Selecting Therapy for dMMR/MSI-H Endometrial Cancer After Chemotherapy

Jubilee Brown, MD

Professor of Gynecologic Oncology

Atrium Health Levine Cancer Institute

Charlotte, NC

CASE SUMMARY

In August 2021, a 64-year-old postmenopausal woman presented with abnormal uterine bleeding lasting 4 months. ​She underwent menopause at 55 years of age. She is a widow, has no children, and lives alone​. She had a medical history of arthritis, obesity (body mass index = 40), and hypertension well controlled with medication​. Her ECOG performance status was 1. She was counseled on surgical options, then scheduled for surgery.​ She had stage IA; grade 1 endometrial cancer​. Immunohistochemistry/molecular testing results showed a mismatch repair deficiency (dMMR)​ and microsatellite instability-high status (MSI-H), ​3+ estrogen receptor–positive​.

In August 2022, she reported intermittent pelvic pain over prior 4 weeks​. CT scan of the chest, abdomen, and pelvis suggested relapsed/metastatic disease with involvement of 1 right external iliac lymph node. Carboplatin/paclitaxel (6 cycles every 4 weeks) was administered, 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 scan of chest, abdomen, and pelvis 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. ​

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DISCUSSION QUESTIONS

• What are the systemic therapy options for a patient with dMMR/MSI-H disease?
• How do you determine which next-line therapy to choose?

JUBILEE BROWN, MD: Let’s talk about the systemic therapy options for patients with metastatic endometrial cancer where you have MSI-high/dMMR—chemotherapy, hormonal therapy, immune checkpoint inhibitors [ICIs], tyrosine kinase inhibitors, and anti-angiogenesis. How do you choose?

VENU MADHAV KONALA, MD: [For] patients with MSI-H/dMMR, we have excellent data on ICIs as single agents either with pembrolizumab [Keytruda] or dostarlimab [Jemperli].

BROWN: Would anybody switch to hormonal therapy in this case, or do you always go to ICIs?

KONALA: This patient has recurrence within 12 months. This is her second recurrence since her diagnosis. For somebody with slow-growing cancer, I think I have used that in the past, but this patient has recurred quite quickly even after chemotherapy.

PETER JIANG, MD: Do you have any data comparing carboplatin/paclitaxel vs pembrolizumab for MSI-high endometrial cancer? Because for other solid tumors, an ICI is more effective, less toxic, and even provides survival benefit, so why would you choose carboplatin/paclitaxel first?

BROWN: That’s a great question. Let me ask, what if she had a partial response to paclitaxel/carboplatin, would that change anything? It sounds like everybody would go straight to ICIs at this point so it might not change.

RAO MORAVINENI, MD: How long was the duration of remission?

BROWN: August to April, so about 8 months.

MORAVINENI: I certainly would not go back on platinum-based chemotherapy, and she may not have a second chance. As Dr Konala alluded to, it’s an aggressive recurrence so she needs the best therapy and a quicker response, too. For that reason, endocrine therapy is out and repeat carboplatin is out from my standpoint.

BROWN: [If] you had initial molecular testing, would you repeat it?

MORAVINENI: I would repeat it.

BROWN: Would you send new next-generation sequencing?

MORAVINENI: I would repeat to make sure the blueprint for this particular recurrence is the same or different where we’re at. Because she needs the best targeted therapy with reasonable lower toxicity and highest response as much as possible.

CASE UPDATE

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

BROWN: How do you choose dostarlimab vs pembrolizumab?

SATVIR SINGH, MD: I don’t think there’s a right or wrong answer, both of these drugs have data. We have more experience with pembrolizumab so it is more [based on] experience…rather than preference. Either one would work well.

JIANG: I don’t have any experience with dostarlimab. I have a lot of experience with pembrolizumab [but] I didn’t choose pembrolizumab this time. I wanted to try a new agent, dostarlimab. I don’t know from comparison which one is better. It depends what you feel comfortable with.

DISCUSSION QUESTIONS

• What factors influence your ICI preference for a patient like this, such as efficacy, safety, comorbidities, logistics, and sites of metastases?

BROWN: So far it sounds like familiarity has been the key. How do you choose which checkpoint inhibitor you’re going to use?

CHUNZI XIA, MD: I have never used dostarlimab in the past. I would go with pembrolizumab.

HARPAUL GILL, MD: I’d echo what everyone said. Obviously, most of us have a lot of familiarity with pembrolizumab. If that patient came across my clinic, I’d be interested to use dostarlimab. I think there was overall survival benefit demonstrated with dostarlimab [but not with] pembrolizumab.¹ It may just be trial characteristics, but I think there’s enough there maybe to make me want to try it.

BROWN: Does anybody see any differences in efficacy, safety, tolerability, comorbidities?

PRIYA RUDOLPH, MD: The only difference is the frequency. It says every 6 weeks for dostarlimab…[however], you can eventually give pembrolizumab every 6 weeks as well.

GARY THOMAS, MD: I’ve used pembrolizumab a lot more. A couple of patients with rectal cancer have come by recently talking about dostarlimab and that trial where everybody had a complete response with it.² I’m anxious to use it because of that, but I have more familiarity with pembrolizumab.

SHERINE J. THOMAS, MD: I would agree with everybody else’s statement that everybody is more familiar with pembrolizumab, and familiarity leads to great use. I don’t have experience with dostarlimab, but it would be a reasonable thing that I would consider if the right patient showed up.

_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. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445}