Advanced Endometrial Cancer - Episode 7

Immune Checkpoint Inhibitors in Advanced Endometrial Cancer

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Bradley J. Monk, MD, FACS, FACOG: Let’s discuss what you guys are excited about. What I’m excited about is immunotherapy. Immunotherapy in ovarian cancer has been very disappointing.

But in cervix and endometrial, it’s very exciting. There are several trials, and I hope the next OncLive® can be cervical cancer based. But we’re going to talk extensively here about checkpoint inhibitors in endometrial cancer. Brian, maybe you could talk about the role of PD-L1 monotherapy in MSI-H [microsatellite instability-high] endometrial cancer, how it has changed your practice, and how it has evolved.

Brian M. Slomovitz, MD: It’s changing the world of endometrial cancer. In our first section, we were high on chemotherapy. My goal in my practice is to even eliminate chemotherapy for these patients. I discussed earlier that 39% to 40% of patients with endometrial cancer will be MSI-H. With immunotherapy, particularly checkpoint inhibitors, we know that there’s a very high response rate to tumors that are MSI-H, which is tumors that have a high tumor mutational burden [TMB].

Tumors that, in laymen’s terms, are recognized by noncell by the body. Something that shouldn’t be there. The first tumors that benefited from single-agent checkpoint inhibition, melanoma, non–small cell lung cancers. We learn that there’s a large subgroup of endometrial cancers, those with MSI-H, that respond quite nicely to single-agent therapy with checkpoint inhibitors. 57% response rate, pembrolizumab. Dave O’Malley, 1 of our speakers, reported that 57% response. Which is crazy, because what you got labeled for was about 38%. They found as they got more and more data, it worked better. When I give it to my patients who are MSI-H, their tumors have a high likelihood of melting away.

Bradley J. Monk, MD, FACS, FACOG: Right.

Brian M. Slomovitz, MD: It’s a class effect. Nivolumab, another story through the NCI-MATCH trial. In the MATCH trial, a large NCI [National Cancer Institute]–sponsored trial that is tumor agnostic, looking at not a specific disease but a mutation. Those patients that were noncolorectal—MSI-H, when given nivolumab, another checkpoint, high response rate. It’s changed the way, particularly in the MSI-H patients, and we’re going to spend a lot of time trying to make cold tumors hot. But in the hot patients, MSI-H, single-agent checkpoint therapy has changed the world.

Bradley J. Monk, MD, FACS, FACOG: Katie, is there any way that someone has not heard of this? You hear Brian talk about it, and you’re like, wow. But this is a message that’s 3½ years old. This was approved on May 23, 2017. Everyone knows it. I know you don’t know what everyone knows, but I’d be shocked if a treating oncologist has never heard of an MSI-H tumor.

Kathleen N. Moore, MD: Yes. This message—the medical oncology community was using immune checkpoint inhibitors long before we were. Colorectal is probably the nearest relative to our endometrial cohort. They’re well versed in this and saw the data as they came out. Really, as the standardization of testing for mismatched repair, as we alluded to earlier, on all patients has come into play. It’s unusual to find a patient, unless they were diagnosed long ago and now, they’ve recurred distantly and we’re testing them. That happens, but this message has permeated the community and people are doing a good job. If anything, when I talk to medical oncology, they’re being more creative with their use of immune checkpoint inhibitors for gynecologic cancers than we are.

Bradley J. Monk, MD, FACS, FACOG: A couple of things. IHC [Immunohistochemistry] for mismatched repair deficiency is not perfect. Maybe only 90%. I think you said, maybe Brian, that the POLE mutations, which are hypermutated, are not detected by IHC. Now, as of June 16 of this year, we will have a TMBindication based on the FoundationOne CDx. Again, IHC is not enough. At least sometimes. Misses POLE for sure. Now you have TMB. Krish, when we get a recurrent patient who might be eligible for pembrolizumab, do we need to send it to FoundationOne? I’m just using that because that’s the companion diagnostic to look for TMB and POLE. Or do you say, “Oh, it’s mismatched repair, enzyme IAC[intra-arterial chemotherapy]? It’s not there, so I’m going to move on.”

Krishnansu S. Tewari, MD: I don’t send it. If I can do it with IHC and get them going, it’s easy for me. The bottom line is that with the combo approved, every patient with advanced endometrial cancer can get pembrolizumab.

Bradley J. Monk, MD, FACS, FACOG: Yes. No question. When they’re mismatched repair deficient or MSI-H on IHC, that’s easy. But I may not want to give them the combination. Sometimes I’ll send it for next-generation sequencing [NGS] just to make sure I’m not missing a single-agent pembrolizumab opportunity. What do you think about that, Brian?

Brian M. Slomovitz, MD:That’s a crucial point. Everyone’s excited about the combo, and we’ll talk about that. But we’ll also mention that there are some toxicities associated with the combo. To get a better response rate and fewer toxicities, we’re not doing our patients justice if we’re not looking for MSI-H.

Kathleen N. Moore, MD: Yes. I would argue for advanced recurrent disease, where unfortunately you know the likelihood is that if they’re stage IV recurrent, so I guess we can discuss this. I don’t see a reason not to do next-generation sequencing. Because you get the POLE, you get MSI-H, you get tumor mutational burden—I’ve actually just found 1 who’s not MSI-H, so she’s going to get pembrolizumab. But you also get everything else that we’re going to talk about, including ERBB2 amplification and mutations. Which are also targetable. I don’t see a reason not to send next-gen. I don’t send it on stage I, but everything else is getting NGS.

Bradley J. Monk, MD, FACS, FACOG: I’m going to put more pressure on you. Also in June, we got to 2020, first-line pembrolizumab for MSI-H CRC [colorectal cancer], first line vs chemotherapy. A randomized phase 3 trial. If you have a metastatic case that’s MSI-H, you’re going to give her a carboplatin-paclitaxel or checkpoint or all 3. I know you wanted to put her on a clinical trial, but what’s the right treatment for that newly diagnosed, MSI-H, widely metastatic patient?

Kathleen N. Moore, MD: We don’t know, to be honest. The trial needs to be done. Some of our colleagues have proposed it several times. It keeps getting turned down, which is frustrating. It’s not standard of care, and you have to counsel your patients about that. However, patients are smart and they know the data.

Bradley J. Monk, MD, FACS, FACOG: Or the triplet.

Kathleen N. Moore, MD: Pembrolizumab.

Bradley J. Monk, MD, FACS, FACOG: Or the triplet.

Kathleen N. Moore, MD: I’ve done that.

Krishnansu S. Tewari, MD: What’s the harm, Brad, about just starting with pembrolizumab? Because if they progress through it, you can give them chemotherapy. That’s the message.

Brian M. Slomovitz, MD:Yes, I never disagree with Katie. But we don’t need a trial. We got single-agent approval in the second line on, what, 17 patients?

Bradley J. Monk, MD, FACS, FACOG: 14, but yes.

Brian M. Slomovitz, MD:A several-hundred-patient trial. We have to report on just 17 patients to get approval.

Kathleen N. Moore, MD: I am fine using I/O [immuno-oncology] in the front line in a well-counseled patient. We’ve learned that lesson the hard way with immunotherapy. MSI colorectal and MSI endometrial, are they more similar? Because if it is similar, we can just move to I/O. I don’t know that we can say that definitively, but I would not fall on the sword against I/O in the front line.

Bradley J. Monk, MD, FACS, FACOG: To your point, Brian, the accelerated approval for MSI-H was mostly CRC. Right? The CRC drug and the endometrial cases with it. Here, vs chemotherapy, to your point, they also sort of dragged endometrial cancer with it. To what Dr Tewari said, what’s the harm? You know it’s going to work. The argument, Krish, to your point, is triplet. Carboplatin-paclitaxel plus pembrolizumab vs pembrolizumab alone. What do you think of that?

Krishnansu S. Tewari, MD: It would be nice to get the trial back on because that whole thing got torpedoed because of COVID-19 [coronavirus disease 2019]. So I don’t know.

Bradley J. Monk, MD, FACS, FACOG: Right. We have a trial funded through NRG Oncology called GY018, which asks this very question. Not just in MSI-H patients but in all comers. But there is a specific MSI-H end point. Thank you, Krish. I know you’ve been a passionate advocate for clinical trial enrollment throughout this pandemic.

Transcript Edited for Clarity