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Sequencing for Advanced Endometrial Cancer

Bradley J. Monk, MD, FACS, FACOG: Let’s discuss HER2 [human epidermal growth factor receptor 2] testing. HER2 testing can be done through either IAC [intermediate atypical carcinoma], FISH [fluorescence in situ hybridization],or even next-generation sequencing [NGS]. I assume you’re HER2 testing your newly diagnosed, advanced serous cancers with the opportunity for trastuzumab. Tell me about that.

Brian M. Slomovitz, MD: First, what’s considered HER2+? Three-plus by IAC. If it’s 2-plus by IAC, then you need confirmation by FISH. That’s what makes it positive. Now a group of investigators led by Dr Amanda Nickels Fader did some groundbreaking research, because we’ve never needed more for these patients. They looked at adding trastuzumab or a HER2 antibody with chemotherapy, carboplatin and paclitaxel. What they found is those patients with uterine serous tumors that were HER2 positive did better than those patients who just got the standard chemotherapy.

Not only that, but they also presented their more recent data this year at the Society for Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer. They found that the effect is best seen in the advanced-stage patients who were given it at the time of diagnosis. It’s adding a molecularly targeted therapy. It’s biomarker driven; it’s making a difference. Truthfully, we need to do more work in investigating the benefits of this because we need better therapies for patients with uterine serous cancers.

Bradley J. Monk, MD, FACS, FACOG: That’s a Level 2A NCCN [National Comprehensive Cancer Network] recommendation.

David M. O’Malley, MD: Yes, the paper is in press with regard to the follow-up, which showed survival analysis. This wasn’t a blinded study. But the benefit persisted to show overall survival benefit. I agree 100% that the greatest benefit is in those patients who are not previously treated. The question is, how long do you give the trastuzumab? For an advanced patient who’s stage IVB, I’m going to give it until toxicity or progression. In a stage IIIC patient, I’m trying to get them out 5, 7 years. Once we get there, I’ll let you know what I do.

Brian M. Slomovitz, MD: This is where the uterine serous stage IV, we’d like to think that those are like ovary where they get 5, 6, 7 lines of therapy. It’s not the case. I agree with Dave: Keep them on a maintenance therapy as long as possible. Because when they recur, yes, we use pembrolizumab-lenvatinib, but even then, there’s a poor prognosis.

Kathleen N. Moore, MD: And it introduces the opportunity to use maintenance. We’ve tried to use maintenance in endometrial cancer several times without an indication, shockingly, with bevacizumab. Although it probably should have been. But this allows us to stop the chemotherapy and continue with something that’s active as maintenance or continued treatment. Which is a nice shift in the treatment paradigm for women who otherwise were left on therapy for a long time.

Bradley J. Monk, MD, FACS, FACOG: Yes, that’s excellent. We’ve established that the frontline treatment, systemic-wise, is carboplatin-paclitaxel. That basically, all patients second line should get pembrolizumab. Pembrolizumab alone if they’re MSI-H [microsatellite instability high] and the combination with lenvatinib if they’re not. That’s well established. We agree. That’s the consensus. We can deal with some of the adverse effects. Krish, many patients fail and need third-line treatment. More and more, to your introductory comments, lines of therapy. How do you decide what the third-line treatment should be after failing those first two regimens?

Krishnansu S. Tewari, MD: Yes. That goes back to what we were talking about, doing next-generation sequencing on the tumor. Trying to find an actionable mutation that’s druggable. Ideally, put them on a trial. But in the absence of a trial, look for a target that there’s an available drug maybe for another indication that we can use for these patients.

Bradley J. Monk, MD, FACS, FACOG: I want to hear from all 3 of you what the best third-line treatment is. Brian, why don’t you go next?

Brian M. Slomovitz, MD: If it’s ER [estrogen receptor] positive and almost all endometrioid tumors present good evidence of mTOR inhibition with aromatase inhibitors as an option for those patients. Even outside that, hormonal therapy is an option. With the responses that we’ve seen in some of those patients within the first 3 lines of therapy, in the end I’m not even sure we should wait for third line if it’s particularly ER positive.

Bradley J. Monk, MD, FACS, FACOG: Katie, what do you think?

Kathleen N. Moore, MD: I’m going to next-gen sequence them and look for targets. Because you will find NF1 mutations. You’ll find things that if you have clinical trials open, you can try to match them to—it’s a needle in a haystack, but we look for that. In the absence of that, for endometrioid, I’ve been a big fan—as is Dr Slomovitz—of CDK4/6 inhibitors. I tend to go to those plus letrozole. I’ve had nice disease stabilization. It’s well tolerated. Maybe it would work for serous, but I’ve just been using it for endometrioid serous to pull out the anti-intergenics if they haven’t seen that. I pull out other chemotherapies. But I’m mainly looking for trials to put them on. There are a lot of trials, thankfully.

Bradley J. Monk, MD, FACS, FACOG: Dave, does it make and sense: carboplatin-gemcitabine or weekly paclitaxel-bevacizumab?

David M. O’Malley, MD: Does it make sense? Probably not. Weekly paclitaxel-bevacizumab is not unreasonable because there aren’t much data. It’s a part of the arm on the KEYNOTE-775 trials, weekly paclitaxel without bevacizumab. The only other thing I would add to this third line is hormonals. Remember the GOG [Gynecologic Oncology Group] did, and they used tamoxifen. It was a nice response rate: close to 24%. When we look at this, the addition of hormonal therapy in the endometrioids is obviously important. In those nonendometrioids, I try to get bevacizumab in. I send next-generation sequencing on all these patients. You’ll occasionally find a BRCA. You may find even some other HR [hormone receptor] mutations, which allow you to try to get a PARP approved. There are options. But all these patients I send for NGS.

Bradley J. Monk, MD, FACS, FACOG: Yes. That’s interesting. Just yesterday, I got a KRAS G12V mutation third line. I’m going to give her binimetinib MEK inhibitor. I hope it gets paid for.

Brian M. Slomovitz, MD: It’ll get paid for. Off-study, the next conversation in third line. It’s important knowing that immunotherapy works with endometrial cancer. There are a couple of studies in the public domain that are going to be looking at re-treating checkpoint failure patients with checkpoint combinations. There is a study by Insight on clincialtrials.gov that is going to be looking at their checkpoint inhibitor in biomarker negative patients with an IDO inhibitor in FGF-mutated patients with an FGF inhibitor. There’s a similar study, an umbrella study, by Genentech and the Alliance using atezolizumab as a backbone in recurrent patients with atezolizumab-bevacizumab for biomarker negative, atezolizumab-PARP for the TP53-type mutations, and atezolizumab with and AKT inhibitor for those with an AKT signature. Even after failing immunotherapy, there may be a role for immunotherapy based on the results of these studies in a second-line setting as well.

Bradley J. Monk, MD, FACS, FACOG: Yes. Katie, you set the landscape. Brian, you gave some specifics. There are a lot of trials for these women. I know all 4 of you have high-enrolling sites.

Transcript Edited for Clarity

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