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In season 3, episode 7 of Targeted Talks, John Nakayama, MD, a gynecologic oncologist at Allegheny Health Network, discusses updates in the endometrial cancer treatment landscape.

In endometrial cancer treatment, there has been a rise in the use of immunotherapies like immune checkpoint inhibitors, says Nakayama. Immunotherapy has been a huge advancement in the field because historically, oncologists only had chemotherapy and bevacizumab (Avastin).

Recently, the FDA’s accelerated approval of lenvatinib and pembrolizumab for the treatment of patients with advanced endometrial cancer that is not microsatellite instability (MSI)-high or mismatch repair deficient, who have disease progression following prior systemic treatment and who are not candidates for curative surgery or radiation. According to Nakayama, this broadened the number of patients that were eligible for pembrolizumab. In the KEYNOTE-775 study, which led to the FDA approval, lenvatinib/pembrolizumab showed good activity.

The role of non-immunotherapies in endometrial cancer is changing, explains Nakayama. FDA-approved agents like everolimus (Afinitor) and bevacizumab are being pushed back in treatment sequencing. The future of endometrial cancer treatment continues to lean toward immunotherapy.

 Thank you for tuning in to another episode of targeted talks. I'm your host, Nicole Tucker. In this episode, I'm speaking with Dr. John Nakayama, a gynecologic oncologist for Allegheny Health Network about updates and the endometrial cancer treatment landscape.

| Thank you for joining me today, Dr. Nakayama. Can we begin with you discussing the most exciting change in the field in recent years?

 I think with endometrial cancer, what we're really seeing the differences is the rise of immunotherapy in particular checkpoint inhibitors. Previously, we only had you know, carbotaxol, adriamycin, maybe a little bit of bevacizumab. Immunotherapy has really changed what our options are, especially in the recurrent setting. And there are open clinical trials looking to bring it into the frontline setting.

 Thank you. And since we're on the topic of exciting news in the field, can you tell me how the combination of lenvatinib and pembrolizumab has impacted treatment since it was granted accelerated approval earlier this year?

 I think that's a great question. I feel like all we're talking about as immunotherapy. But that's, that's what it is. Every person that comes into h n, when we take out their tumor, we send it for MMR testing to see you know, do you have any loss of expression of these of these markers? And not only is that important for screening for Lynch syndrome, but it's the first step to decide, are you a good candidate for immunotherapy or not. And you can look at tumor mutational burden MSI, all that stuff that I mentioned before, but that is a small fraction of the population.

 Depending on the study that you look at, maybe around 30% of the people are going to be eligible for pembrolizumab alone. What's different about KEYNOTE-775 is that these people are the people that aren't MSI high or MMR deficient, so that is a larger fraction of the population. And the surprising thing was how high their response rates were, and that they had such a high fraction of people with the harder to treat to treat histologies like serous tumors.

 Results from a KEYNOTE-775 study, which led to the approval of lenvatinib and pembrolizumab were recently published in the 

. What are your thoughts on the study results?

 I think it's a very interesting trial, I think that, you know, it gives options to that group of people that weren't able to get pembrolizumab alone, right? It gives all those people an option with a very decent response rate.

You have to be cognizant of the kind of person that you're putting on because, you know, this, this combination does come with some toxicity. So, understanding what those toxicities are, how to manage them, and how to dose interrupt or dose reduce, it is critical to having success. Because if you don't set up the patient for success, like talking with their primary care doctor to make sure that their hypertension is well controlled, telling them that they may need to have their thyroid replaced, in terms of like Synthroid or something like that. Having all those processes in place is going to make them stain on the drug combination much more likely.

 Thank you. And what are the implications of these combined study results?

This is recurrence. So, in this study, they looked at okay, these people that did not, that did not qualify for pembrolizumab, and this is how well they did in recurrence. Well, what if they tried it in an earlier setting? Is there activity there? I kind of alluded to previously like there are multiple trials open right now they're looking at the carboplatin and Taxol backbone, and then adding in some sort of checkpoint inhibitor either with the carboplatin and Taxol or as a maintenance setting. Is it possible that it's sort of like an analogous situation like people that have a predilection for going with immunotherapy? Well, maybe they should go with pembrolizumab. Is there a role for analogous combination in an earlier setting?

 Moving along in the treatment landscape, what role does bevacizumab continue to play?

| In endometrial cancer, bevacizumab in my practice primarily is used in the recurrent setting. Its response rate is similar to what we see in with other second-line agents. It's gotten pushed back a little bit with the introduction of immunotherapy. There have been some small phase 2s that have looked at it with in combination with other drugs, But, in general, I reserve it for recurrent disease.

| What research supports your choice of when to use bevacizumab in your patients with endometrial cancer?

 The data of bevacizumab in endometrial cancer is relatively limited. There are some small phase 2 data that supports its use and in recurrent setting.

What novel therapies are you excited to see clinical trial results for?

 I think everybody was excited about the possibility of the SIENDO trial in that when they looked at selinexor. Unfortunately, it didn't meet its primary endpoint. But they did show that in the P 53. Population, that there were better outcomes. So, I'm very excited to see how they move forward with that. I think that when we think immunotherapy right now, we're talking a lot about checkpoint inhibition, which I when I talk to my patients about checkpoint inhibition. It’s kind of like that old movie spinal tap, where they go to the amp and they turn up the amp to 11 instead of 10. It turns your immune system up. But that's just kind of like a gross way to just tell your immune system to attack. What I think is more interesting right now is now they're looking at, well, let's take some of your tumor. Let's build up those tumor infiltrating lymphocytes and give them back to you. Are there any vaccine options? Maybe not from a treatment standpoint, but I think circulating tumor DNA is interesting. Maybe we can see use that as a method to detect recurrence earlier, or maybe even see if our some of our trials might be better targeted, or our treatments might be better targeted in a way that's non- invasive.

 Thank you. What improvements are still necessary in endometrial cancer treatment?

 | Well, we're never happy, right? I add every time you make an advancement. The next question is, how do you do even better? To talk about what we are improving on right now is like we just mentioned, checkpoint inhibitor immunotherapy. So, how can we improve on that? Well, we need to target the patients better. Yes, we're looking at MMR, MSI tumor mutational burden, and name your test of choice. But we know that a lot of those people, even though we think they're more likely to respond in that subgroup, we're not having the greatest response rates. Figuring out a way to determine who are the people that are really going to benefit from checkpoint inhibition is critically important. The other thing is, one of the big promises of immunotherapy is their long duration of response and some individuals and if we could figure out who those super responders are going to be, that would be a huge advantage for endometrial cancer.

 Lastly, Dr. Nakayama, what key advice can you give to your peers on how to approach endometrial cancer treatment today.

| As we all know, it's important to make sure that you have the appropriate testing done on your patients’ tumors, making sure that you have some sort of testing that's been done to look to see if they are at risk for Lynch syndrome, to see if they might be a candidate for immunotherapy. And at AHN, we're even starting to notice that they're starting to report out p53 on a lot of our endometrial cancers, which could be useful if selinexor or something like that becomes FDA approved in the future.

 We haven't really talked about it, but in the subset of people with serous uterine cancer, we're also making sure that people are screened and treated with Herceptin if that is appropriate for them.

In season 3, episode 7 of Targeted Talks, John Nakayama, MD, discusses updates in the endometrial cancer treatment landscape.

The Evolution of Endometrial Cancer Treatment 

During a Targeted Oncology™ Case-Based Roundtable™ event, Thomas J. Herzog, MD, discussed the results of the KEYNOTE-775 trial of lenvatinib plus pembrolizumab versus chemotherapy in patients with advanced endometrial cancer. 

Lenvatinib/Pembrolizumab Shows Survival Benefit in Endometrial Cancer

During a Targeted Oncology™ Case-Based Roundtable™ event, Bhavana Pothuri, MD, MS, discussed with participants their experiences managing adverse events of immunotherapy for advanced endometrial cancer.

Dosing and Toxicity: Managing Adverse Events of Single-Agent ICIs in Endometrial Cancer

A regular approval has been granted to dostarlimab for the treatment of mismatch repair deficient recurrent or advanced endometrial cancer.

FDA Approves Dostarlimab for dMMR Recurrent/Advanced Endometrial Cancer

Early findings from the phase 2 OATH trial show treatment with ONA-XR plus anastrozole elicits a 4-month progression- free survival rate of 77% and overall response rate of 22% in patients with HR-positive metastatic endometrial cancer.

ONA-XR and Anastrozole Signals Early Clinical Activity in HR+ Endometrial Cancer

During a Targeted Oncology case-based roundtable event, Robert Coleman, MD, discussed dosing of lenvatinib plus pembrolizumab in patients with endometrial carcinoma. 

Roundtable Discussion: Coleman Examines Dose Management in Endometrial Cancer

Casey M. Cosgrove, MD, an assistant professor in the Department of Gynecologic Oncology at The Ohio State University College of Medicine in Columbus, discusses biomarker-guided treatment for endometrial cancer.

According to Cosgrove, to take the next step in endometrial cancer, experts must learn from the successes shown in other cancer types. By using biomarkers, oncologists are informed about which treatment to use for patients, and which patients should not be treated.

Cosgrove says that the precision medicine landscape for endometrial cancer is exciting. There is a lot of ongoing research that will provide more information. This may eventually lead to oncologists taking a more individualized approach to the treatment of patient with endometrial cancer, explains Cosgrove.

The topic of biomarkers for endometrial cancer was discussed further in an 

during which Cosgrove answers questions about the key targets in endometrial cancer, important clinical trials, and guideline updates that have potential to change endometrial cancer treatment in the near future. Cosgrove also discusses biomarker testing during the interview.

With many different types of cancers, we’re starting to look at a more specialized approach as to how we can better take care of our patients. Endometrial cancer certainly has many opportunities where we can identify molecular markers or things that we can’t see under the microscope to help guide the best way to treat these patients.

We can use biomarkers to treat patients, to guide which trial metric to use, [or] which type of treatment we want to use. But we can also use biomarkers to tell us which patients should be treated or maybe even…should not be treated. It’s an incredibly exciting area of research for endometrial cancer because it allows us to home in on their individual types of cancers and treat them with the most individualized approach.

Videos

Casey M. Cosgrove, MD, discusses biomarker-guided treatment for endometrial cancer.

Opportunities for Individualizing Endometrial Cancer Treatment

David O’Malley, MD, a professor in the department of obstetrics and gynecology at The Ohio State University College of Medicine and the director of the division of gynecologic oncology at the OSUCCC–James, discusses the background and updated results of the KEYNOTE-158 trial (NCT02628067) looking at pembrolizumab (Keytruda) monotherapy in patients with advanced endometrial cancer.

The phase 2 KEYNOTE-158 investigated pembrolizumab in patients with advanced solid tumors and microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status. In patients with endometrial cancer, at a median follow-up of 42.8 months, there was an objective response rate (ORR) of 48% (95% CI, 37%-60%).

In updated results presented at the 2022 European Society for Medical Oncology Congress, there was a median time from first dose to data cutoff (January 12, 2022) of 54.5 months (range, 14.7-71.4). The ORR was 50% and median duration of response was 63.2 months (range, 2.9-63.2). At the data cutoff, out of 94 patients, 22 patients (23.4%) had completed therapy, 67 (71.3%) had discontinued therapy, and 5 (5.3%) remained on pembrolizumab treatment. According to O’Malley, the estimated rate of a DOR of at least 4 years with pembrolizumab was 66%.

 We presented updated long-term follow-up results of KEYNOTE-158. Recently, we published the results in the 

, which showed approximately 50% ORR with patients doing very well for long term and continuing the duration of response. That trial actually contributed to extending the approval of pembrolizumab, specifically to endometrial cancer for pembrolizumab in patients who [have] MSI-high or dMMR endometrial cancer.

The updated results that we presented are looking at longer-term follow-up. We had approximately 55 months of median follow-up with our patients and we show that the ORR is 50%. With that 50% ORR, we actually had two-thirds of patients [who] extended for 4 years or more of duration of response.

David O’Malley, MD, discusses the background and updated results of the KEYNOTE-158 trial looking at pembrolizumab monotherapy in patients with advanced endometrial cancer.

Long Duration of Response Seen for Pembrolizumab in Endometrial Cancer

Wesley Burkett, MD, a fellow in gynecologic oncology at the University of North Carolina School of Medicine, discusses the next steps for treating patients with endometrial cancer.

The current standard of care options for treating this patient population are to use Immune and targeted therapies. However, options remain limited, leaving a need for more strategies to be evaluated and developed.

On top of this, Burkett emphasizes the need to address the disparities that exist in this space as patients' outcomes are directly impacted.

 I think we have been able to have more bio directed treatments for endometrial cancer. Of course, there are other issues with endometrial cancer that definitely have to be addressed. That includes some disparities in treatment outcomes or cancer outcomes in endometrial cancer.

I think that is something that we definitely need to address and we should have. It needs to be addressed yesterday. [We are] working forward and trying to minimize and make sure we are providing appropriate and equitable care to everyone and figuring out ways that we can help to narrow that gap.

Wesley Burkett, MD, discusses the next steps for treating patients with endometrial cancer.

News

Future Directions to Improve Outcomes for Endometrial Cancer

David O’Malley, MD, a professor in the department of obstetrics and gynecology at The Ohio State University College of Medicine and the director of the division of gynecologic oncology at the OSUCCC–James, discusses updated results from the KEYNOTE-158 trial (NCT02628067) of pembrolizumab (Keytruda) in patients with advanced endometrial cancer.

The open-label, multicohort, phase 2 KEYNOTE-158 study retrospectively analyzed patients enrolled in the trial who had microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) advanced endometrial cancer. Data from this analysis presented at the European Society for Medical Oncology 2022 Congress showed that this subset of patients had an objective response rate (ORR) of 50%. For those who had 1 prior line of therapy, ORR was 59% versus 44% for those who received multiple prior lines.

Notably, the rate of durable response at 4 years was 66%, suggesting pembrolizumab is effective as long-term treatment that potentially cures some patients, O’Malley says. In terms of overall survival (OS), the 4-year OS rate was 59% in all patients, including those who did not respond, and it was 66% in responders. This shows that patients with recurrent MSI-H/dMMR endometrial cancer can have long-term survival with pembrolizumab.

 It was fairly consistent between 1 prior therapy and more than 1 prior to therapy: [an ORR of] 59% versus 44%. But a really important aspect of this is that of the 50% ORR, you had a two-thirds chance of extending that beyond 4 years, potentially curing two-thirds of women with recurrent endometrial cancer. And when we look at the OS of the entire cohort, at 4 years, 59% of those patients were alive—the entire cohort, not just those who responded—so if you responded, the chance that [OS] extended beyond 4 years or more was 66%. We're really talking about potentially curing women with recurrent [endometrial] cancer who have dMMR deficient or MSI-H.

David O’Malley, MD, discusses updated results from the KEYNOTE-158 trial of pembrolizumab in patients with advanced endometrial cancer. 

Pembrolizumab Shows Long-Term Responses in MSI-H/dMMR Endometrial Cancer

Shannon N. Westin, MD, MPH, an associate professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery at the University of Texas MD Anderson Cancer Center, discusses the design and results of the phase 2 ENPAC trial (NCT02684227) that showed the promise of enzalutamide (Xtandi) plus carboplatin and paclitaxel in patients with advanced or recurrent endometrioid endometrial cancer.

The results of the study showed that of the 35 patients who were evaluable for response had a response rate of 71% (95% CI, 54%-85%), with 83% (95% CI, 66%-92%) of patients remaining progression-free for at least 6 months. Moreover, there was a median overall survival of 32 months and median progression-free survival of 14 months.

Westin discusses these results as well as the design of the trial that focused on patients with endometroid endometrial cancer as this patient population showed initial promise when combining the 3 drugs together.

 We chose enzalutamide because of protein data that we had explored, that demonstrated high levels of androgen receptor expression in [patients with] endometrial cancer, specifically those with endometrioid type. Those levels were higher than what we see with prostate cancer, and obviously prostate cancer is where these androgen receptor antagonists have really been utilized. So, we were intrigued by our findings that [results in patients with] endometrial cancer looked so similar, so what we planned was to combine the enzalutamide with that standard of care paclitaxel and carboplatin.

 These 3 drugs had never been combined previously, so we did have a safety lead in where we demonstrated that the combination was tolerable, and we did not see any dose limiting toxicities. The way we designed the second half of the study, is we had a 4 week lead in of just the enzalutamide, and that was predominantly for translational endpoints, so we could see pre and post treatment biopsies around that enzalutamide and understand what the drug did to the tumor and how the tumor responded to that single agent treatment. Then patients were transitioned on to the 3-drug combination.

 We were very excited to see high response rates were response rates approached 75%, so almost all patients had a reduction, we only had just a few patients with progression of disease. And importantly, progression free survival was about 14 months and so we were very excited about the results of this single arm study.

Shannon N. Westin, MD, MPH, discusses the promising results of the ENPAC trial that showed the effectiveness of adding enzalutamide to standard of care chemotherapy for patients with recurrent endometriod cancer.

Results of the ENPAC Trial Shows Promise in Recurrent Endometroid Cancer

, a fellow in gynecologic oncology at the University of North Carolina School of Medicine, discusses his excitement for the approval of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

The FDA approved this combination for patients who had disease progression after systemic therapy in any setting and were not candidates for curative surgery or radiation based on the results of the 

 (NCT03517449). Results from this study showed a 5-year survival rate of approximately 17% in patients with advanced endometrial cancer who have distant metastases.

Moreover, the median progression-free survival for these patients on the combination therapy was 6.6 months (95% CI: 5.6, 7.4) compared with 3.8 months (95% CI: 3.6, 5.0) for patients on investigator’s choice chemotherapy (HR 0.60; 95% CI: 0.50, 0.72; 

 .0001). Survival results also benefitted the combination arm with a median overall survival at 17.4 months (95% CI: 14.2, 19.9) vs 12 months (95% CI: 10.8, 13.3) in the control arm (HR 0.68; 95% CI: 0.56, 0.84;

=0001) and a median duration response at 9.2 months vs 5.7 months, respectively.

Burkett discusses why these results excite him for patients with endometrial cancer, and how he thinks this combination can lead to other treatments like it in the future.

Yeah, I think it's been very exciting because we hadn't had many very effective treatments for [patients with] recurrent endometrial cancer, especially after platinum therapy. So this gives us another option that actually is more efficacious than what we've previously have used.

 Patients are, when they come in, they're interested in hearing more about these targeted therapies, and it just gives us another treatment regimen that we can use. I think it's kind of what we've been talking about recently, [how] it's just a nice opening to many different types of treatments that hopefully will be coming down the line.

Wesley Burkett, MD, adiscusses his excitement for the approval of pembrolizumab in combination with lenvatinib for patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient.

Pembrolizumab and Lenvatinib Approval Opens New Door in Endometrial Cancer Treatment

David Barrington, MD, obstetrics & gynecology specialist at Ohio State University Comprehensive Cancer Center, discusses the next steps for oncologists treating patients with stage 1B, grade 3 endometrial cancer.

The future of this space will rely heavily on evaluating results from various clinical trials to provide more guidance and recommendations for treatment options. Particularly, Barrington notes that immunotherapy will continue to play a large role in this setting when used alone and in combination with other treatments.

In addition, emerging clinical and preclinical data examining immunotherapy checkpoint inhibitors, molecular therapy, and immunotherapy, aim to further change the landscape for these early stage cancers.

We're starting to see immunotherapy play a larger and larger role in the recurrent setting in the ongoing clinical trials looking at immunotherapy in combination with traditional cytotoxic chemotherapy, comparing the 2 in combination to traditional cytotoxic chemotherapy. As we see it, I think we're going to continue to see immunotherapy gain traction, either in combination treatment or as a standalone therapy.

David Barrington, MD, discusses the next steps for oncologists treating patients with stage 1B, grade 3 endometrial cancer.


Future Directions for Treating Stage 1B, Grade 3 Endometrial Cancer 

David Barrington, MD, obstetrics & gynecology specialist at Ohio State University Comprehensive Cancer Center, discusses the results investigators found in determining treatment patterns and recommendations for patients with endometrial cancer.

Using the National Cancer database, Barrington et al evaluated race, facilities, region, and more to see what factors were most associated with variation in treatment patterns for this patient population. Through examining the many factors, experts concluded that there is a lot of confusion when it comes to managing patients with 1B grade 3 tumors.

David Barrington, MD, discusses the results investigators found in determining treatment patterns and recommendations for patients with endometrial cancer.