Physicians Discuss Immunotherapy Discontinuation in Endometrial Cancer

Jubilee Brown, MD

Professor of Gynecologic Oncology

Atrium Health Levine Cancer Institute

Charlotte, NC

DISCUSSION QUESTIONS

• What aspects of study designs and efficacy data from NRG-GY018 (NCT03914612) and RUBY (NCT03981796) studies stood out to you? What end points are most meaningful to you in this setting?​
• In your experience, how long do patients typically remain on single-agent immune checkpoint inhibitor (ICI) for advanced, mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) endometrial cancer?​
• What is the longest a patient has remained on an ICI? ​

JUBILEE BROWN, MD: What aspects of the study design and efficacy data from these 2 studies stood out to you? What end points are most meaningful to you in this setting? I think that’s important. When we design these studies, we choose end points [deliberately].

JIGARKUMAR PARIKH, MD: The pembrolizumab [Keytruda] study [NRG-GY018] does not have overall survival [OS] data, right?

BROWN: That’s correct, not yet.

PARIKH: I feel like OS is probably a more important end point for a frontline setting, so I think dostarlimab [Jemperli] data are stronger in that regard than the pembrolizumab data.¹

RAO MORAVINENI, MD: In terms of the pembrolizumab study, was it a 1:1 randomization or 2:1? And second, how many of those patients were split among stage III vs stage IV frontline vs recurrent?

BROWN: It was a 1:1 randomization.² If we look at stage…I think the majority of patients had stage III and recurrent disease. I don’t think there were very many with stage IV disease, but I don’t know the exact numbers.

MORAVINENI: For those studies, we knew that the drugs are effective. But in terms of which one to choose, how much, and in what patient populations, the split among the stages is blurred to say the least. We need more mature data on pembrolizumab.… I would favor the dostarlimab. The data are very clear on the other side in terms of every 6 weeks being convenient, the numbers are there, and high-risk patients are [included]. It’s a more straightforward trial and easier to convince the patient.

BROWN: Does the duration of maintenance therapy give you any pause?

MORAVINENI: Yes, it does make a difference, but I would like to see that the pembrolizumab [study], once they do the 3-year readout, is valid and shows a similar benefit. But I would not assume pembrolizumab would do that because we have seen these ICIs, they are different drugs with different data in different tumors. I would not extrapolate that, but I would be happy to see. It’s an unanswered question.

JOANNA METZNER-SADURSKI, MD: I am very impressed with the RUBY data for the high-risk patients, with the 2-year rate of OS of [83.3% with dostarlimab] in dMMR vs [58.7%] with placebo. I am a fan of pembrolizumab. It was the first drug…and whenever you needed the drug you could get it [via] compassionate use. It will be hard to switch, but I do think the data look very strong.

PRIYA RUDOLPH, MD: The Kaplan-Meier curves, especially for MSI-H tumors, [for progression-free survival] are massively separated and continue to separate [in both trials].^1,2 I’m not sure I’m convinced that we need to continue with this long-term maintenance because those curves are continuing to separate. As far as the MMR proficient patients, those curves are continuing to separate and it appears much more so with pembrolizumab, although that patient [trial population] was a little lower risk.

Still, I don’t know that I’m convinced that we need to give 3 years of maintenance. It also brings the question about subsequent treatments. We’re using these drugs up front, so we’re going to be stuck with single-agent lenvatinib [Lenvima] for our second-line treatment. Of course, there are other chemotherapy options as well. On the other hand, you could potentially give a break from immunotherapy. At least for patients with MSI-H tumors, you can go back [on ICI] or you can add lenvatinib to pembrolizumab. It gives a break from immunotherapy and a potential for using that option in the second [line].

BROWN: Those are good points. I especially appreciate your point about what happens if somebody fails post-immunotherapy. Then our options are fewer. The hope is that fewer patients are going to fail and recur at all. Do you feel like we have enough data to not offer maintenance immunotherapy in a setting like this?

RUDOLPH: I think maintenance for 1 year, maybe 2 [is acceptable]. I’m not sure where 3 [years] is coming from. A lot of times, when we use immunotherapy, we use it for 2 years and you maximize the response at that point. I don’t know that I’m convinced it has to be 3 years.

BROWN: It’s interesting because you do come at it from a standpoint where you’ve seen these drugs in other types of cancers. I feel like what we have is the data here. We don’t have 3 years of maintenance vs nothing, or 1 year, or 2 years. It will be interesting to see how all of these turn out as other trials come up.

PARIKH: Another point to consider is that in the RUBY data, one-third of the population [had higher-risk disease].¹ That is probably the reason for the design to give 3 years of maintenance, because they took a higher number of patients with high risk in that study.

BROWN: Yes, good point. In your experience, what’s the longest that you’ve treated a patient on an ICI, either for endometrial cancer or something else?

MORAVINENI: My [longest duration for a patient] is year 4 in lung cancer.

SATVIR SINGH, MD:In lung cancer, we had data for 2 years of pembrolizumab maintenance.³ I gave it to a patient for 3 years and then stopped and it recurred in 6 months. And then I had to go back. I tried again, it didn’t work, and then had to switch to chemotherapy. To the point stated earlier that maybe 2 years is enough, in lung cancer it is 2 years but now I’m not stopping because I had a bad experience after stopping. The patient’s disease recurred, and so I’m going to give it indefinitely now to any patient if the insurance allows. If the insurance does not allow, [I will not]. We have another patient who said no after 2 years, [so] we had to stop.

BROWN: Have you used circulating tumor DNA [ctDNA] or anything like that?

SINGH: For monitoring? I have not used it but that could be a good point in using that to monitor because it is available for lung cancer. We can certainly use it. For endometrial cancer, I have not. Is that available to use?

BROWN: We’ve been using it sometimes but there are scant data, so we’re hoping to do it enough that we can prove it.

SHERINE J. THOMAS, MD: I don’t have data in endometrial cancer, but I certainly have a patient with triple-negative breast cancer who completed well over 2 years of therapy, had a pretty aggressive recurrent [disease] but went into CR. [Atezolizumab (Tecentriq)] lost its triple-negative indication,⁴ but the insurance let her continue for a time, and we agonized over whether or not to stop it. She got vitiligo from the [atezolizumab], but she was continuing to do well. Eventually, after 3 Signatera [ctDNA] tests being negative and PET scans being negative, we finally backed off of it and she’s done well for now. It’s been another year or so. I’ve done it in other malignancies.

_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. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774}

_{4. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche. August 27, 2021. Accessed August 9, 2023. https://bit.ly/3ypzC6K}