Kathleen N. Moore, MD, MS, is an associate director of clinical research at the Stephenson Cancer Center, the director of the Oklahoma TSET Phase I Program, and a professor in the Section of Gynecologic Oncology at Oklahoma University (OU) College of Medicine, OU Health.

I’m going to close. It’s been a lot of fun for me. I’m going to go around, though, and I want you guys to make a prediction. Look into your crystal ball at where we’re going to be in a year. I don’t mean relative to the pandemic. Where is the treatment of endometrial cancer going to be in a year? Are we going to be at the same place? Our field is evolving so quickly that we’re going to be in a different place. I’m going to start with you, Brian. Where are we going to be in a year?

 A year is too short to achieve my goal of eliminating chemotherapy-based disease. But we alluded to this earlier, I think we’re going to rely more and more on our molecular classifications. 

-mutated tumors are going to be treated differently than non-

 tumors. I’ll say it in the strongest possible way, all patients with endometrial cancer are going to get immunotherapy before they succumb from their disease. I’m not sure of the exact line, but all patients are going to get some form of immunotherapy.

 Krish or Dave, where do you think we’re going to be in a year? Maybe a year is too close.

 I think in a year, even without the GY018 trial, we’re going to be adding pembro [pembrolizumab] in the first line to adjuvant therapy. I think in 3 years, the front line is going to be pembrolizumab alone.

 Particularly in the MSI [microsatellite instability]-high, yes. Dave, go ahead.

 We’re going to see the approval of len/pem [lenvatinib, pembrolizumab] in the recurrent setting for full approval, so our European and ex-US colleagues can have that option for their patients. We need to move and will move with information and education like we’re doing here today with regard to more molecular-based therapy, even in early stage disease. In a year, we’re going to be using more chemotherapy in patients with 

 mutations, and we’re going to be using, as you said, immune therapy in those deficient patients.

 Yes, thank you for that. Katie, go ahead. Last word.

 A year is a little short, but I do agree that we’ll confirm len/pem [lenvatinib, pembrolizumab]. I think that’ll be a positive study. That’ll be a confirmatory approval that will go global. I think there are data coming out in the next year that will inform the next series of trials. You brought up 

 212B. There’s a lot of work with specific KRAS inhibitors and SHIP2 inhibitors that can target something that’s really common in endometrial cancer; 30%, 35% have a 

We’re learning that right now. These studies are ongoing. We’re going to be able to target KRAS. That’s going to open up a bunch of new therapies for our patients. The work being done with molecularly targeted therapies, AKT inhibitor olaparib in particular, is very interesting. I think we’re entering a molecularly guided era beyond MSI and HER2with targets that heretofore were not targetable, which is exciting for all solid tumors. Who doesn’t want to target KRAS?

 We’d like to target TP53 directly, but that’s a little more pie in the sky.

 Yes. Thank you for that. From a practical perspective, and you guys said all these, probably within the year, Dave, dostarlimab will get approved in MSI-high, second line. That’ll be some good competition. Many of you said KEYNOTE-775 will be approved in second line for non–MSI-high, pembrolizumab, lenvatinib, a global approval. To your point, CDK4/6 inhibitor, letrozole will probably get compendium listed, too. We’ll have 3 new opportunities, depending on where you are in the world. Then the molecular staging will evolve with some of these combinations, for those of you who do phase 1 studies, that we haven’t thought about because we’re better defining these unique populations and going from heterogeneity to homogeneity. I want to thank you four. I know you’re very busy here. It’s been fun to see you. Thank you all for this rich and informative discussion. Thank you.

Videos

Future of Advanced Endometrial Cancer

 We’ve talked about chemotherapy regimens, and I’d like to finish with a couple of them. Trastuzumab works well with chemotherapy. It really doesn’t shrink tumors alone. There is now this whole concept of adding an oral anti-HER2 TKI [tyrosine kinase inhibitor] with an antibody. That never really worked with the anti-VEGF space, so bevacizumab plus an anti-VEGF TKI. But this idea of tucatinib plus trastuzumab has had some traction in breast cancer. As you can see, we’ve learned a lot from breast cancer biology and we’re leveraging that, such as CDK4/6 in endometrial. Dave, I know you’re working on this, this tucatinib/trastuzumab idea. Tell me, does that make any sense? Are you excited about it? I hope you are, because I am.

 I’m so glad you pronounced that. That’s a tongue twister, those 2 in a row, tucatinib and trastuzumab. You’re so good. We just talked about the pan-TKIs and the activity. This is a basket trial. They have to have HER2 overexpression or amplification. Cervix, uterine cancer, biliary tract, urethral and nonsquamous non–small cell lung cancers. Obviously, the uterine cancers are what we’re talking about here. If you have a patient who has overexpression or amplification for HER2/neu, they’ll be put on one of these 5 cohorts. They also have a breast cohort and another GI [gastrointestinal] cohort in these patient selections. They’ll do an initial early first cohort. If they see some activity, that will be expanded into a larger second stage. Hopefully, we’ll see some results as exciting as we’ve seen in breast cancer.

 With your leadership and since HER2 is so commonly over expressed in serous cancers, you’ve allowed prior adjuvant chemotherapy, trastuzumab to be eligible. And again, I know Brian, you’re the chemotherapy-free “ambitionist.” You get chemotherapy, HER2, you get some maintenance HER2, and then you layer on the tucatinib and you get tumor shrinkage. I’m really excited about this.

This is open in the US Oncology Network. I know you have it open at The Ohio State University and other centers. It all starts, back to our initial conversation, with biomarker testing. Biomarker testing creates the opportunity. Brian, there’s another study that I’m aware of, and I’m sorry to list so many studies, but not really. Because studies are what help us gain discovery in patients and improve outcomes. I apologize that it’s taken so much of our audience’s time. But I’m happy to talk about it. Tell us about selinexor and the SIENDO trial.

 Selinexor, this is another large, randomized phase 3 trial in women with advanced endometrial cancer. They get their chemotherapy first, and then following chemotherapy—it’s a maintenance trial. The patients are randomized to selinexor versus placebo in the maintenance trial to help keep the disease away longer. It’s another exiting trial that we’re looking forward to.

 Katie, all of you mentor your colleagues. This is another mentor trial in which Katie Moore is mentoring Debra Richardson, MD, FACOG, FACS. I know you’re passionate about this. Do you have any comments on this? This is a molecule that’s approved for liquid tumors. I’m excited to open, and it’s brand new.

 Yes. This is an interesting agent. It is now on the NCI CRADA [National Cancer Institute Cooperative Research and Development Agreement], and there are a bunch of studies coming out across solid tumors. It’s a nuclear exporter inhibitor. It hits XPO, so it presents exportive oncogenes. It keeps them localized so that they do their oncogenic things. It has a nice history, proof of principle in hematologic tumors and solid preclinical data. Vicky Makker, MD, who has led a lot of the early development for this asset, just published in 

, the work in ovarian cancer, looking at homologous recombination proficient tumors. It has some potential for gynecologic malignancies. This is an interesting opportunity to study it again as maintenance in endometrial cancer. Like trastuzumab, it’s not something we’ve been successful with at this point. But we’re starting to get to a place where we can offer women something other than continuous carbo/taxol [carboplatin, paclitaxel]. The mechanism is very different. There doesn’t seem to be a biomarker yet, but it’s very cool.

 It is the first-in-class nuclear pore inhibitor. As you say, it inhibits trafficking of some of these oncogenic drivers.

Novel Targets for Advanced Endometrial Cancer

 Let’s talk about some novel targets. One of the questions I always have is chemotherapy versus hormonal therapy. I know, Brian, you’ve been a passionate advocate for everolimus, letrozole, one of the chemotherapy-free regimens beyond pembrolizumab, lenvatinib—that’s a second one. Now the third one is an aromatase inhibitor, a CDK4/6. Tell us about this third chemotherapy-free combination. You’ve got letrozole, mTOR everolimus; you’ve got pembrolizumab, lenvatinib; and now you have CDK4/6, AI. Tell us about that.

 There are many different options for endometrial cancer. Katie alluded toward this. Right now, we’re doing it mostly on trial, it’s tough to get off trial. But there was a recent study presented at ESMO [the European Society for Medical Oncology annual meeting] by the ENGOT [the European Network for Gynaecological Oncological Trial] group, the PALEO trial, looking at a CDK4/6 inhibitor plus letrozole, versus letrozole alone. They really did significantly better as far as progression-free survival [PFS] in the CDK4/6 plus letrozole group. Within the GOG [Gynecologic Oncology Group], we have a single-arm activity trial opening up.

Again, this mimics what we’re learning in breast cancer, where it’s an FDA approved indication, that a CDK4/6 plus letrozole is likely going to be, we saw it in PALEO and we’re likely going to confirm it, an active regimen for patients with endometrial cancer. It has a different set of adverse events, a different toxicity profile. But it provides more options, which is great when we’re talking about treating our patients with endometrial cancer.

 Yes, we talked about trastuzumab adding to chemotherapy to treat serous patients who are HER2positive. I’m hoping that a CDK4/6, AI would get compendium listing, which the HER2 opportunity is. Did your everolimus, letrozole ever get compendium listing?

 Yes, it did. That’s everolimus, letrozole versus what Dave alluded to, the progestin, tamoxifen in GOG-3007, and it got listed in the NCCN [National Comprehensive Cancer Network] guidelines. The key there, we saw a similar response rate to hormones, but our progression-free survival in the chemotherapy-naive patients was 24 months. It’s an active regimen, very tolerable. Not to forget in this age of COVID-19 [coronavirus disease 2019], which we keep hoping to talk about in past tense, but we’re not, oral regimens could keep patients out of the infusion center.

 Yes. Krish, you’ve had the pleasure of training under Dr Desai. I can remember talking to you about some of these patients who were treated initially with antihormonal therapy and lived for a long, long time, particularly with lung metastases in his patients. Do you ever use hormonal therapy before chemotherapy?

 To your point, I love to use it first. I love trials, but that’s exactly the patient population, these patients who come in with recurrent disease in their lungs. You put them on tamoxifen, Megace [megestrol], or I actually like Brian’s regimen now better. They can cruise for years without chemotherapy. I don’t know what it is about the lung metastases, although I have seen benefit in abdominal metastases, as well, in older patients who don’t want chemotherapy. It’s a very important thing to remember when you have a lot of these patients who are frail and have medical comorbidities. For endometrioid cancers, this is a really effective set of combination options in which patients can just cruise.

If they don’t, just like to your point earlier Krish, try it. If it doesn’t work, you can go to chemotherapy. That’s fine. You’re not going to lose that much ground over 2 months potentially. That’s an important thing that I think people forget in endometrial cancer, even though they’re so used to it in breast cancer.

: Real quick, cross-trial comparison. We’re not allowed to do it. But GOG-209 was reported: measurable disease, 52% response rate, as Katie mentioned earlier, 24-month PFS. Chemotherapy, you lose your hair, toxicity, tingling, everything. Everolimus, letrozole, chemotherapy naïve, get the prescription, take it home: 53% response rate, 24-month PFS. Same outcome, different profile.

 Interesting, lower extremity edema. Wee1 inhibitors, Krish. Tell us about that, I saw these data presented on the Wee1 inhibitor AZD1775 [adavosertib] in the serous tumors. I’m not very familiar with that.

 It’s another checkpoint inhibitor, but it’s not an immunologic checkpoint. This is a cell cycle checkpoint inhibitor. This is a novel mechanism of action. It inhibits the molecule that shuttles cells into the mitotic phase. This is about 30 patients, 34 patients with serous cancers. Response rates were about 30% with this drug, with a median PFS of 6 months. It’s an active drug in this group of patients. I can’t remember how many prior lines of therapy they had, but they were pretty heavily pretreated.

 I came to Arizona in 2010, and we were doing the same agent with chemotherapy in cervical cancer. It sounds like this is the best opportunity. It took us a decade to figure it out. But I hope that they take it forward.

 Yes, me too. I remember John Farley, MD, was looking at that with cervical cancer, through the GOG.

Endometrial Cancer: Chemo-Free Regimens on the Horizon

 I want to talk about some of the large phase 3 trials. Probably the first to report will be the proof-of-principle concept for the accelerated approval of pembrolizumab-lenvatinib, which is called KEYNOTE-775. Why don’t you go ahead and tell us about that, Dave?

 Yes, we just mentioned 1 of the options for beyond second-line therapy, beyond carboplatin-paclitaxel. This is looking at 1-on-1 randomization in that second, above a group of patients, looking at lenvatinib-pembrolizumab vs weekly paclitaxel or doxorubicin. These are the 2 standard-of-care arms. Standard of care vs lenvatinib-pembrolizumab. The 2 options are doxorubicin—or weekly paclitaxel. That should hopefully read out in the next year or so. We look forward to seeing those results.

 Yes, the good news is that this will give a global opportunity. We have the accelerated approval in the United States, but pembrolizumab and lenvatinib is not available internationally. Not only will this convert the accelerated approval potentially to full approval in the United States, but it will give an international opportunity. I’m very excited about that. We’re trying to add checkpoint inhibitors frontline. We talked about the NRG-GY018 trial, which adds pembrolizumab to chemotherapy. Brian, I know you’re trying to add dostarlimab to frontline chemotherapy. Tell me about RUBY.

 Yes. In the RUBY trial, which is an ENGOT [European Network of Gynaecological Oncological Trials]–GOG [Gynecologic Oncology Group] initiative, we’re using carboplatin and paclitaxel as the standard-of-care arm. Patients are randomized to placebo vs addition of dostarlimab. A nice thing about this trial is it includes carcinosarcomas. We haven’t focused a lot on that, but carcinosarcomas are in the realm of advanced breast and endometrial cancers. We need better treatment options for them. They’re likely to respond to immunotherapy. We’re well on our way. We’re accruing nicely to that trial. Those results may—if it’s a positive trial, we may add dostarlimab to the frontline therapy.

 Think of this: We’ve got pembrolizumab in the frontline and dostarlimab in frontline. Now Katie Moore, you’re mentoring Dr Shannon Westin from The University of Texas MD Anderson Cancer Center with durvalumab. It’s so exciting. The endometrial space is so robust. Tell us about the study that you call DUO-E. 

 DUO-E is the best trial. The trial has paclitaxel-carboplatin vs paclitaxel-carboplatin with durvalumab and durvalumab maintenance versus paclitaxel-carboplatin-durvalumab in the durvalumab-olaparib maintenance. It’s incorporating a PARP inhibitor with an immune checkpoint inhibitor into the maintenance setting for advanced endometrial cancer. Of course, this is stratified by MSI-H [microsatellite instability high]. This is open globally and accruing quite well.

There are some early data coming out of NRG Oncology that probably the benefit is going to be in combinations. Endometrial cancer, for the most part, does not have the HRD [homologous recombination deficiency] signature that we think of in ovarian cancer. We’re going to see a lot of single-agent activity. But in combinations, it does appear to be active. Dr Westin has led a lot of those studies out of MD Anderson. The PARP inhibitor story is an interesting 1 in endometrial cancer in understanding that the biomarkers for relevant combination are going to be key. This will be a big opportunity for us to see if the patients do better with the combination.

 That’s very exciting. Krish, again, you’re our big advocate of anti-VEGF I/O [immuno-oncology]. Tell us about this cabozantinib-nivolumab opportunity.

 We just heard about this at the virtual ASCO [American Society of Clinical Oncology 2020 Annual Meeting]. This was an interesting study because it’s combining a VEGF receptor to inhibitor cabozantinib with nivolumab vs nivolumab alone. Then they also have this other cohort—we were talking about carcinosarcoma. They had about 9 or 10 women with carcinosarcoma. The combination was exciting because more than half the patients had 3 or more prior lines of therapy. Median PFS [progression-free survival] for the combo was about 6 months versus 2 months with the nivolumab alone. Even among the carcinosarcomas, 6 or 7 of these 9 patients had had prior I/O, and all 6 of those patients had partial responses [PRs]. It’s an exciting combination, and it deserves a further look.

 You’ve got I/O plus VEGF. KEYNOTE-775 second line, LEAP-001 frontline, cabozantinib-nivolumab—unbelievable. Three studies. Then we add chemotherapy to I/O, in RUBY. Right? And NRG-GY018. Then Katie Moore and the group are adding PARP inhibitors. What a wonderful opportunity for combinations: VEGF, chemotherapy, and PARP. Go ahead, Brian.

 Yes, I know you mentioned LEAP in the first line. Just to be complete, there’s also, in Europe, the AtTEnd trial, which is a RUBY with carboplatin-paclitaxel plus or minus atezolizumab. One of the things we’re really excited about is we’re finally doing an I/O adjuvant trial in the advanced stage. This is available for public consumption. We’re going to enroll 990 patients. For those patients with advanced 

-positive stage I or II disease or stage III or IV disease with no measurable disease, carboplatin and paclitaxel plus or minus pembrolizumab. We’re looking at it in the advanced measurable setting, and now the GOG is going to be doing this study with ENGOT in the advanced adjuvant setting. Those patients can get radiation based on clinician discretion while they’re still in the trials.

 Yes. KEYNOTE-B21 is listed on clinicaltrials.gov. Thank you. Incidentally, Brian, Dr Slomovitz is the GOG partners endometrial cancer lead and is a passionate advocate for all these studies.

Emerging Agents: Treatment of Endometrial Cancer

 [human epidermal growth factor receptor 2] testing. 

 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 

 testing your newly diagnosed, advanced serous cancers with the opportunity for trastuzumab. Tell me about that.

+? 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 

 antibody with chemotherapy, carboplatin and paclitaxel. What they found is those patients with uterine serous tumors that were 

 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.

 That’s a Level 2A NCCN [National Comprehensive Cancer Network] recommendation.

 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.

 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.

 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.

 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?

 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.

 I want to hear from all 3 of you what the best third-line treatment is. Brian, why don’t you go next?

 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.

 I’m going to next-gen sequence them and look for targets. Because you will find 

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.

 Dave, does it make and sense: carboplatin-gemcitabine or weekly paclitaxel-bevacizumab?

 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 

 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.

 Yes. That’s interesting. Just yesterday, I got a 

 G12V mutation third line. I’m going to give her binimetinib MEK inhibitor. I hope it gets paid for.

 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 

-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 

-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.

 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.

Sequencing for Advanced Endometrial Cancer

Brian, I want you to weigh in on what I asked Katie. How do you decide in a pretreated patient? The label for pembrolizumab, lenvatinib is you’ve got to have the molecular signature, you have to have had prior systemic therapy, and you can’t be cured with surgery or radiation. Who is it not right for? Or is it basically right for most patients in the second line?

 It’s going to be right for most patients in the second line. We always have to talk about the future, until it gets approval in the first line. Because we’re doing the trial, which is accruing nicely. It’s a Merck-sponsored trial that we’re doing. It’s outside of the GOG [Gynecologic Oncology Group] but it’s accruing nicely. It’s looking at pembrolizumab, lenvatinib in the first-line setting.

Versus chemotherapy, versus carboplatin, paclitaxel.

: Versus chemotherapy in the first-line setting. Now remember, the other thing about what you just said is the label for pembrolizumab, lenvatinib as written is for a prior systemic therapy.

: They could have gotten 1 dose of cisplatin and 40 mg of…with 1 week of radiotherapy, and they’re indicated to get it. They could have gotten 1 week of Megace and be eligible for pembrolizumab, lenvatinib. It’s a game changer. I know we’re going to talk about the ongoing trials. I think that this one has the potential to have the most impact. Because as I mentioned earlier, it may knock chemotherapy off the pedestal for the first-line treatment of endometrial cancer. It’s exciting.

The toxicities that Dave was talking about, they’re there. In the trenches, we’re learning how to better handle those toxicities. We’re starting at lower doses of the lenvatinib. We’re learning how to deal with some of the diarrhea and hypertension, which happens. It’s an extremely exciting time. Every second you were talking about cervix and ovarian cancer, I’m thinking, let’s get back to endometrial.

 Let’s try not to use the word toxicity, because that word is toxic. These are adverse reactions. All systemic therapies have some adverse reactions associated with them. I just want to review with you, this is a combination. You have the immune-related adverse reactions related to the pembrolizumab, and then those related to lenvatinib. Lenvatinib really is 2-fold. It’s an oral anticancer therapy, so it has some fatigue and some GI [gastrointestinal] disturbances. But it also has the anti-VEGF effect, which includes hypertension, proteinuria, wound healing, and so on. You have to balance the IO [immune-oncology] aspect, the oral aspect, and the anti-VEGF aspect, and we’re good at it. 

All of you said you were excited about it. All of you inferred that it’s probably better than chemotherapy. Then you said, Brian, well, we’re comparing it to chemotherapy, in the existing label indication KEYNOTE-775, and comparing it in the front line in LEAP-001. So Dave, 88% of patients have to interrupt or dose reduce their lenvatinib. You start at 20 mg, and you go 20 to 14 to 10 to 8 mg, what’s the right starting dose? Is it 20 mg? Or is it 14 mg?

: I don’t start at 20 mg on anybody. But it’s more a practical reason. I start at 18 mg. There’s a package insert, or a tab, of 18 mg. It gives you a 10 mg and two 4 mg. Thus, if you know that 70% are going to be dose reduced, and as you said, almost 90% would have dose interruption, it allows you to get down to 14 mg much easier than waiting for a new script and a new co-pay and all that. I start at 18 mg. If they need dose reduction, they have the 4 mg there. It works perfectly. There are people who are starting at 14 mg. There may be some induction. That’s why I’m a little apprehensive to go all the way down to 14 mg on all my patients, but it’s also very reasonable. I like 18 mg.

But the study was 20 mg. Where are the data on 18 mg?

: There are no data on 18 mg. There are no data on 14 mg….

There are no data starting at 14 mg, but there are lots of data that if you start at 20 mg you get to 14 mg in the induction effect. I’m not trying to conflict against you, I’m just saying, I try to follow the recipe. Go ahead. Any of the 3 of you, Krish, Brian, or Katie, who want to chime in on this.

: I start at 20 mg, and we’ve had to drop down to 14 mg and down to 10 mg on a few patients. But I’ve got quite a few patients who are tolerating it pretty well. The worst I’ve seen is maybe some grade 1 or 2 hypothyroidism.

: Yes. I honestly do think there are regional differences in patients. But we have a lot of patients who present late for care and with very advanced disease and a lot of comorbidities. I don’t start at 20 mg and neither do my partners for recurrent disease. They’re so sick, and if they get sick on 20 mg, they’re not going to dose reduce, they’re just going to come off and go to hospice. For us, we start at 14 mg, although you might have just persuaded me, Dave. I like what you just said about starting at 18 mg. Maybe I can start at 14 mg and then escalate up. But I start at 14 mg, and I get 2 months in, and then if they’re doing fine, I escalate them to 18 mg. I’m going to be honest, in our sick population, I can think of 3 patients who were told they needed to go on hospice who are now going to have more time because of this drug.

I was real worried about the toxicity, and I was not a super believer, but it works. I like 14 mg because I haven’t harmed anybody, and I can escalate them. That’s what we do.

: What about the induction? What about the induction piece?

: Well, the induction piece is interesting. Does it help to get that higher level? I’m not sure of the answer to that. I don’t know we’ll ever have the answer to that. But one thing, Katie, that you just said, they’re going to get to this next holiday. There’s an 11% complete response [CR] rate. I have some sustained partial and near complete response using this combination. Are we talking that we may be able to cure recurrent endometrial cancer?

In the label, 94 patients, 38.3% response rate, 69% of them remained progression free for 6 months. Krish, to your point, your induction, you taught me that this anti-VEGF effect impacts ascites. If I have a recurrent endometrial cancer that for sure is not MSI [microsatellite instability]-high because that doesn’t exist, I want her to get some serious anti-VEGF activity to help her with her symptomatic ascites. It’s individualization, there’s no one-size-fits-all, but that’s an example where I want to get some anti-VEGF effect because what’s hurting her is her cancer. If I don’t get control of that ascites, she’s going to get a malignant bowel obstruction.

: I totally agree with you, Brad. The patient I was just talking about presented with 8-liter paracenteses for 3 consecutive weeks. Then she came to me for a clinical trials consult. She’s dying. Now we’ve got her on study, and we’re at like 2 liters a week now, from 8 to 2 liters. It’s not perfect, she’s not a CR, but she’s walking and functional and eating again. It’s that VEGF, it’s amazing.

It is. To your point, if she throws up her lenvatinib, you haven’t accomplished anything.

: I don’t switch to 18 mg, I keep it at 14 mg. Brad, to your point, we don’t know the activity, come on, we just got over niraparib. We almost lost niraparib because we started at 300 mg and there were too many adverse events. If they’re doing great, have them go up to 18 mg. It works.

Krish says, what about Doxil, or liposomal doxorubicin? Liposomal doxorubicin, for all intents and purposes is inactive as a single agent in ovarian cancer. With response rates of around 10%, or I don’t know what it is.

Both. I was talking ovarian cancer. But it’s like 0% in endometrial cancer.

: Yes. Zero in endometrial. Look at the AURELIA trial, it’s 10%, 13% with bevacizumab.

Right. My passion, though, for dose intensification of pembrolizumab, lenvatinib is because I get 40% response rate for it. I get a durable duration. To Dr Moore’s point though, if it’s intolerable, it’s going to be 0%. You’re all right.

: My patients are not that sick when we put them on the combination. But I’m doing this talk from my St. Joseph Hospital office. I just remembered what my nurse navigator always says, when this combination works, it really works. Disease isn’t gone, I can scan them and it’s still there, but it’s not hurting them, it’s stable. They’re doing great on the combo.

Any closing comments on the activity and the tolerability of pembrolizumab, lenvatinib in non–MSI-high endometrial cancer?

: The message needs to get out. This is something that we need to push out. The question about, do you go to chemotherapy first or do you use this? I don’t know. I feel like maybe we need to use this first. It’s probably more active, is my gut feeling. But that’s something we need to sort out and get into the community a lot more, and tailored instructions as to how to manage the toxicity. Although, again, medical oncologists know how to use lenvatinib. They’ve been using it for a long time. They understand the hypertension’s fast, they know how to manage the fatigue, and they know how to manage the diarrhea. And they understand pembrolizumab. They’re probably ahead of us on that. It’s just remembering to use it.

Dave, you were going to talk about the importance of the multidisciplinary team, go ahead.

: Yes, absolutely. I have an amazing nurse practitioner who works with me, and they take these phone calls and they have strict SOPs [standard operating procedures] in place, with regard to hypertension, with regard to diarrhea. If you’re working together, it can really help control these symptoms.

 I agree with that completely. Pembrolizumab, lenvatinib doesn’t start when you take the medicines, it starts when you decide to take the medicines. From that point, you’ve got to get the blood pressure under control, to Dave’s point, getting your nurse extenders involved, and preparing for the diarrhea. If you’re prepared, I find that it’s a tolerable regimen, and obviously, we talked about the efficacy.

Recurrent Endometrial Cancer: Safety of Combination Therapy

Let’s transition and talk about the best treatment for second-line non–MSI [microsatellite instability]-high recurrent endometrial cancer. Katie Moore, you mentioned that pembrolizumab got accelerated approval for all MSI-high tumors, that that message is out there, that we’re using it, we’ve seen fantastic responses, sometimes over 50% in some cohorts. But most patients are not MSI-high. This has created a high unmet medical need, a need that we’ve been working on intently. Then ultimately, there was a study that led to accelerated approval again, but this time not in the MSI-high subgroup. Dave, tell us about this opportunity.

: When we look at this group of patients, we have lenvatinib and pembrolizumab, which has, as I said, about a 37% response rate [RR]. The problem is the toxicity, which we’ve all alluded to. You’re talking about 70%, maybe even more, dose reductions, and about 90% if you include the interruptions. When we look at these patients, we get some amazing responses. In the waterfall plot of this original paper, basically everybody responded. That’s unheard of in second-, third-line endometrial cancer. We see this group of patients receive these opportunities. But we must get better at managing the toxicities.

Katie Moore, I’ve heard people say that if you get frontline carboplatin and paclitaxel in the adjuvant setting, and if it’s been, I don’t know, 6 or 12 months, because of some of these adverse events of the pembrolizumab, lenvatinib combination, that maybe you should go back to chemotherapy first. You talked about the expectation for GOG-209, that this was chemotherapy sensitive. What’s the expectation of retreatment let’s say with carboplatin and paclitaxel, so that we can make an assessment? Should we do that in the second line and relegate pembrolizumab, lenvatinib to third line, or do doxorubicin, something completely different?

: Yes. That is the question. The answer is, we don’t know. We all guess. There is no defined platinum-free interval for endometrial cancer. Although people talk about it, it’s all made up data. There’s no 6- or 12-month interval that predicts re-response to platinum. It’s never been prospectively studied. The ongoing studies that we’re going to talk about at the end of this, do allow patients who had adjuvant paclitaxel, carboplatin, and they have variable periods, usually it’s a year,when they can come on these frontline metastatic studies. We will have those data coming. We’ll see if anybody responds. Is it like ovarian cancer? I bet not.

: I don’t know if I should say I wish it were, but we kind of wish it were, where we could repeat use platinum. I don’t think we can. We’re going to learn it. That’s coming. But it does present this clinical dilemma where you have these patients who received adjuvant therapy on the GOG-258 regimen or whatever, and 2 years later, they recur. Do you go right to this lenvatinib, pembrolizumab combination, which has the highest response rates we’ve ever seen in second-line endometrial cancer? Or should you start with, and this is with MSS [microsatellite stable] of course, should you start with chemotherapy again and see if they re-respond?

Krish, you’ve been on all targeted therapies, all of you have,you’ve been an advocate of this anti-VEGF checkpoint combination in cervical cancer and also here. Tell us about the biology. Why would an anti-VEGF make IO [immuno-oncology] work in a cold tumor where it otherwise is not working?

: Yes. It’s interesting. This is what’s exciting about it. Because we know that VEGF is immunosuppressive, especially in the tumor microenvironment. It’s this combination that allows for the tumor immune microenvironment to be reprogrammed, if you will. That’s where the synergy comes in. But we always say cross-trial comparisons are never good. But I like to cross tumors and stuff. If you look at PAOLA, you have patients who are HRD [homologous recombination deficiency] positive but they’re not necessarily 

mutated. But they need something else other than just the olaparib to work in the maintenance setting, so you add BEV [bevacizumab]. In this case, you have a microsatellite stable patient and they could benefit from pembrolizumab, but they need something else. That’s where the combination with anti-VEGF comes in.

I do that all the time. I try to look at other tumor types and get smarter and learn from my colleagues in ACC [adenoid cystic carcinoma], so atezolizumab, bevacizumab.

But it didn’t work in ovarian cancer. Why, Katie Moore, why? It didn’t work in IMagyn050, presented at ESMO [the European Society for Medical Oncology annual meeting].

: Yes. That’s why we don’t want this disease to be more like ovarian cancer….

Any comments on that, Katie? This is not an ovary discussion, but it’s weird, isn’t it?

: I thought it was going to be positive. Ovary is just not these other tumors as much as want it to be. The synergy that was seen in HCC [hepatocellular carcinoma] and renal cell and increased T-cell trafficking and all the things that should have worked, and maybe they did happen, we don’t know. Maybe they did happen in the ovarian cancer tumors, but it didn’t matter. It probably comes down to lack of understanding of biomarkers. We have a lot to learn, but it didn’t work in ovary, unfortunately. But here it does work in endometrial cancer.

: Yes. It’s cervical cancer. It’s chemotherapy with or without bevacizumab, plus or minus pembrolizumab. It’s for the first line of recurrent metastatic cervix cancer. I’m hoping it’s going to be a positive trial. Like I said, we should know in 2021.

Yes. IMagyn050, we were hoping; it didn’t work. But we haven’t given up. KEYNOTE-826 is your regimen, Krish, GOG-240, chemotherapy, bevacizumab, first-line metastatic cervical, adding pembrolizumab to it.

Combination Therapy for Recurrent Endometrial Cancer

 Dave, I’m saving the best for you. I have news for the world that pembrolizumab isn’t the checkpoint inhibitor. Right? Shocking. I know sometimes you think that way. But we have 6 FDA-approved checkpoint inhibitors. You work on probably No. 7 and No. 8. You work on balstilimab and dostarlimab. Tell us a little about dostarlimab in endometrial cancer. Because that’s likely to be the next FDA-approved checkpoint inhibitor.

 I would love for that to happen. I love competition. Competition is good for our patients. It’s good for the cost of health care. I hope that that occurs. This is a nice presentation, but these data on endometrial cancer are basically 2 trials. One on endometrial-proficient patients and 1 on deficient patients. These were 100 in the deficient arm, 140 in the proficient arm. What we showed was a 45% response rate in the deficient group and 13% response rate in the proficient group. Very consistent with what we’ve seen, particularly in the deficient. But we also have seen a group of patients here, about 13% response rate with single agent. We’ve alluded to the lenvatinib-pembrolizumab data, which had about a 37% response rate. It doesn’t compete with that combination. But we do see some activity.

Emerging ICI Therapy for Advanced Endometrial Cancer

Let’s discuss what you guys are excited about. What I’m excited about is immunotherapy. Immunotherapy in ovarian cancer has been very disappointing.

But in cervix and endometrial, it’s very exciting. There are several trials, and I hope the next 

® can be cervical cancer based. But we’re going to talk extensively here about checkpoint inhibitors in endometrial cancer. Brian, maybe you could talk about the role of PD-L1 monotherapy in MSI-H [microsatellite instability-high] endometrial cancer, how it has changed your practice, and how it has evolved.

 It’s changing the world of endometrial cancer. In our first section, we were high on chemotherapy. My goal in my practice is to even eliminate chemotherapy for these patients. I discussed earlier that 39% to 40% of patients with endometrial cancer will be MSI-H. With immunotherapy, particularly checkpoint inhibitors, we know that there’s a very high response rate to tumors that are MSI-H, which is tumors that have a high tumor mutational burden [TMB].

Tumors that, in laymen’s terms, are recognized by noncell by the body. Something that shouldn’t be there. The first tumors that benefited from single-agent checkpoint inhibition, melanoma, non–small cell lung cancers. We learn that there’s a large subgroup of endometrial cancers, those with MSI-H, that respond quite nicely to single-agent therapy with checkpoint inhibitors. 57% response rate, pembrolizumab. Dave O’Malley, 1 of our speakers, reported that 57% response. Which is crazy, because what you got labeled for was about 38%. They found as they got more and more data, it worked better. When I give it to my patients who are MSI-H, their tumors have a high likelihood of melting away.

 It’s a class effect. Nivolumab, another story through the NCI-MATCH trial. In the MATCH trial, a large NCI [National Cancer Institute]–sponsored trial that is tumor agnostic, looking at not a specific disease but a mutation. Those patients that were noncolorectal—MSI-H, when given nivolumab, another checkpoint, high response rate. It’s changed the way, particularly in the MSI-H patients, and we’re going to spend a lot of time trying to make cold tumors hot. But in the hot patients, MSI-H, single-agent checkpoint therapy has changed the world.

Katie, is there any way that someone has not heard of this? You hear Brian talk about it, and you’re like, wow. But this is a message that’s 3½ years old. This was approved on May 23, 2017. Everyone knows it. I know you don’t know what everyone knows, but I’d be shocked if a treating oncologist has never heard of an MSI-H tumor.

 Yes. This message—the medical oncology community was using immune checkpoint inhibitors long before we were. Colorectal is probably the nearest relative to our endometrial cohort. They’re well versed in this and saw the data as they came out. Really, as the standardization of testing for mismatched repair, as we alluded to earlier, on all patients has come into play. It’s unusual to find a patient, unless they were diagnosed long ago and now, they’ve recurred distantly and we’re testing them. That happens, but this message has permeated the community and people are doing a good job. If anything, when I talk to medical oncology, they’re being more creative with their use of immune checkpoint inhibitors for gynecologic cancers than we are.

A couple of things. IHC [Immunohistochemistry] for mismatched repair deficiency is not perfect. Maybe only 90%. I think you said, maybe Brian, that the 

 mutations, which are hypermutated, are not detected by IHC. Now, as of June 16 of this year, we will have a TMBindication based on the FoundationOne CDx. Again, IHC is not enough. At least sometimes. Misses 

 for sure. Now you have TMB. Krish, when we get a recurrent patient who might be eligible for pembrolizumab, do we need to send it to FoundationOne? I’m just using that because that’s the companion diagnostic to look for TMB and 

. Or do you say, “Oh, it’s mismatched repair, enzyme IAC[intra-arterial chemotherapy]? It’s not there, so I’m going to move on.”

 I don’t send it. If I can do it with IHC and get them going, it’s easy for me. The bottom line is that with the combo approved, every patient with advanced endometrial cancer can get pembrolizumab.

Yes. No question. When they’re mismatched repair deficient or MSI-H on IHC, that’s easy. But I may not want to give them the combination. Sometimes I’ll send it for next-generation sequencing [NGS] just to make sure I’m not missing a single-agent pembrolizumab opportunity. What do you think about that, Brian?

That’s a crucial point. Everyone’s excited about the combo, and we’ll talk about that. But we’ll also mention that there are some toxicities associated with the combo. To get a better response rate and fewer toxicities, we’re not doing our patients justice if we’re not looking for MSI-H.

 Yes. I would argue for advanced recurrent disease, where unfortunately you know the likelihood is that if they’re stage IV recurrent, so I guess we can discuss this. I don’t see a reason not to do next-generation sequencing. Because you get the 

, you get MSI-H, you get tumor mutational burden—I’ve actually just found 1 who’s not MSI-H, so she’s going to get pembrolizumab. But you also get everything else that we’re going to talk about, including ERBB2 amplification and mutations. Which are also targetable. I don’t see a reason not to send next-gen. I don’t send it on stage I, but everything else is getting NGS.

I’m going to put more pressure on you. Also in June, we got to 2020, first-line pembrolizumab for MSI-H CRC [colorectal cancer], first line vs chemotherapy. A randomized phase 3 trial. If you have a metastatic case that’s MSI-H, you’re going to give her a carboplatin-paclitaxel or checkpoint or all 3. I know you wanted to put her on a clinical trial, but what’s the right treatment for that newly diagnosed, MSI-H, widely metastatic patient?

 We don’t know, to be honest. The trial needs to be done. Some of our colleagues have proposed it several times. It keeps getting turned down, which is frustrating. It’s not standard of care, and you have to counsel your patients about that. However, patients are smart and they know the data.

 What’s the harm, Brad, about just starting with pembrolizumab? Because if they progress through it, you can give them chemotherapy. That’s the message.

Yes, I never disagree with Katie. But we don’t need a trial. We got single-agent approval in the second line on, what, 17 patients?

A several-hundred-patient trial. We have to report on just 17 patients to get approval.

 I am fine using I/O [immuno-oncology] in the front line in a well-counseled patient. We’ve learned that lesson the hard way with immunotherapy. MSI colorectal and MSI endometrial, are they more similar? Because if it is similar, we can just move to I/O. I don’t know that we can say that definitively, but I would not fall on the sword against I/O in the front line.

 To your point, Brian, the accelerated approval for MSI-H was mostly CRC. Right? The CRC drug and the endometrial cases with it. Here, vs chemotherapy, to your point, they also sort of dragged endometrial cancer with it. To what Dr Tewari said, what’s the harm? You know it’s going to work. The argument, Krish, to your point, is triplet. Carboplatin-paclitaxel plus pembrolizumab vs pembrolizumab alone. What do you think of that?

 It would be nice to get the trial back on because that whole thing got torpedoed because of COVID-19 [coronavirus disease 2019]. So I don’t know.

Right. We have a trial funded through NRG Oncology called GY018, which asks this very question. Not just in MSI-H patients but in all comers. But there is a specific MSI-H end point. Thank you, Krish. I know you’ve been a passionate advocate for clinical trial enrollment throughout this pandemic.

Immune Checkpoint Inhibitors in Advanced Endometrial Cancer

: Brian, I think this study GOG-258, which was first authored by Daniela Matei, MD, published in 

, of both—we’ve been talking radiation versus chemotherapy—but this is both versus chemotherapy. I think the reason it was published in 

 is because it did not show that chemotherapy and radiation was better than chemotherapy. It was published to encourage people to stop giving chemotherapy and radiation. But I don’t know. Brian, tell me what you think about GOG-258 and what’s the real interpretation.

: To Katie’s point, GOG-258’s really a group of high-risk individuals. In GOG-249, there was no difference because if you’re not going to recur, it doesn’t matter what you give. But GOG-258 was truly high-risk individuals. They gave the best chemotherapy that we thought at the time. The study made an assumption going in that Taxol/carbo [paclitaxel and carboplatin] was going to be the best chemotherapy, because it was prior to the publication of GOG-209. They compared it to a regimen of a heavy dose of cisplatin, 50 mg with radiation, followed by 4 doses of carboplatin and paclitaxel.

What they found is the addition of the radiation for the entire group did not have a superior outcome to those patients who just got chemotherapy alone. Now there’s a subgroup analysis in those patients that had a target to radiate. Meaning, if they didn’t give whole pelvic, if it was more target directed, those patients may benefit from some radiotherapy. But in general, the typical advanced-stage patient, node positive, node was resected, endometrial cancer, the study is definitive evidence that says chemotherapy alone is enough. We don’t need to radiate those patients.

: Thanks, Brian, that’s very succinct. I keep coming back to you, Krish. In your practice, when do you use chemotherapy and radiation in endometrial cancer?

: All right. Well, that’s pretty simple.

: I told you, if they’ve got advanced disease then chemotherapy. If they’ve got high-risk, early stage disease, it’s adjuvant radiotherapy.

: I love the practicality and quite frankly, I agree with you. Dave, there was this paper called PORTEC-3, which I don’t understand. I’m not even going to start. I’m turning it over to one of my smartest friends. Tell me what this trial is. It’s gotten a lot of attention. Put this PORTEC-3 into perspective.

: Well, PORTEC-3 was a European trial. It’s actually 2 publications. The first publication looked at the clinical outcomes in a very—you used the word heterogenous group earlier in this conversation. This was a very mixed bag. So stage I, grade 3 with deep invasion, or lymph vascularization, or both. As well as stage II, stage III or any patients with stage I to III serous or clear cell endometrial cancer. So, a very mixed group of patients. Basically, what they compared was whole pelvic radiation versus chemotherapy plus whole pelvic radiation. We were having a conversation….

: Wait, Dr Tewari said if I got a positive node, the control arm is chemotherapy.

: Well, you have a very strong argument with regard to data that we’ve already reviewed, that the control arm should have been chemotherapy. In some of these patients, the control arm should have been nothing or vaginal cuff brachytherapy to support the previous PORTEC trials. So when we look at this, we call into question, but when you bring in stage III, it’s a diverse group of patients, to say the least. But interestingly, they showed improvements with the chemotherapy. As we’ve already talked about, that should have been no surprise. To the radiation therapist on the clinical trial, I think it was.

So 5-year overall survival benefits by about 7%. The hazard ratio was about 0.7. Failure-free survival, the same thing, about a 6% improvement. When we look at those groups of patients, the addition of chemotherapy to radiation showed improvement in this entire population. We can talk more about the population, the molecular changes, but I’ll stop there.

: I think I’m going to keep moving. To your point, and thank you for being so good natured, it shows that chemotherapy works when used in the adjuvant setting, which is what Dr Tewari said. He said it when he subanalyzed GOG-122 and he practices it, as all of you do, and Dr Slomovitz says that the addition of radiation doesn’t do much to it. I think we’ve set the standard.

GOG-258 and PORTEC-3 Studies in Endometrial Cancer

: Krish, you had mentioned this high-risk, high-intermediate risk GOG-99 group, deeply invasive, maybe limited to the uterus, serous tumors, cervical involvement. You had participated and been an advocate for this study led by Scott McMeekin, MD, FACOG, FACS until his untimely death, GOG-249. Tell us what the intention was of GOG-249 trying to beat pelvic radiation as the standard in that high-risk limited to the uterus subgroup.

: It was taking a riff on what was done in cervical cancer and trying to see if chemotherapy could make the radiation work a little better and also eradicate distant metastases. There was a lot of thought that even serous cancers are going to respond better to this treatment approach because of the chemotherapy. But it really didn’t pan out. They had a good percentage of serous cancers in the study. But right now, if I have a high-risk, early stage endometrial cancer, I’m treating them with adjuvant radiotherapy.

: That would be the ASTRO [American Society for Radiation Oncology] guidelines. Katie Moore, so what it was is pelvic radiation, limited to the uterus, but still serious cancer, versus vaginal brachytherapy in 3 doses of chemotherapy, trying, as you said Krish, to get a systemic effect. Is the reason that that study did not show superiority of vaginal brachytherapy in chemotherapy because we only gave 3 cycles? What do you think?

: No, I don’t think so. I think we have a lot to learn from this study. I’m hopeful we’ll do some subgroup analyses from it. But I think the same problem plagued this study as has plagued other stage I endometrial cancer studies, is that we’re just not great at predicting that group of patients who are really high risk. The GOG-99 criteria, I respect them and the time, but I think they’re not the criteria that really identify the patients who need therapy. It’s probably all 3 risk factors. If you look at the breakdown, and I think we’ll see this from the GOG-249 exploratory. But if you look at those who have deep invasion, high grade and are of older age, all 3, that may be the group who benefits from chemotherapy. They’re all clinical factors. We haven’t incorporated the pathologic factors we’ve talked about, as well, to really identify that 15% who need more help. Then the rest probably don’t need it.

: Yes. Krish, you wrote a very nice subset paper of GOG-122, chemotherapy versus radiation in node-positive disease. You said, “Well, what if there’s just 1 node? Maybe radiation is good enough.” But your findings suggested even where there’s 1 node, that 3C1 tumor, that chemotherapy is better, right?

: That’s right. It’s exploratory. But you’d think that a single positive node, radiation should be just as effective. But we found that if it was a single positive node, chemotherapy is still better. We also found, even if there was just isolated cervical involvement, chemotherapy is better.

: Again, to Brian and Dave’s point, chemotherapy works. It works regardless of the cell type as Dave was saying.

GOG-249 Study in Early-Stage Endometrial Cancer

 Krish, I’m going to come back to you. You said, “Let’s treat the patient.” What are some of the challenges you have in treating in an adjuvant setting, so after hysterectomy? Or do you have it all worked out in your mind? In other words, who should get adjuvant treatment? I’m not going to ask you to get into the studies. We’re going to that next. But just summarize, in a statement or 2, who needs adjuvant treatment for endometrial cancer.

 You’ve got a well surgically staged patient; you can use the GOG-99 criteria to determine if they adjuvant radiotherapy. If you’ve got a surgically staged patient with a positive node, they need chemotherapy.

 I love it. See, we’re getting simple here, guys. If you have a deeply invasive or a grade 3 tumor or cervical extension, you give them pelvic radiation. In other words, it’s a chemotherapy world. I love it. Let’s talk now, Katie Moore, about what the standard chemotherapy is, published this year by our friend David Miller. Tell us about GOG-0209.

 Right. We’ve been waiting for this publication. We saw the abstract for it in 2011 or 2012, and we’ve been waiting for this paper for a long time. The reason it took so long is actually not laziness. It’s just that the patients did really well. It took a long time to reach the end points. This is how long it takes to do trials. This was a really important study. It’s very different from preceding studies that had set the standard of care in the past, which had been Adriamycin and cisplatin, after a series of studies done in stage IV recurrent disease. GOG-0209, led by Dr David Miller, had those patients, but also had adjuvant patients. You just referred to that, Dr Monk. For these patients who are fully staged and apparently stage I, then you find a node. Now we call stage IIIC1 or IIIC2. They were all included as well. It’s a very different prognostic group of patients included in GOG-0209. It took what was the community standard at that time—paclitaxel and carboplatin, which is identical to what we do in ovarian cancer—and compared it with what had been the preceding winning arm in endometrial cancer, which was a triplet: paclitaxel, Adriamycin, and cisplatin, which requires GCSF support to give. It was a noninferiority study. No one thought it was going to be better, but it is as good and certainly far more convenient and less toxic. GOG-0209 showed us that, indeed, it is noninferior. It’s pretty much identical if you look at the overall end point, which was overall survival. Why it took so long? If you look at overall survival, it’s completely noninferior and almost identical. If you look at the paper, the curves basically sit on one another with medians of 37 and 41 months.

Probably the most interesting part—and really why I wanted to see the paper—is that they did break out the adjuvant group from the measurable disease group. Because I’m interested to see what that looks like in a nonbiologic therapy era. We’re going to talk about the biologic therapies coming up. But if you use just chemotherapy, what do you get? These are benchmarking data. If you look at the measurable disease—identical, 20 to 22 months median—that’s better than what we’ve seen in the past.

 PFS for the nonmeasurable—basically, these patients are cured. They just never reached it. We had like 112 months vs nonreached. They had a lot of patients in this group cured with chemotherapy. It gives us standard toxicity comparisons that I don’t think we need to belabor here. We all know that paclitaxel-carboplatin is well tolerated and certainly better tolerated than the triplet. I believe we all moved to this many years ago. But if there was any question of what the superior regimen or backbone should be, it should be well established now that it’s paclitaxel-carboplatin.

 Very succinct. Thank you. Global standards. Dave, I’m going to ask you a tough question. I think I know the answer. I’m not sure. Are the endometroid tumors or the serous tumors more chemotherapy sensitive? Or you don’t know? Or they’re the same? Does it matter? Are the endometroid tumors less sensitive or more sensitive than the serous tumors?

We’re seeing across time that both of them respond to chemotherapy almost equally. As we look at some of the other challenges with the poor prognosis of serous cancers, they are usually explained by other risk factors. As we look at these trials, we see that both types respond to chemotherapy. Maybe it’s slightly more in serous, but it’s not enough to deny anybody chemotherapy based on their histology.

I like speaking after Dave because I get to look smarter. I agree. The only other thing is that the chemotherapy is the same for grade 3 endometrioid cancers. Grade 1 and 2 are more hormonally responsive. Fewer cells are in the cell cycle. The low-grade endometrioid cancer doesn’t respond as well to chemotherapy as high grade. But high-grade endometrioid, serous, and carcinosarcomas are in the same category.

The PFS for those patients with tumor is worth repeating. It’s measurable disease. What’s the PFS from GOG-0209?

You guys have done such a great job teaching the world that these cervical and endometrial cancers are chemotherapy sensitive. That’s what I was trying to get you to say, Dave. And that’s probably the right answer. With PFS of over 20 months, they both work.

GOG 0209 Study in Advanced Endometrial Cancer

 Surgery is important. Anatomic, typical FIGO [International Federation of Gynecology and Obstetrics] staging is important. The molecular biology of the tumor is important. Dave, bring us back to practicality. I do a robotic hysterectomy as I did yesterday. What does the pathologist do with that tissue? What are the typical biomarkers that are the global standard in endometrial cancer?

 First of all, we need to assess the nodes. Most of us are doing sentinel lymph nodes at this point, and we think that adds to this dividing into stage III, which obviously is a higher risk. We have that. Let’s get the information we need surgically with the hysterectomy and at least sentinel lymph nodes, at the very least, mismatching pair proteins through IHC [immunohistochemistry] at the time of diagnosis. At this point, I would advocate—based on prognostic factors and potential treatment options, as well as identification of people with Lynch syndrome potentially or families with Lynch syndrome—that we do that as a baseline.

What is an evolution? Even though the NCCN [National Comprehensive Cancer Network] Guidelines changed last year, looking at this molecular classification based on the PORTEC trial that is still having a difficult time getting payers to reimburse and thus having my pathologist do these extra tests. What are some of the other things? Well, MSI [microsatellite instability]. Should we be doing that PCR [polymerase chain reaction] test if the MMR [mismatch repair] proteins are all intact? We’re not doing that yet, but that’s something I do on recurrence. How about the IHC for 

 that Katie and Brian have mentioned? That should probably be done routinely, but we need to make sure the payers are paying that. As we look at the 

 and the next generation sequencing, as well as additional mutational analysis, there are some other subgroups that maybe will identify their predictive in the future.

Krishnansu S. Tewari, MD, University of California, Irvine

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