Garg Breaks Down the Treatment Landscape in Endometrial Cancer

Ruchi Garg, MD

There have been many advances in the treatment of gynecologic malignancies over recent years. For patients with endometrial cancer, options have evolved with the phase 3 RUBY trial (NCT03981796) evaluating dostarlimab (Jemperli), the phase 3 NRG-GY018 (NCT03914612) study of pembrolizumab (Keytruda), paclitaxel, and carboplatin, and more.^1,2

According to Ruchi Garg, MD, patients diagnosed with endometrial cancer are first met with a surgical management approach, which is often followed by adjuvant therapy or observation, depending on the stage of disease. Other treatments that have made an impact in this space include immunotherapy and targeted therapy, which is an emerging option.

The molecular biology of endometrial cancer continues to be investigated and is currently an exciting space. Several trials are focused on evaluation combination therapies and the addition of immune checkpoint inhibitors to a mostly chemotherapy backbone for patients with either recurrent or primarily metastatic disease.

Therapeutic options are assessed by testing for the mismatch repair genes done through immunohistochemistry, staining 4 different mismatch repair genes, next-generation sequencing, and looking at microsatellite instability.³

In an interview with Targeted Oncology^TM, Garg, chair of gynecologic oncology at City of Hope Atlanta, Chicago, and Phoenix, discussed the evolution of the treatment landscape for patients with endometrial cancer and what trials to watch out for in the future.

Targeted Oncology: Can you broadly discuss the treatment landscape for endometrial cancer?

Garg: Most commonly, most patients will initially present with postmenopausal bleeding. That's seen in about 70% to 80% of patients. With that, a whole workup has to be ensued, including an endometrial biopsy in the patient who 1, has a high suspicion of cancer. Even if they don't, for anyone who has postmenopausal bleeding, the gold standard is to get a biopsy. Once a biopsy is done, it determines if there is endometrial cancer, the factors that we look at, or the grade of the cancer, and what's the histology, the subtype, the cellular type of the cancer, and that determines if further is needed. For example, for high-grade cancers, my routine practice is to perform a CAT scan to make sure there's no metastatic disease prior to going for a surgical option. But in lower grade cancers, we can just do a full exam and make sure there is no concern for metastatic disease prior to proceeding with surgical management.

With the surgical options, the most adopted method that we utilize is our robotic, laparoscopic minimally invasive surgery approach, where we end up doing a hysterectomy with the removal of tubes and ovaries. That's the most common method along with doing the dissection where we can talk about the variety of lymph node dissection. The newest protocol is doing something called sentinel lymph nodes, rather than doing the full lymph node dissection. In more advanced or more high-risk endometrial cancers, there is a role for doing omentectomy, which is the fatty apron that sits inside the abdomen and that can be exposed to these cancer cells as well. Subsequently, we determine, based on the pathology, whether the patient can go on observation, if they qualify, or whether they need some adjuvant therapy to decrease their risk of the recurrence of cancer.

Immunotherapy has changed the treatment landscape. What can you discuss about the role of immunotherapy in this space?

Immunotherapy has impacted endometrial cancer management. In fact, at the Society of Gynecologic Oncology meeting that was in March of this year, we had treatment changing trials that were presented including NRG GYO18 [NCT03914612] and RUBY [NCT03981796]. They both established the role of immunotherapy, even in upfront settings for endometrial cancer. Essentially, the NRG GYO18 trial, looked at [patients with] advanced endometrial cancer, stage III and IV, and looked at the use of pembrolizumab, which is 1 of the commonly used immunotherapies, along with chemotherapy, and compared that with chemotherapy. Subsequently, immunotherapy maintenance was also part of the protocol.

There was a significant progression-free survival and a difference that was noted. One of the factors that we look at is mismatch repair deficiency [MMR] in endometrial cancers. In that cohort of patients, the progression-free survival was 74% vs 38% with almost a 70% difference in relative risk essentially. However, even in the cohort that was proficient for this, for MMR, there was a progression-free survival, a difference that was noted for 13 months vs 8 months. Therefore, the new standard of care, and even NCCN guidelines, says that we should be utilizing carboplatin and paclitaxel along with pembrolizumab [Keytruda] for advanced endometrial cancers in upfront or recurrent settings when they are chemotherapy-naïve.

Similarly, the RUBY trial showed the benefit of dostarlimab along with the chemotherapy. It's a PD-1 inhibitor, and it looked at the PD-1 inhibitor combination with chemotherapy vs chemotherapy and again, found a profound effect on the [progression-free survival] where it was almost double at 36% vs 18%. It was even more pronounced in the mismatch repair deficient patients where it was about 61% vs 15% or so. Immunotherapy is now in an upfront setting. Prior to this, we had trials that showed that in recurrent settings in patients who had the mismatch repair deficiency, we should be using pembrolizumab or dostarlimab. Then also, in non-deficient or proficient MMR patients, we use a combination of lenvatinib [Lenvima] and pembrolizumab.

What can you discuss about the role of targeted therapies?

There is a lot more coming up on targeted therapies. One practice-changing one was the utilization of HER2 therapy. Trastuzumab is a commonly used drug for breast cancer, but it has been shown to be effective in patients with advanced serous type endometrial cancers. The trial that was done basically showed that there was a significant progression-free survival advantage in those patients with the utilization of HER2 therapy along with chemotherapy, and then continuation of maintenance of HER2 therapy until toxicity or progression of disease. That's been 1 of the targeted therapies that's been utilized.

Another targeted approach that's up and coming in patients with early endometrial cancer is where we are looking at the ProMisE classification, which is The Proactive Molecular Risk Classifier for Endometrial Cancer. This came about with the Cancer Genome Atlas studies that were undertaken, and in 2013, they looked at the genomic profile of the endometrial cancers and came up with 4 molecular subtypes which are the targets that have been identified. They all have shown to have a prognostic value and prediction of response to treatment and outcomes for patients.

Where this is going is that once we do the surgery or get the pathology specimen, we are hoping to get all this testing done. Then, if there are patients who have the POLE ɛ mutation tumors, then we know they have better prognosis, and then we may end up de-escalating therapy because we're finding out that we may be overshooting some of these patients just because we don't know and bucket them all. That's how the targets are being utilized. There are ongoing, large, randomized, international studies that are happening and looking at that.

Are there any ongoing trials in this space that have caught your eye recently?

[Concerning] the trials that are ongoing at our institution, one is [the] GOG-3064 trial [NCT05173987], which is a phase 3 randomized trial where it's utilizing pembrolizumab with chemotherapy in dMMR patients as first-line [therapy]. This is going to end up being a confirmatory trial for the GY018 trial. Then the other trial is GY012 [NCT03660826], which is an NRG trial. That is a randomized phase 2 study that is...a multi arm trial that's utilizing single-agent olaparib, which is a PARP inhibitor that actually is utilized in ovarian cancer patients pretty commonly. And [it is] comparing single-agent cediranib vs combination of cediranib and olaparib and then combination of olaparib and durvalumab which are...other targeted therapies. This is being utilized in recurrent and persistent endometrial cancers. ...We just had a poster for that at ASCO, so there's been some interim analysis that has been with positive outcomes.

Then there's GY025. That's another...NRG trial that's up and coming. That's a phase 2 trial that…looks at other immunotherapy and molecular markers...in [patients with] recurrent endometrial cancer. Then there's an ASCO trial, which is the TAPUR trial [NCT02693535], [including] basket trials that are occurring that are looking at specific markers. If these patients are advanced, or have recurrence, and we're looking at their specific molecular markers, and then targeting that…these are trials that are tumor agnostic, so they're not…specific to any type of tumor, they're targeting the specific markers. So, there's a lot that's happening in the space.

What unmet needs still exist in the space?

We still need a lot of clarification in the high-risk and early high-risk endometrial cancer space. The serous type and the clear cell type are the ones that we still are unsure about what to do and as to what is the best method. Sometimes it does feel like we are either over treating or under treating, and there is a trial that’s ongoing and looking at that.

Sentinel lymph nodes have been routinely implemented in patients with endometrial cancer. We definitely see the role of that in early endometrial cancer, and I think the role in advanced endometrial cancer patients, our high-risk patients, is still to be fully defined. Then, I think the other unmet need would be that if we have an approval of immunotherapy in the upfront setting, because we were always utilizing it in the recurrent setting prior to that, what is the data and what is next after if we use our immunotherapy option upfront when the patient recurs? What’s our next go to regimen? We just don’t have a clear sense of that.

What do you think is important for fellow oncologists to take away from this discussion?

There’s still a lack of patient education, even amongst community physicians and general practitioners, when a patient presents with any kind of aberrant, persistent, abnormal bleeding, even in a younger patient. Granted, the majority of endometrial cancers occur in ages between 60 and 70, or that’s when it peaks, but there are about 5% of endometrial cancers that occur in less than 40-year-olds, and more so are coming up in less than 50-year-olds. A lot of them are due to chronic anovulation and obesity, but we do need to keep genetic mutations in mind. These patients should be ruled out for Lynch syndrome, even if they don't have the genetics, and even if they don't have cancer in their family.

I will often have patients who will say, ‘I just had 1 small spotting episode last year, and then nothing else happened, so I didn't go until now, when things got worse.’ Well, if they had gone earlier, they may have had a different stage. We've seen that also with the COVID pandemic. There's been a definite effect on patients with endometrial cancer, which is a highly curable cancer in early stages. The COVID pandemic has made cancer care complex and the treatment delays that have occurred have had a huge impact.

REFERENCES:

1. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334

2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312

3. Moreira I, Bartosch C, Teixeira M, Ferreira M. Molecular classification of endometrial carcinoma: protocol for a cohort study. JMIR Res Protoc. 2022;11(8):e34461. Published 2022 Aug 4. doi:10.2196/34461