Arend Discusses Immune Checkpoint Inhibition for Recurrent dMMR Endometrial Cancer

Rebecca Arend, MD (MODERATOR)

Assistant Professor

O’Neal Comprehensive Cancer Center at The University of Alabama at Birmingham

Birmingham, AL

EVENT REGION California, Nevada, and Arizona

PARTICIPANT LIST Eric Schaefer, MD | Harish Madala, MD | Khaleel Ashraf, MD | Charles Lattuada, MD | Christiane Zoghbi, MD | Somasekhara Bandi, MD | Kathryn Ann Arrambide, MD | Shadi Haddadin, MD | Solly Chedid, MD | Lorena Adrijana de Idiaquez Bakula, MD

CASE SUMMARY

In August 2021, a 64-year-old postmenopausal woman presented with abnormal uterine bleeding lasting 4 months. She has a history of arthritis, obesity (body mass index = 40), and well-controlled hypertension. Her ECOG performance status was 1. She was counseled on surgical options and then scheduled for surgery. She received a diagnosis of stage IA, grade 1 endometrial cancer. Immunohistochemistry and molecular testing results showed the disease is mismatch repair deficient (dMMR), microsatellite instability–high (MSI-H), and 3+ estrogen receptor positive.

In August 2022, she reported intermittent pelvic pain over the prior 4 weeks. A CT scan of the chest, abdomen, and pelvis (CT CAP) suggested relapsed/metastatic disease with involvement of 1 right external iliac lymph node. Carboplatin/ paclitaxel was administered for 6 cycles every 4 weeks. Chemotherapy was well tolerated, and a complete response was recorded at the end of the regimen.

In April 2023, disease relapse was documented on routine follow-up. CT CAP showed heterogeneously enhancing mass in right suprarenal space, multiple bilateral pulmonary nodules, and a new right internal iliac lymph node in addition to the previously observed positive lymph node. Fine needle aspirate of the suprarenal mass confirmed metastatic endometrioid adenocarcinoma. The patient was counseled about systemic therapy options, during which she repeatedly expressed concerns about adverse events.

DISCUSSION QUESTION

• What is the reasoning behind the approach you would take next?

AREND: Thirty-three percent of the group chose a single-agent immune checkpoint inhibitor [ICI], and 67% chose pembrolizumab [Keytruda] plus lenvatinib [Lenvima]. Dr Schaefer, what are you going to do?

SCHAEFER: [I chose] pembrolizumab plus lenvatinib because they’re symptomatic. I want a quicker debulking of the tumor.

AREND: Interesting. Even though she has MSI-H status, you’re going to go for lenvatinib plus pembrolizumab?

SCHAEFER: If she wasn’t symptomatic and this was found for some other reason, I’d do single-agent pembrolizumab. But [if] she was symptomatic, it would lead me to use lenvatinib plus pembrolizumab.

MADALA: For MSI-H, I would prefer the single-agent [ICI].

AREND: What single agent are you using?

MADALA: Dostarlimab [Jemperli].

AREND: How about you, Dr Ashraf?

ASHRAF: This is one area where I would like your input. There are clear data that show pembrolizumab and lenvatinib have a combination efficacy, and that’s what I would have done if the patient was not MSI-H. I agree with the other participants, even though I might still choose a single-agent [ICI], but I can see pembrolizumab plus lenvatinib as a reasonable option.

AREND: If they’re MSI-H and they’ve never seen immuno-therapy, I will always give single-agent immunotherapy. I have seen some incredible responses. Dr Schaefer, you may have used it somewhere and felt you didn’t see a response quite fast enough. It’s interesting how we all have our anecdotal experiences. We give the single-agent immunotherapy to 5 patients, then we try something else, and we have a couple who have the phenomenal response, so that’s what we tend to do.

There are data showing increased overall response rates with combination therapy, even in the dMMR population.¹ I don’t want to expose patients to the toxicity of lenvatinib unless I know they absolutely need it, so I give them the benefit of the doubt. My practice usually is to use dostarlimab, but there’s really no difference. I tended to do that before pembrolizumab had the [approval for] every 6 weeks, because we had the GARNET study [NCT02715284] open [in our institution],² so I had a lot of experience with it. It spaced out treatment, so that’s what I tended to use. That’s my practice. There’s no right or wrong way.

LATTUADA: I’ve had a tough time with lenvatinib in multiple other tumor types, like [hepatocellular carcinoma] and [renal cell carcinoma]. I’ve only treated 1 or 2 patients with endometrial cancer, but are there any data that [show] lenvatinib will salvage a failing pembrolizumab protocol?

AREND: That is a great question, and that’s something we are looking at in clinical trials. I don’t think we have those data, but I don’t think it is unreasonable to add lenvatinib, potentially. I was asked what to do with [a patient] who was progressing on single-agent pembrolizumab [and] was MSI-H. It was already [more than] 1 year since she had carboplatin [Paraplatin] plus paclitaxel [Taxol], to which she had a complete response. This is a complete data-free zone, but my recommendation was for them to try the RUBY trial [NCT03981796] regimen,³ which is carboplatin plus paclitaxel plus dostarlimab, and continue dostarlimab maintenance if she had a response. She has already progressed on pembrolizumab, she’s MSI-H, and she responded to chemotherapy in the past. There are some data as to why chemotherapy reduces cell death and increases new antigens, and maybe that could trigger her tumor to respond again.

ZOGHBI: In other types of cancers, even when we have MSI-H—for example, in lung cancer—if you need the quicker response, would you not consider adding a low dose of lenvatinib, awaiting the pembrolizumab to start working? We know adding an agent up front might be better, but it’s not always the truth. I also agree that lenvatinib is difficult to use with some cancers, and I don’t know [whether] it is true in endometrial cancer because I don’t see too many patients with it. Maybe starting a lower dose of lenvatinib [is] something we can do to balance the toxicity and get some benefit up front in these patients, especially [those who are] symptomatic.

AREND: It’s interesting that almost 70% of us said they would start with lenvatinib plus pembrolizumab in a patient who is dMMR. I appreciate the comments about potentially giving a little kick to make things go faster in a [patient who is] symptomatic, but I just think it’s interesting. I would give the single-agent [ICI].

ASHRAF: This patient initially got only carboplatin plus paclitaxel, which is now the standard of care, right? If the patient came to me today, I would treat them with the RUBY trial regimen of carboplatin, paclitaxel, and then immunotherapy.

AREND: Exactly, this was all [before the] RUBY trial. You’re right, it’s going to be a moot point. We’re never going to see [patients who are] dMMR in the recurrent setting who haven’t had maintenance immunotherapy. We went back and forth about how to put the wording on the [National Comprehensive Cancer Network] panel. But in somebody like this with recurrence and measurable disease, she absolutely would have gotten immunotherapy in combination with chemotherapy.

DISCUSSION QUESTION

• What are the systemic therapy options for patients with metastatic MSI-H/ dMMR endometrial cancer and when should they be used?

AREND: Let’s start with chemotherapy, including a rechallenge with chemotherapy.

BANDI: If a patient relapses after 6 months, I think it’s fair game to rechallenge with carboplatin plus paclitaxel.

AREND: Yes.

ARRAMBIDE: I would think about it in somebody who had lasted more than 1 year and didn’t have a lasting toxicity issue with the taxane. In somebody who had bad neuropathy, I’m probably not going back there. But in somebody who had a lovely response with a long duration, I want to make sure that bridge is burned before I abandon it.

AREND: That’s fair. For hormonal therapy, specifically, this patient had 3+ [estrogen receptor] positivity. Who wants to tell me about using hormonal therapy in this setting?

HADDADIN: It’s probably not going to be my first choice, but I would probably use it in an older patient who can’t get chemotherapy or immunotherapy, or if they say no. Sometimes patients look at more toxic therapies and say, “I’m just not doing that.” There are patients who refuse [any] infused therapy.

AREND: In [older] women with an [ECOG] performance status of 2 who don’t want the toxicity of chemotherapy or immunotherapy, I use megestrol acetate [Megace] all the time. If somebody had a PI3K mutation or an AKT mutation and was MMR proficient, then I use everolimus [Afinitor] plus letrozole [Femara]. So I’ll use hormonal therapy in combination with mTOR therapy.

LATTUADA: Normally, we do immunohistochemistry [IHC] for MMR. If it comes back as proficient, should we do molecular testing for MSI, or do you think they’re equivalent in endometrial cancer?

AREND: I would say yes, I would encourage doing more comprehensive testing. On more than a handful of occasions, I have gotten patients who were MMR proficient and either were tumor mutational burden–high or MSI-H. Most [patients who are] MSI-H will be dMMR, but it’s not 100%, and it may have to do with tissue quality. It may have to do with some subjectivity in IHC testing, but I always do both.

How about bevacizumab [Avastin] or other antiangiogenic agents? Is anybody using that in endometrial cancer?

CHEDID: [Not] as a single agent. In the past 5 to 7 years, I’ve probably used it [approximately] 5 or 6 times. I haven’t had a single patient respond.

AREND: What about combining it with chemotherapy?

CHEDID: In colon cancer, it adds a little bit, when you look into it. In lung cancer, it adds a small amount. In endometrial cancer, it also adds a small amount with carboplatin and taxanes, but it doesn’t add a lot of toxicity. It does have some [toxicity], but it also doesn’t add a huge amount of efficacy, either.

AREND: I don’t know [whether] you are familiar with some of the data that came out on using bevacizumab with TP53-mutated tumors. Adding bevacizumab to chemotherapy wasn’t better in all-comers, but it was in those with the TP53 mutation, so sometimes I’ll do that.⁴ Additionally, I extrapolate from ovarian cancer sometimes. So, especially in somebody who has progressed within 6 months of platinum, I’ll not infrequently use weekly paclitaxel with bevacizumab in my individual patients. I’ve seen some very good efficacy.

How many [of you] are repeating molecular testing? Would you get another biopsy and repeat the molecular testing?

MADALA: Yes. I at least try to at the time of progression.

AREND: I do, too—more out of curiosity. There are not any real data, especially if you haven’t gotten targeted therapy, that [show] the tumor is going to change a whole bunch. I also find it interesting [that when I first had the tests] in my practice, I was doing FoundationOne CDx, and now I tend toward Caris. We see different results with different companies in the same patient, so there is some variability. [I] also [want] to make sure I’m not missing a mutation that would make them eligible for a clinical trial.

CASE UPDATE

Through shared decision-making, ICI monotherapy was planned. The patient started on dostarlimab with instructions to continue follow-up every 3 months.

DISCUSSION QUESTIONS

• What aspects of the study designs and efficacy data from the NRG-GY018 (NCT03914612) and RUBY 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 ICI for advanced, dMMR/MSI-H endometrial cancer?

BANDI: We basically see immune-mediated adverse effects beyond 2 years with other cancers. I don’t think it’s useful beyond 2 years. It may be useful, but I think we can stop and see how they do.

AREND: Yes, I agree.

ARRAMBIDE: Is there any population that has been looked at after relapse or retreatment with immunotherapy? I suspect the data are not that old.

AREND: They are not.

ARRAMBIDE: I’ve had somebody who has stayed on for [approximately] 3 years and did fine. It was hard to convince them to go off. Their insurance company convinced them.

AREND: Sometimes patients are attached to being on therapy. I was even talking with one of my fellows about whether I’m going to use it in everybody who's MMR proficient. My answer is no, I’m not going to use it in my patients who are completely resected with no measurable disease, [with] stage III or IVA, [as] up-front or adjuvant treatment. I’m not giving them immunotherapy if they’re MMR proficient. Are they going to want maintenance therapy? Some patients know the data and are begging for it, [whereas] some patients don’t want to stay on maintenance therapy. It involves joint decision-making. [There are] patients who don’t want to come off therapy, but there are [also] patients who don’t want the toxicity.

ARRAMBIDE: Would this also be the population of completely resected patients where you would look at cell-free DNA?

AREND: Absolutely, and that’s one of my research [subjects] I am looking at. Those data are going to be fascinating to see. I am looking at that prospectively right now.

DE IDIAQUEZ BAKULA: Based on your studies…once a patient goes into remission, on average, how long after that do you see the DNA become undetectable?

AREND: For somebody who is on treatment?

DE IDIAQUEZ BAKULA: Yes. Instead of keeping the patient for 2 or 3 years on treatment, especially if you have other tools that may suggest the remission is real, I ask myself: What’s driving that [additional] 1 or 2 years of treatment? I think it’s driven by the companies, not necessarily response.

How many more months are necessary to consolidate the response? These are patients in whom the treatment works well. Even after you stop it, the immune response remains for some time, so I’m not sure that continuing the drug for 6 or 7 months offers a substantial benefit.

AREND: I agree with you. I’m hearing that from a lot of you, and we all agree that 3 years is excessive, especially if [a patient] has no evidence of disease on CT scan and is [minimal residual disease] negative.

Now, if [a patient] has low-volume disease that you’re monitoring, but it’s stable and they have residual disease, then that’s a different story. But I completely agree.

DE IDIAQUEZ BAKULA: For patients who are dMMR, would you consider using immunotherapy short term?

AREND: If they’re dMMR and were completely resected but there was a lot of disease, I absolutely would try and get them the immunotherapy, even though they weren’t eligible for the trial.

ARRAMBIDE: To [answer] which response end points were the best, the HR [ for progression-free survival in the studies] speaks to me [From the Data^3,5].

AREND: I agree with you.

ARRAMBIDE: That’s an HR we don’t see in medical oncology.

AREND: I appreciate that. I totally agree with that.

_REFERENCES

_{1. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330}

_{2. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022;10(1):e003777. doi:10.1136/jitc-2021-003777}

_{3. 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}

_{4. Thiel KW, Devor EJ, Filiaci VL, et al. TP53 sequencing and p53 immunohistochemistry predict outcomes when bevacizumab is added to frontline chemotherapy in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2022;40(28):3289-3300. doi:10.1200/JCO.21.02506}

_{5. 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}