The Evolution of Endometrial Cancer Treatment

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.

Transcript:

0:04 | 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.

0:20 | Thank you for joining me today, Dr. Nakayama. Can we begin with you discussing the most exciting change in the field in recent years?

0:28 | 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.

0:55 | 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?

1:08 | 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.

1:51 | 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.

2:32 | Results from a KEYNOTE-775 study, which led to the approval of lenvatinib and pembrolizumab were recently published in the New England Journal of Medicine. What are your thoughts on the study results?

2:44 | 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.

3:03 | 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.

3:49 | Thank you. And what are the implications of these combined study results?

3:58 | 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?

4:55 | Moving along in the treatment landscape, what role does bevacizumab continue to play?

5:01 | 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.

5:30 | What research supports your choice of when to use bevacizumab in your patients with endometrial cancer?

5:37 | 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.

5:49 | What novel therapies are you excited to see clinical trial results for?

5:54 | 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.

7:22 | Thank you. What improvements are still necessary in endometrial cancer treatment?

7:28 | 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.

8:33 | Lastly, Dr. Nakayama, what key advice can you give to your peers on how to approach endometrial cancer treatment today.

8:41 | 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.

9:18 | 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.