A 64-Year-Old Woman With Advanced Endometrial Carcinoma - Episode 4

Advanced Endometrial Carcinoma Treatment Selection

Variables that impact choice of therapy for patients with advanced endometrial cancer.

Robert L. Coleman, MD, FACOG, FACS: This patient fell into the typical algorithm. She was treated with adjuvant radiation for her high risk for local recurrence. She had a distant recurrence. She was treated with combination chemotherapy, paclitaxel and carboplatin, and then recurred again after a relatively short time. She was given lenvatinib and pembrolizumab, which aligns very well with the treatment algorithm for patients who have microsatellite-stable tumors. This would have been right along the lines of what we would have hoped for. Fortunately, because of the accelerated approval mechanism, we had access to this drug well before its regular approval in July. But this patient did fall in line with the treatment algorithm that we would have ordinarily undertaken with the availability of that combination.

Most of us who take care of gynecologic patients are pretty familiar with what platinum-free interval is. Most of this has been focused in ovarian cancer, where we use this as a way to discriminate these large terms, such as platinum-sensitive, platinum-resistant, and platinum-refractory, as descriptions of patient cohorts. The same isn’t as clear in endometrial cancer. We have noticed that patients who have a “longer” platinum-free interval may have a higher likelihood to respond, but there’s no guarantee that that’s the case.

The performance of platinum in endometrioid and the other histologies of endometrial cancer can be quite variable. Based on the fact that if we know the genetic landscape of endometrial cancer can be all over the place with respect to copy number high and copy number low type tumors, those that carry microsatellite stability or POLE mutation, and those that have a serous or clear-cell phenotype, you can imagine that the linkage between time off of platinum and re-response to platinum might not be as crisp as we see with ovarian cancer.

Having said all that, we generally follow similar guidelines. If a patient has responded to previous platinum and has been away from platinum for a period—usually 6 months; not because there’s something magical about 6 months, but that generally aligns with at least 1 assessment after completion of therapy where there was no increase in disease or recurrence—it tells us that the response that was seen in the face of the previous chemotherapy has at least been durable for that period. It’s nothing magical, and we don’t have the precision from our testing algorithms to be able to determine who’s platinum-sensitive or platinum-resistant, but we’ve used those clinical parameters to at least consider the reintroduction of therapy.

For patients who have progressed within that timeframe, based on what I just mentioned, those patients either didn’t have a durable response or had progression of disease in a very short time after completing chemotherapy, which means that it was probably growing while they were on therapy. In that situation, many of my colleagues and I would choose something alternative, like we saw in the KEYNOTE-775 trial, those particular other alternatives for management.

If this patient had had an MSI [microsatellite instability]-high or deficient MMR [mismatch repair] tumor at the very beginning, we would have noted that. I don’t think it would have changed our treatment today, but this patient would have fallen into a category of a high-intermediate risk type of situation. There are trials being developed right now that are looking at the potential to provide lasting treatment effect or even cure with the use of immune checkpoint inhibitors as an adjuvant for patients who are getting treatment for this high or intermediate risk state. That’s moving this concept of immune-based therapy all the way into the adjuvant setting. That’s not available right now outside of the clinical research environment.

However, if you think about the activity of single-agent pembrolizumab in patients who have microsatellite-high tumors or are deficient in MMR, it’s sufficiently high enough to challenge chemotherapy. This drug does have FDA approval for use in this particular setting. And so while we haven’t been able to clearly document that we can replace combination chemotherapy in that first-line setting, it’s the focus of ongoing research. But in the patients who have gone through chemotherapy and are no longer candidates for curative intervention, pembrolizumab and dostarlimab are the immune checkpoint inhibitors that are approved for use as a single agent for treatment, which would be balanced against chemotherapy. We’re excited that we have these options for those patients. That’s why it’s important that we document the status of that tumor so that we can potentially leverage these exciting new therapies.

Transcript edited for clarity.

Initial Presentation

  • A 64-year-old postmenopausal woman presented with abnormal uterine bleeding for about 2 months. She has two grown children, underwent menopause at 57 years of age, has no known family history of cancer.
  • PMH: BMI is 32, and she has hypertension that is controlled with medication
  • PE: Notable for large uterus and right lower quadrant abdominal tenderness on palpation

Clinical work-up

  • Endometrial biopsy: endometrioid adenocarcinoma, FIGO grade 1
  • Surgery: ELAP TAH BSO with bilateral pelvic node dissection
  • Pathology: grade 2 endometrioid adenocarcinoma, 18 negative pelvic nodes, invasive 2.1 cm of 2.3 cm myometrium
  • Molecular testing shows MSS, MMR proficient, and HER2-

Treatment

  • Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
  • 14 months after completing radiotherapy, she presented with new RLE edema and right hydroureter
  • She then was treated with carboplatin/paclitaxel chemotherapy which was well tolerated
  • Nine months later the patient has disease relapse with metastases to the paraaortic lymph nodes and lung
  • She is now treated with lenvatinib/pembrolizumab