities to be more precision medicine—focused and not just treat every single patient the same way."

In an interview with OncLive during the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies^™, Westin, director of Early Drug Development and Phase I Trials in the Department of Gynecologic Oncology and Reproductive Medicine of the Division of Surgery at the University of Texas MD Anderson Cancer Center, discussed future directions in endometrial cancer.

OncLive: The field is shifting away from the use of chemotherapy as a systemic treatment to the use of other modalities. How is precision medicine being used in this space?

Westin: I'm excited. We are in such a great place with endometrial cancer. It used to be that we didn't get much attention from many of the companies that are making the cool novel agents. However, now everyone realizes that endometrial cancer has such a wealth of targets that it makes so much sense to really focus on [the use of] precision medicine for this particular cancer type. More and more [often], we're seeing amazing results. Whenever we get more amazing results, more people are interested in studying the disease, which is a boon to our patients.

Attacking the cancer via the HER2 pathway has proven to be pretty successful in recent years. Could you speak to some of the success that has been seen?

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, and colleagues, presented an update of their research at the 2020 SGO Annual Meeting. This was a trial that combined the standard-of-care, paclitaxel and carboplatin, with trastuzumab (Herceptin). They were really smart; they did a very good job of selecting the right patient population. What we know is that HER2 is more highly overexpressed in a specific subtype of endometrial cancer called uterine serous. As such, investigators only enrolled [patients with] uterine serous carcinoma and they selected them based on their HER2 expression. [Patients] had to have either 3-plus protein expression on immunohistochemistry or they could have 2-plus, but then they had to demonstrate FISH overamplification of HER2. If they had those molecular criteria, they were allowed to enroll on the trial.

The trial randomized patients to receive standard chemotherapy versus chemotherapy plus trastuzumab. Results demonstrated really impressive progression-free survival outcome improvement. [That finding] had already been published a couple of years ago. At SGO, investigators re-presented those data with further follow up, and that [benefit] was still confirmed. However, even more exciting, was that an overall survival benefit was also observed. We don't really see that [too much] in uterine cancer, so that was really exciting.

The one caveat is they included any chemotherapy-naïve uterine serous tumor, so they had a population that was only stage III and IV and [some patients received this as] up-front treatment and then a population of patients [had recurrent disease]. The benefit definitely seemed to be more profound for those patients who were being treated in the up-front setting; that did seem to be driving both of the survival outcomes. A benefit was still observed in the recurrent setting, but it was not as profound.

What are some of the other novel targets and agents that are being examined?

As far as other targets, we were very fortunate. Uterine cancer has a number of targetable abnormalities. We've seen a lot done with the PI3K pathway, which is a really common pathway that is aberrant in about 80% of endometrial cancers. We're seeing really interesting combinations around that [pathway]; this includes a combination with everolimus (Afinitor), which targets mTOR, which is part of that pathway, and letrozole. Either drug on its own is okay in uterine cancer, but the combination together [is a completely different story]. In a selected endometrial cancer population, specifically endometrioid cancer, we see wonderful response rates and they’re durable. That combination is actually [being examined] in a trial right now in comparison with chemotherapy to determine whether we can get rid of chemotherapy in the up-front setting for this population and instead use a more targeted therapy.

What's going on with immunotherapy?

Of course, I'd be remiss if I didn't talk a little bit about immunotherapy; there’s a lot of excitement around this approach in endometrial cancer. We know in endometrial cancer, about 20% to 30% [of patients' tumors] are going to have microsatellite instability—high (MSI-H) disease, so they're eligible for single-agent checkpoint inhibition. At SGO, we saw an update of the GARNET trial, which was evaluating a drug called dostarlimab, a PD-1 inhibitor. The investigators saw really beautiful response rates of about a little over 40% in tumors that were MSI-H.

That's 1 population; the rest of the population is the patients with microsatellite stable (MSS) disease. About 70% to 80% of all uterine tumors are going to be MSS. However, we were really excited to see the data from Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center, regarding the combination of lenvatinib (Lenvima) with pembrolizumab (Keytruda). That [approach] does seem to help achieve that sensitivity to the checkpoint inhibition in those tumors that don't have microsatellite instability.

Investigators demonstrated durable and deep responses [with this combination]. In these patients, when they respond, their duration of response has not even been reached yet. [Based on these data, that combination] did receive an FDA approval for an indication in those with MSS disease. That drug combination is actually being evaluated in a trial right now that is comparing it with chemotherapy.

We are really excited to see all these nonchemotherapy options coming into the mainstream. It will be interesting to see the results of those trials.

What are some of the emerging targets that are generating excitement?

The ones we discussed are definitely the biggest splashes, but there's a number of other really cool targets that are a little bit earlier [in development] and are not quite ready for prime time. Investigators presented their data of a Wee-1 inhibitor, adavosertib (AZD 1775), which is an agent that can target a p53 mutation indirectly. Basically, [the agent] plays on the cell's inability to repair its DNA. Investigators demonstrated about a 30% response rate [with the agent] in uterine serous tumors that are more likely to have that p53 mutation. It will be very interesting to see [more data with this agent]; this was just a single-arm study, a small study, but very intriguing results.

Additionally, a lot of data are coming out regarding PARP inhibition, which, of course, is very "hot" in ovarian cancer; however, what we found is that uterine cancers can express the same gene aberrations in the homologous recombination pathway that might make them sensitive to inhibition with PARP. Those are just some of the cool things that are coming down the pike.

What are some of the key challenges that are still faced in this disease?

One thing, that's a good problem to have, is that the majority of these patients do very well. As such, there's a growing patient population that does have advanced stage or recurrent disease. This does make it tricky to ensure that we're designing trials appropriately and utilizing our resources correctly to best serve our patients.

The other issue is an issue that we face across many solid tumors: What does a molecular aberration mean? If you get a biopsy on a patient at diagnosis and you find these 3 mutations, is that still relevant 3 years later when they're experiencing a recurrence? Do we have to keep doing these biopsies and these expensive sequencing tests or can we look at things like liquid biopsies and circulating tumor cells? Is that going to be the wave of the future? To date, in endometrial cancer, we just don't know how relevant those changes are; that is always a struggle.

Also, a lot of times, these amazing precision medicines [that we have] can sometimes come with many adverse events, a lot of toxicity. [Combinations] such as lenvatinib/pembrolizumab or [drugs such as] adavosertib can have toxicities; that’s not to say that [these events are] worse than [those seen with] chemotherapy, but they're not necessarily better either. Practitioners are trying hard to understand how to get out in front of these problems, how to prevent them, and how to ensure that patients tolerate a treatment that could really help them.

Many times, what can happen is, a patient can be a on a great drug combination but if she doesn't tolerate it from the beginning, she may decide to come off that treatment, even if it's working for her. As such, it's really on us to ensure that we're managing those toxicities and mitigating them where we can so that our patients can achieve the benefit that they deserve.

Where is research headed?

We're doing some early work around the androgen receptor, which is kind of exciting. Most people, when they think of androgen, they think of prostate cancer, which is appropriate. Several drugs target that androgen receptor. We're doing a trial that is combining chemotherapy with a drug called enzalutamide (Xtandi) that targets the androgen receptor. The reason for that is because when we looked at data from the Cancer Genome Atlas and the Cancer Proteome Atlas, we found that androgen receptor is actually higher expressed in endometrial cancer as compared with prostate cancer—this is just really an eye-opening thing. As such, we thought, "Huh. This drug may just work." To this end, we do have a nice ongoing pilot study that is combining that drug with chemotherapy. It is too soon to tell what that might mean but we are really trying to explore new directions and new targets when we can.